International Journal of Carbohydrate Chemistry
Volume 2016 (2016), Article ID 4760548, 42 pages
http://dx.doi.org/10.1155/2016/4760548

Review Article

Biosynthesis and Biological Activity of Carbasugars

Silvia Roscales and Joaquín Plumet

Facultad de Química, Departamento de Química Orgánica, Universidad Complutense, Ciudad Universitaria, 28040 Madrid, Spain

Received 13 March 2016; Accepted 15 May 2016

Academic Editor: Sławomir Jarosz

Copyright © 2016 Silvia Roscales and Joaquín Plumet. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The first synthesis of carbasugars, compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene moiety, was described in 1966 by Professor G. E. McCasland’s group. Seven years later, the first true natural carbasugar (5a-carba-R-D-galactopyranose) was isolated from a fermentation broth of Streptomyces sp. MA-4145. In the following decades, the chemistry and biology of carbasugars have been extensively studied. Most of these compounds show interesting biological properties, especially enzymatic inhibitory activities, and, in consequence, an important number of analogues have also been prepared in the search for improved biological activities. The aim of this review is to give coverage on the progress made in two important aspects of these compounds: the elucidation of their biosynthesis and the consideration of their biological properties, including the extensively studied carbapyranoses as well as the much less studied carbafuranoses.

1. Introduction

In addition to their well-known role as chemical units for (a) release of energy such as sucrose or glucose, (b) energy storage such as starch, and (c) key component of the cell wall of green plants such as cellulose, carbohydrates are key elements in a variety of biological processes. In fact, the concept of glycomics has been defined as “the functional study of carbohydrates in living organisms” [1]. Carbohydrates are key elements in a variety of processes such as signaling, cell-cell communication, and molecular and cellular targeting. Many biological processes involve carbohydrates and, in consequence, structural changes, absence, deficiency, or excess of some carbohydrates are strongly related to many diseases. In this context, it should be pointed out that synthetic-carbohydrate vaccines show potential advantages over those based on carbohydrates from natural sources. Thus, medicinal chemistry techniques can potentially be used to derivatize and modify synthetic carbohydrates to make vaccines that are more immunogenic than those based on natural carbohydrates. For selected, general, and recent reviews on these aspects of carbohydrate chemistry, see (a) general references [2–5]; (b) synthetic aspects [6–9]; (c) carbohydrates in biological and medicinal chemistry [10–14]; (d) glycobiology [15]; (e) signaling, cell-cell communication, and molecular and cellular targeting [16–21]; (f) therapeutic potential of glycoconjugates [22, 23]; (g) carbohydrate-based vaccines [24–28].

On the other hand, novel carbohydrate structures whose biological functions were not always obvious have been discovered. For instance, intriguing compounds such as sialyl Lewis-x (sLex) [29–31] or glycosylphosphatidylinositols (GPIs) are now known to play a pivotal role in numerous biological functions [32–37]. Moreover, carbohydrates constitute a very useful source of enantiomerically pure starting materials. They have been used for the synthesis of a wide range of compounds and have been found to be useful chiral auxiliaries which allowed the introduction of a range of functionalities in a highly enantioselective manner [38, 39].

On this basis, the search for new carbohydrate derivatives with analogous or even improved biological properties compared to those of the parent structures (carbohydrate mimetics) [40–43] appears to be an attractive matter of research. The carbasugars (initially, the term pseudosugars was coined for this family of compounds, although they are currently known as carbasugars [44]), compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene group (Figure 1), fall within this category [45–49]. The structural resemblance of carbasugars to the parent sugars may facilitate their recognition by enzymes or other biological systems in place of the related true sugars. On the other hand, these compounds could be more stable toward endogenous degradative enzymes.

Figure 1: Monosaccharides and carba monosaccharides.

The aim of this review is to give coverage on the progress made in the biosynthesis and biological activity of carbasugars until March 2016, including both carbapyranoses and carbafuranoses.

2. Natural Occurrence of Carbasugars

2.1. Natural Carbafuranoses

Carbafuranoses are scarcely encountered in nature as free compounds. Nevertheless, they are subunits of products isolated from natural sources, in particular carbanucleosides [50, 51]. To the best of our knowledge, only two five-membered cyclitols derivatives have been isolated from natural sources (Figure 2): Caryose 1 [52–54], isolated from the lipopolysaccharide fraction of Pseudomonas caryophylli (a plant pathogenic bacteria), and calditol 2, isolated from the thermoacidophilic archaebacterium Sulfolobus acidocaldarius, a thermoacidophilic archaeon belonging to Sulfolobus species. These species were found to grow between 75 and 80°C, with pH optimum in the range of 2-3 [55–58]. The original proposed structure for calditol, an open-chain branched nonitol 3, was soon questioned by various research groups. To unambiguously clarify this point, four isomeric cyclopentane-based structures were synthesized by Sinaÿ et al. Among them, compound 2 was found to be fully identical to the natural product present in several Sulfolobus species [59, 60].

Figure 2: Structure of Caryose 1, proposed structure of calditol 3, and structure of calditol 2.

2.2. Natural Carbapyranoses

Carbapyranoses are rarely encountered in nature with carba-α-D-galactopyranose (4, Figure 3) being the only “genuine” carbasugar isolated from natural sources (Streptomyces sp.) [61].

Figure 3: Some natural carbapyranoses: carba-α-D-galactopyranose, cyclophellitol, MK7607, and streptol.

However, they are abundant as subunits of other natural products. On the other hand, a large number of highly oxygenated cyclohexane and cyclohexene derivatives, closely related to carbasugars, have been isolated from nature. Among them were epoxides [62, 63] such as cyclophellitol (isolated from Phellinus sp.) [64–68] (5, Figure 3), cyclohexene derivatives such as MK7607 (isolated from Curvularia eragrostidis) [69] (6, Figure 3), streptol (isolated from Streptomyces sp.) [70, 71] (7, Figure 3), pericosines A–E (isolated from Periconia byssoides) (8–14, Figure 4) [72, 73], carbonyl compounds such as the gabosine family (isolated from various Streptomyces strains) [74–76] (15–28, Figure 5), COTC (isolated from Streptomyces griseosporeus) [77] (29, Figure 5), and valienone (isolated from Streptomyces lincolnensis) [71] (30, Figure 5).

Figure 4: The pericosines.

Figure 5: Gabosines, COTC, and valienone. The absolute configuration of gabosines H (23) and J (25) remains, to the best of our knowledge, unknown.

Aminocarbasugars, such as valienamine (31), validamine (32), hydroxyvalidamine [78] (33), and valiolamine [79] (34) (Figure 6), have been mainly found as subunits of more complex molecules (vide infra). These derivatives are secondary metabolites exclusively produced by microorganisms. They have been detected only as minor components in the fermentation broth of Streptomyces hygroscopicus subsp. limoneus [80]. Aminocarbasugars are mainly found in validamycins, acarbose, and related carbaoligosaccharides. For instance, validamine has been obtained from these carbaoligosaccharides using different methods such as microbial degradation procedures [81–85], chemical degradation of validoxylamine, see the following, using NBS [86, 87], and several biotechnological processes [88–90].

Figure 6: Aminocarbasugars valienamine, validamine, hydroxyvalidamine, and valiolamine.

Validamycins (Figure 7) are a family of antibiotics discovered during the screening for new antibiotics from the fermentation culture of Streptomyces hygroscopicus [91–94]. The main component of the complex is validamycin A (35), a pseudotrisaccharide consisting of a core moiety, validoxylamine A (43), and D-glucopyranose. The core consists of two aminocyclitols, valienamine (31) and validamine (32), which are connected through a single nitrogen atom. Validamycin B (36) differs from validamycin A in the second aminocyclitol unit which, in validamycin B (36), is hydroxyvalidamine (33). The minor components of the validamycins complex, validamycins C–F (37–40) and validamycin H (42), contain validoxylamine A (43), as the core unit, but they differ in at least one of the following features: (a) the position of the glycosidic linkage, (b) the number of D-glucopyranose residues, or (c) the anomeric configuration of the D-glucopyranose unit [95–98]. Validamycin G (41) contains validoxylamine G (45) as its core unit.

Figure 7: The validamycins family.

Acarbose (Figure 8, 46) [99, 100] is one of the most clinically important compounds containing carbasugar units, since it is currently used for the treatment of type II insulin-independent diabetes. This disease is a metabolic disorder that is characterized by hyperglycemia in the context of insulin resistance and relative lack of insulin [101, 102]. In addition to acarbose, marketed by Bayer, there are two drugs, structurally related to acarbose, which belong to this class of α-glucosidase inhibitors: miglitol 47 (Sanofi) and voglibose 48 (Takeda) (Figure 8). Acarbose is a starch blocker and inhibits α-amylase, an intestinal enzyme that releases glucose from larger carbohydrates [103, 104]. Acarbose is a carbatrisaccharide which was found in a screening of strains of various Actinomycete genera and its structure was determined by degradation reactions, derivatization, and spectroscopic analysis. It is composed of valienamine (31), a deoxyhexose (4-amino-4,6-dideoxyglucose), and maltose. The carbadisaccharide core of acarbose, known as acarviosin (49), is postulated to be essential for its biological activity. The core unit, 49, is also linked to a variable number of glucose residues, resulting in several other components in mixture with acarbose. The formation of these components is highly dependent on the composition of the carbon source available in the culture medium. Media containing glucose and maltose will result in a specifically high yield of acarbose and the lower components, while media with high concentrations of starch will yield longer oligosaccharide species. The transglycosylation involved in this process was proposed to be catalyzed by an extracellular enzyme, acarviosyl transferase, found in the culture of the acarbose producer [105]. Acarbose has been the subject of interest and excellent reviews have been published, covering various specific aspects on the biochemistry and molecular biology of this compound [106–117].

Figure 8: Structures of acarbose, acarviosin, and marketed products 47 (miglitol) and 48 (voglibose).

The amylostatins, with general structure 50 (Figure 9), are related to acarbose analogues because they contain acarviosin core 49. Amylostatins were isolated in the culture filtrate of Streptomyces diastaticus subsp. amylostaticus [118, 119].

Figure 9: The amylostatins.

Adiposins (51, Figure 10) were isolated from Streptomyces calvus [120–127]. Structurally, adiposins are related to acarbose (46) and amylostatins (50) since they contain acarviosin core 49. They are formed by an aminocarbasugar (valienamine, 31) and a deoxy sugar (4-amino-4-deoxyglucose).

Figure 10: The adiposins.

Oligostatins (52, Figure 11) were obtained from culture broths of Streptomyces myxogenes [128–132]. They are carbaoligosaccharide antibiotics consisting of penta-, hexa-, and heptasaccharides containing hydroxyvalidamine rather than valienamine.

Figure 11: The oligostatins.

Trestatins (53, Figure 12) were isolated from fermentation cultures of Streptomyces dimorphogenes [133, 134]. These carbaoligosaccharides contain one to three dehydrooligobioamine units and terminate with one residue of α-D-glucopyranose linked 1,1- to the preceding glucose unit. Therefore, unlike oligostatins 52 and amylostatins 50, the trestatins are nonreducing carbohydrates.

Figure 12: The trestatins.

Trehalase inhibitor salbostatin (54, Figure 13) is a metabolite of Streptomyces albus species [135–137]. This basic nonreducing carbadisaccharide consists of valienamine linked to 2-amino-1,5-anhydro-2-deoxy glucitol.

Figure 13: Structure of salbostatin.

In 1995, the pyralomicins (55–58, Figure 14) were isolated from the strain of Actinomadura spiralis (which was later renamed Microtetraspora spiralis) [138, 139]. Their chemical structures consist of benzopyranopyrrole chromophores containing a nitrogen atom which is also shared with 1-epi-valienamine [140]. Pyralomicins are, thus far, the only examples of natural products having an aminocarbasugar unit, acting as the glycone, attached to a polyketide-derived core structure [141–143].

Figure 14: The pyralomicins.

3. Biosynthesis of Carbasugars

3.1. Carbafuranoses

The biosynthesis of carbapentofuranoses has only been considered in the literature, to the best of our knowledge, in the context of the more biologically relevant carbocyclic nucleosides and in the case of cyclitol calditol 2.

3.1.1. Carbocyclic Nucleosides

Biosynthetic studies on aristeromycin (59) and neplanocin A (60) (Figure 15) [144–147] had established that the carbocyclic ribose ring was biosynthesized from D-glucose via enone 61, the first-formed carbocyclic intermediate. After reduction of the double bond in 61, the reduction of ketone function of the resulting product 62 in an antifashion and phosphorylation afford the carbocyclic analogue of 5-phosphoribosyl-1-pyrophosphate 63 (Scheme 1). A detailed description of this sequence was described in [45, pages 1923-1924].

Scheme 1: Proposed biosynthesis of carbaphosphoribosyl-1-phosphate from glucose.

Figure 15: Structures of aristeromycin 59 and neplanocin 60.

3.1.2. Biosynthesis of Calditol

Calditol 2 constitutes the cyclitol moiety of lipids such as 64 (Figure 16) and related compounds which are present in microorganisms belonging to the Archaea domain. As shown in Figure 16, the cyclitol fragment is linked to the rest of the molecule by ethereal bonding [148].

Figure 16: Structure of the lipids isolated from Archaea.

From labeling experiments, a biosynthetic “inositol-like” pathway for the cyclopentanoid part of calditol has been proposed [149–152]. The sequence involves the formation of a 1,5 carbon bond, followed by a stereospecific reduction at C-4 (Scheme 2). Regarding Caryose 1, no biogenetic proposal has been found in the literature.

Scheme 2: Proposed biosynthesis of calditol 2.

3.2. Carbapyranoses

3.2.1. Sedoheptulose 7-Phosphate

Sedoheptulose 7-phosphate (75) is a key intermediate in the biosynthetic pathway of valienamine and gabosines A, B, C, and H. This compound derives from the pentose phosphate pathway [153, 154]. The pentose phosphate pathway is the source of NADPH 68 used in reductive biosynthetic reactions and consists in two phases: the oxidative generation of NADPH (Scheme 3) and the nonoxidative interconversion of sugars (Scheme 4).

Scheme 3: Oxidative phase: (i) Glucose-6-phosphate dehydrogenase; (ii) 6-phosphogluconolactonase; (iii) 6-phosphogluconate dehydrogenase.

Scheme 4: Nonoxidative phase: (i) ribulose-5-phosphate-3-epimerase; (ii) ribulose-5-phosphate isomerase; (iii) transketolase.

In the oxidative phase, NADPH is generated (step (a)) from glucose 6-phosphate 65 and starts with dehydrogenation 65 at C1 to give 6-phosphoglucono-δ-lactone 67 in a reaction catalyzed by glucose 6-phosphate dehydrogenase [155] and mediated by NADP⁺ (66). The next step (step (b)) is the hydrolysis of 6-phosphoglucono-δ-lactone 67 by a specific lactonase (6-phosphogluconolactonase [156]) to give 6-phosphogluconate 69. In step (c), this six-carbon sugar is then oxidatively decarboxylated by 6-phosphogluconate dehydrogenase [157] to yield ribulose 5-phosphate 70.

In the nonoxidative phase, ribulose-5-phosphate 70 is transformed into xylulose-5-phosphate 71 and ribose-5-phosphate 72 via epimerization at C-3 (catalyzed by the enzyme ribulose-5-phosphate-3-epimerase [158, 159]) and isomerization catalyzed by ribulose-5-phosphate isomerase [158] (through an enolate ion), respectively. Finally, a sequence of retroaldol-aldol reactions mediated by thiamine pyrophosphate 73 and catalyzed by transketolase [160–162] results in the formation of sedoheptulose-5-phosphate 75 and glyceraldehyde-3-phosphate 74.

3.2.2. Biosynthesis of Gabosines

The cyclization process of sedoheptulose 7-phosphate (75) to a six-membered carbocyclic intermediate, 2-epi-5-epi-valiolone 77 [163–166], is catalyzed by a sedoheptulose 7-phosphate cyclase (Scheme 5).

Scheme 5: Transformation of sedoheptulose-7-phosphate 75 into valienone 30.

These enzymes are phylogenetically related to the dehydroquinate synthases (DHQS) and use Co²⁺ as preferred cofactor. Dehydroquinate synthase (DHQS) is able to perform several consecutive chemical reactions in one active site. There has been considerable debate as to whether DHQS is actively involved in all these steps or whether several steps occur spontaneously, making DHQS a spectator in its own mechanism. DHQS performs the second step in the shikimate pathway, the transformation of 78 (3-deoxy-D-arabino-heptulosonate-7-phosphate) into 79 (3-dehydroquinate), which is required for the synthesis of aromatic compounds in bacteria, microbial eukaryotes and plants (Scheme 6) [167, 168].

Scheme 6: Transformation of 3-deoxy-D-arabino-heptulosonate-7-phosphate into 3-dehydroquinate.

The reaction is assumed to be initiated by transient dehydrogenation of C-5 to ketone 76, which sets the stage for the elimination of phosphate, followed by reduction of the C-5 ketone and ring-opening to produce the corresponding enolate. The latter then undergoes intramolecular aldol condensation to give 2-epi-5-epi-valiolone 77. This compound is epimerized at C2 (compound 80) and dehydrated via syn elimination to yield valienone 30 (Scheme 5). However, how exactly these final processes take place under the enzymatic point of view still remains obscure.

The transformation of 2-epi-5-epi-valiolone 77 into gabosines A, B, C, and N requires a considerable number of steps such as dehydration, oxidation, reduction, and epimerization as depicted in Scheme 7 through reduction product 81 [169].

Scheme 7: Proposed transformation pathway of 2-epi-5-epi-valiolone 77 into gabosines A, B, C, and N.

It seems possible that the reduction at C-7 and the oxidation at C-1 (gabosines numeration) follow a similar mechanism, as described for the formation of 6-deoxy-4-keto sugars [170, 171]. It is expected that a large number of enzymes will be involved in the conversion in a manner that is not yet understood.

In this context, a new hypothesis for the biosynthesis of gabosines from 77 has recently been proposed on the basis of an unexpected experimental observation [172]. When compound 82 (Scheme 8) was submitted to a simultaneous oxidation-elimination protocol by reaction with m-CPBA, a separable mixture of the expected α-hydroxymethyl enone 83 (10%) and β-hydroxymethyl enone 84 (68%) was obtained.

Scheme 8: Proposed mechanism for the formation of compound 84 from 82.

The formation of 84 may be explained on the basis of a keto-enol equilibrium process followed by sulphide elimination. Considering that a similar keto-enol process had been observed [173] in a previous synthesis of gabosines N and O, a biosynthetic proposal starting from 2-epi-5-epi-valiolone 77 and involving keto-enol equilibrium cascade reactions has been formulated (Scheme 9).

Scheme 9: Biosynthesis of gabosines from 2-epi-5-epi-valiolone 77.

These kind of isomerizations have been observed in different biogenetic routes such as the transformation of ribulose-5-phosphate 70 into xylulose-5-phosphate 71 and ribose-5-phosphate 72 (see Scheme 4).

3.2.3. Biosynthesis of Validamycins

Valienone 30 and the reduction product validone 87 are the more proximate precursors of validoxylamine A 43, the aglycone moiety of validamycin A 35 (Scheme 10) [174, 175]. In the transformation of 30 into 87, the stereochemistry of the reduction probably reflects the result of a nonenzymatic partial epimerization at C-6 of 87 due to enolization of the keto group at C-1.

Scheme 10: Biosynthesis of validoxylamine 43 from valienone 30.

Two alternative possibilities can be envisaged for the formation of validoxylamine 43, from 30 and 87 (Scheme 10). Either transamination of 30 would give valienamine 31, which would then reductively couple 87 or, alternatively, 87 would be transaminated to give validamine 32, which would then couple 30. However, circumstantial evidence in favor of the second of these two scenarios comes from experimental observations using feeding experiments. Finally, incorporation of the glucose moiety should be mediated by a glucosyl transferase enzyme.

On the other hand, studies on Actinoplanes sp. have identified glutamate 88, a typical substrate of transaminases, as the most efficient nitrogen donor. Also, aspartate 89 and the α-nitrogens of asparagine 91 and glutamine 90 were also found to be good nitrogen sources in glutamate-depleted cultures [176]. It should be indicated that glutamate, aspartate, glutamine, and asparagine are interconnected in typical reactions of amino acids metabolism as indicated in Scheme 11. The transformation of 89 into 91 is catalyzed by asparagine synthetase [177, 178].

Scheme 11: Biochemical interconversion of amino acids glutamate, aspartate, glutamine, and asparagine. (i) Asparagine synthetase.

As we have previously indicated, the validamycin A fermentation also produces a number of minor components. Some of these, such as validamycins C (37), D (38), E (39), and F (40), are derived from validamycin A 35. The formation of the validamycin congeners which differ from 35 in the structure of the second cyclitol moiety would require the transamination of other ketocyclitols, such as 6-hydroxyvalidamine 33 for validamycin B (36) and valiolamine (34) for validamycin G (41) (Scheme 12).

Scheme 12: Biosynthesis of validamycins A (35), B (36), C (37), D (38), E (39), F (40), and G (41).

3.2.4. Biosynthesis of Acarbose [179]

With the exception of 2-epi-5-epi-valiolone (77), none of the ketocyclitols 5-epi-valiolone (80), valienone (30), and validone (87) involved in the biosynthesis of the valienamine moiety of validamycins were incorporated (feeding experiments) into the valienamine moiety of acarbose. In consequence, the pathways in the formation of both metabolites seem to be substantially different [180, 181].

In a first approach to the biosynthesis of acarbose, it is assumed that the first intermediate generated is deoxythymidine diphosphate- (dTDP-) acarviose (93). It should be pointed out that thymidine diphosphate dTDP (92, see Scheme 13) misnamed deoxythymidine diphosphate [182] consists in a pyrophosphate group attached to the nucleoside thymidine [183]. The acarviosyl moiety of this intermediate can be transferred to of maltose. It should be pointed out that acarbose is formed from maltotriose by two routes: (a) 60% of the acarbose is formed by attachment of maltose, produced by removing a glucose exclusively from the nonreducing end of maltotriose, to the pseudodisaccharide core unit. (b) The other 40% of acarbose is formed by direct attachment of maltotriose to the core unit followed by loss of the terminal glucose from the reducing end [184].

Scheme 13: Proposed biosynthetic pathway to acarbose 46 and structure of dTDP 92.

A reasonable route for the formation of dTDP-acarviose (93) involves the introduction of the nitrogen atom into the deoxy sugar moiety via transamination of dTDP-4-keto-6-deoxy-D-glucose (94) to dTDP-4-amino-4,6-dideoxy-D-glucose (95). This compound then forms Schiff’s base with 2-epi-5-epi-valiolone (77) which undergoes 2-epimerization, 5,6-dehydration, and final imine double bond reduction to 93 (Scheme 13).

An alternative hypothetical pathway involves the reduction of the keto-sugar 77 to 1-epi-valiol (99). Further activation of the C1 hydroxyl group as a phosphate (100) and subsequent nucleophilic displacement by the nitrogen of amino sugar 95 would afford pseudosaccharide 101. This compound, after epimerization at C2 and 5,6-dehydration, would give dTDP-acarviose (93) (Scheme 14) [185].

Scheme 14: Alternative biosynthesis of dTDP-acarviose 93.

More recently and on the basis of genetic and biochemical studies, a new mechanism for the biosynthesis of acarbose has been postulated. The acarbose gene clusters (Acb) [186–189], involved or proposed in the sequence, are also indicated (Scheme 15).

Scheme 15: Revised proposal of the biosynthetic pathway to dTDP-acarbose 93. NDP (compound 106): nucleotidyl diphosphate.

It should be indicated that a gene family is a set of homologous genes within one organism. A gene cluster is part of a gene family. The size of gene clusters can vary significantly from a few genes to several hundred genes. Regardless of the similarity of the DNA sequence of each gene within a gene cluster, the resulting protein of each gene is distinctive from the resulting protein of another gene within the cluster. The Acb corresponds to one of the 25 known gene clusters from Actinoplanes sp. SE50/110 identified and sequenced. Another Acb biosynthetic gene cluster from Streptomyces glaucescens has also been identified and sequenced.

In this mechanism, the cyclitol precursor, 2-epi-5-epi-valiolone (77), is phosphorylated to give 2-epi-5-epi-valiolone-7-phosphate (102) in a process mediated by the enzyme 2-epi-5-epi-valiolone 7-kinase. Compound 102 is then epimerized at C2 to give 5-epi-valiolone-7-phosphate (103). Further steps involving dehydration (104), carbonyl reduction and phosphorylations (105), nucleotidylation [190] (106), and final nucleophilic displacement by the nitrogen atom of 95 would afford compound 93 [191–194]. In Scheme 15, the transformation 105-106 constitutes a nucleotidylation reaction: the transfer of an entire nucleotidyl unit, rather than just a phospho group [195].

3.2.5. Biosynthesis of Pyralomicins

The biosynthetic gene cluster for the biosynthesis of pyralomicin antibiotics (PrI) has been isolated, cloned, and sequenced from Nonomuraea spiralis IMC A-0156 [196]. The 41 kb (1000 base pairs) gene cluster contains 27 open reading frame ORFs [197, 198] predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide (peptides that are not synthesized by ribosomes) synthetases (NRPS) and polyketide synthases (PKS) [199–204] required for the formation of the benzopyranopyrrole core unit. Other enzymes such as four halogenases [205] an O-methyltransferase [206–208] and an N-glycosyltransferase [209, 210] necessary for further modifications of the core structure of pyralomicins have also been identified. In particular, the N-glycosyltransferase is involved in the transfer of either glucose or a pseudosugar (cyclitol) to the aglycone.

The formation of the cyclitol moiety of pyralomicyns is depicted in Scheme 16. This pathway appears to be mediated through the actions of several enzymes including the 2-epi-5-epi-valiolone synthase PrlA, a putative phosphomutase (PrlB), a cyclitol kinase (PrlU), two cyclitol dehydrogenases (PrlV and PrlW), and a 2-epi-5-epi-valiolone phosphate epimerase (PrlX). This cassette of genes shares high homology with the cyclitol biosynthetic genes from the salbostatin (vide infra) [211] and acarbose gene clusters.

Scheme 16: Proposed mode of formation of the cyclitol moiety of pyralomicins. 77: 2-epi-5-epi-valiolone; 102: 2-epi-5-epi-valiolone-7-phosphate; 107: 5-epi-valiolone-7-phosphate; 103: valienone-7-phosphate; 108: valienol-7-phosphate; 109: valienol-1-phosphate; 110: NDP-valienol.

3.2.6. Biosynthesis of Salbostatin

In silico analysis of the putative biosynthetic gene cluster of salbostatin from Streptomyces albus ATCC 21838 [211] revealed 20 open reading frames. The salbostatin genes SalF, SalL, SalM, SalN, SalO, and SalR were found to be homologous to AcbR, AcbM, AcbL, AcbN, AcbO, and AcbP from the acarbose pathway, respectively (see above). That suggests that the biosynthesis of the aminocyclitol moiety of salbostatin may be very similar to that of acarbose (Scheme 17).

Scheme 17: Proposed biosynthetic pathway for salbostatin.

Thus, 2-epi-5-epi-valiolone 77 is first converted to its activated form, 2-epi-5-epi-valiolone 7-phosphate 102, by the action of the 2-epi-5-epi-valiolone 7-kinase (AcbM). Epimerization at the C-2 position by AcbO gives 5-epi-valiolone 7-phosphate 107. This compound is proposed to be converted to 5-epi-valiolone 7-phosphate 111 or valienone-7-phosphate 103 which were dehydrated (from 111) or reduced (from 103) to 1-epi-valienol 7-phosphate 112. From 112, 1-epi-valienol-l-phosphate 113 and then NDP-1-epi-valienol 114 were successively formed. Condensation of NDP-1-epi-valienol 114 with deoxy-glucosamine 115 (biosynthesized from N-acetylglucosamine) may finally result in the formation of salbostatin-6′-phosphate 116 which is then converted into salbostatin 54.

4. Biological Activity of Carbasugars

As we have previously pointed out (see Section 1) and according to Professor McCasland “pseudo-sugars may be found acceptable in place of corresponding true sugars to some but not all enzymes or biological systems, and thus might serve to inhibit growth of malignant or pathogenic cells” [212]. The similarity between carbasugars and sugars may be highlighted considering that synthetic 6a-carba-β-DL-fructopyranose was found to be almost as sweet as D-fructose [213–215]. In the context of enzymatic inhibition [216], the structural similarity between true sugars and carbasugars can cause inhibition of enzymes involved in the digestion of carbohydrates which can lead to important consequences under medical point of view. For instance, the inhibition of carbohydrate digestive enzymes is considered a therapeutic tool for the treatment of type 2 diabetes [217]. In the following, some applications of carbasugars and derivatives as enzymatic inhibitory agents will be highlighted.

4.1. Biological Activity of Carbafuranoses

The carbocyclic analogue of 5-phosphoribosyl-1-pyrophosphate (cPRPP, Figure 17) is the only reported carbafuranose with significant biological activity [218–220]. This compound shows enzymatic inhibitory activity against the enzyme 5-phosphoribosyl R-1-pyrophosphate (PRPP) synthetase [221–223] with values [224] of 186 μM (human type PRPP synthetase) and of 3811 mM (Bacillus subtilis PRPP synthetase). The enzyme PRPP synthetase converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP) (Scheme 18). The resulting PRPP acts as an essential component of the purine salvage pathway (used to recover bases and nucleosides that are formed during degradation of RNA and DNA) and the de novo synthesis of purines. Mutations that lead to superactivity (increased enzyme activity or deregulation of the enzyme) result in purine [223] overproduction. Superactivity symptoms include neurodevelopmental disorders [225]. On the other hand, there is evidence that the activity of PRPP synthetase is elevated in tumors. Then, inhibitors of this enzyme show antineoplastic activity [226, 227].

Scheme 18: Conversion of ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP).

Figure 17: Carbocyclic analogue of 5-phosphoribosyl-1-pyrophosphate (cPRPP).

4.2. Biological Activity of Carbapyranoses

4.2.1. Cyclophellitol and Derivatives

(+)-Cyclophellitol (5) was found to be a specific inhibitor of β-glucosidases (enzymes that hydrolyze glycosidic bonds to release nonreducing terminal glucosyl residues from glycosides and oligosaccharides [228]) [229, 230] with potential inhibition of the human immunodeficiency virus (HIV) and with possible antimetastatic therapeutic activity [231–233]. Several unnatural cyclophellitol derivatives also show interesting biological properties [234–237]. For instance, (1R,6S)-cyclophellitol 120, the unnatural diastereomer of cyclophellitol 5, is a potent α-glucosidase inhibitor and cyclophellitol aziridines 121 are potent and selective irreversible inhibitors of retaining glycosidases [238–243] (see Figure 18).

Figure 18: Structures of cyclophellitol 5, (1R,6S)-cyclophellitol, 120, and cyclophellitol aziridines, 121.

Several natural and synthetic epoxyquinones and epoxyquinols with structures related to both cyclophellitol and gabosines (see below) also show interesting biological properties. The chemistry and biological activities of these compounds have been described in authoritative reviews and will not be considered here [62].

4.2.2. MK-7067, Carbagalactopyranose, Carbaglucopyranose, Streptol, and COTC

The unsaturated carbapyranose (+)-MK7067 6 exhibited an effective herbicidal activity [69]. Carba-α-D-galactopyranose (4) was found to have a low antibiotic activity against Klebsiella pneumonia MB-1264 [61], whereas the L-enantiomer is inactive [244].  5a-Carba-α-DL-glucopyranose (±)-122 (Figure 19) is a glucokinase inhibitor [245, 246]. Carbasugar (±)-122 and the β-anomer (±)-121 were used as synthetic analogues of glucose anomers to study the mechanism of glucose-stimulated insulin release by pancreatic islets [247]. It was found that alpha isomer (±)-122, but not the beta-isomer (±)-121, inhibited both glucose-stimulated insulin release and islet glucokinase activity in a concentration-dependent manner. On the other hand, a cellobiose phosphorylase from Cellvibrio gilvus recognizes only the beta-D-form of 5a-carba-glucopyranose (±)-121 [248].

Figure 19: Structures of α-and β-glucopyranose (only D-enantiomers are shown), streptol 7, and COTC 29.

Streptol (7) inhibited the root growth of lettuce seedlings at a concentration <13 ppm.

The 2-crotonyloxy-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone, COTC (29), and derivatives have been shown to display notable toxicity towards a range of different cancer cell lines. The general mechanism for anticancer activity of COTC is depicted in Scheme 19 [249–253].

Scheme 19: Proposed mode of action of COTC and derivatives.

After conjugate addition of glutathione (γ-L-glutamyl-L-cysteinylglycine, GSH) to the enone moiety of 29, the resulting enol 123 undergoes expulsion of crotonic acid to generate exocyclic enone 124. It should be pointed out that the rate of formation of enol 123 is substantially increased by enzymatic catalysis via glutathione transferase (GST). Alkylation of intracellular proteins and/or nucleic acids by 124 then leads to cell death. Other processes may also contribute to the anticancer activity of this compound and derivatives. For instance, the GSH conjugate 126, derived by trapping the exocyclic enone 124 with GSH, and bis-GSH adduct 127 are competitive inhibitors of human glyoxalase 1 (Glo1). This enzyme is vital for cell survival as part of a detoxification system for cytotoxic 2-oxoaldehydes or other toxic species and the inhibitors have previously been demonstrated to have anticancer properties [254, 255]. On these bases, it seems logical to have carried out extensive efforts for the synthesis of new analogues COTC [256–264].

A key enzyme in the biosynthesis of clinically important aminoglycoside antibiotics such as neomycin, kanamycin, and gentamicin [265, 266] is 2-deoxy-scyllo-inosose synthase (DOIS), which catalyzes the carbocycle formation from D-glucose-6-phosphate 65 to 2-deoxy-scyllo-inosose (DOI, 128, Scheme 20 [267]).

Scheme 20: Transformation of D-glucose-6-phosphate into 2-deoxy-scyllo-inosose.

5a-Carba-DL-glucose-6-phosphate (129) is an irreversible inhibitor of DOIS. The proposed reaction mechanism for this inhibitory action is shown in Scheme 21 [268]. Thus, after the initial oxidation at C4 and subsequent elimination of a phosphate compound, (±)-129 was converted within the enzyme into an α,β-unsaturated methylene cyclohexanone (±)-131. This α,β-unsaturated carbonyl intermediate is attacked by a specific nucleophilic residue in the active site (Lys-141) through a Michael-type 1,4-addition, resulting in the formation of compound 132.

Scheme 21: Mechanism of irreversible inhibition of DOIS by 5a-Carba-DL-glucose-6-phosphate.

4.2.3. Pericosines and Gabosines

Pericosines A–C (8–10) exhibited significant growth inhibition against several tumor cell lines. In particular, pericosine A (8) shows significant in vitro cytotoxicity against P388 lymphocytic leukemia cells [269] also showing significant in vivo tumor inhibitory activity. In addition, pericosine A inhibited [270] the protein kinase EGFR (the epidermal growth factor (EGF) stimulates cell growth, proliferation, and differentiation by binding to its receptor EGFR. Human EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds. Mutations that lead to EGFR overexpression or overactivity have been associated with a number of cancers [271]) and topoisomerase II (topoisomerases are isomerized enzymes that act on the topology of DNA. Type II topoisomerases cut both strands of the DNA helix simultaneously in order to manage DNA. They use the hydrolysis of ATP, unlike type I topoisomerases which are ATP-independent [272]). Gabosine E (20) showed [273] a weak inhibitory effect on the cholesterol biosynthesis in cell line tests with HEP-G2 (this line has been found to express a wide variety of liver-specific metabolic functions. Among these functions are those related to cholesterol and triglyceride metabolism [274]).

On the other hand, gabosines A (15), B (16), F (21), N (18), and O (28) present DNA-binding properties [275, 276]. Gabosine C (17) is the known antibiotic KD16-U [277] and its crotonyl ester is the previously considered carbasugar COTC. Gabosine J (25) inhibits α-mannosidase, an enzyme involved in the cleavage of the alpha form of mannose [278], and some derivatives such as α-gabosinol 133 and β-gabosinol 134 inhibit β-galactosidase and β-glucosidase, respectively (Figure 20) [279].

Figure 20: Some biologically active gabosine derivatives.

Some compounds structurally related to gabosines also show interesting biological properties. For instance, compound (+)-135 has been reported [280] to be a cytotoxic and potential contraceptive agent. On the other hand, nigrospoxydon A (136) shows activity against Staphylococcus aureus ATCC 25923, a clinical isolate with the designation Seattle 1945 that is used as a standard laboratory testing control strain [281]. It has also been published that the closely related esters (−)-137 and epoxydine B (138) display antibacterial, antifungal, and antialgal activities (Figure 20) [282]. The synthetic compound (+)-RKTS-33 (139) has inhibitory activity toward death receptor-mediated apoptosis [283, 284]. The racemate of compound 140 is a nuclear factor-κB [285, 286] inhibitor and therefore a suitable candidate as anti-inflammatory and anticancer agent [287]. Finally, compound 141 shows [288] synergetic effect with cisplatin against lung cancer cell line A549 [289], through the inhibition of GSTM1 [290].

4.2.4. Carbaglycosides

O-Linked alkyl carba-β-D-glycosides 142 and 143 (Figure 21) have been shown [291] to be useful as primers for biocombinatorial glycosylation involving efficient uptake in B16 mouse melanoma cells, the most frequently used murine melanoma model [292]. Uptake of the carbaglycosides resulted in β-galactosylation and subsequent sialylation of the galactose residues incorporated, to give rise to glycosylated products having a glycan similar to that in ganglioside GM3, a type of ganglioside, molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. The letter G refers to ganglioside, and M is for monosialic acid as it has only one sialic acid residue. The numbering is based on its relative mobility in electrophoresis among other monosialic gangliosides. Recently, gangliosides have been found to be highly important molecules in immunology. Natural and semisynthetic gangliosides are considered possible therapeutics for neurodegenerative disorders [293, 294]. This indicates that carbasugars can be stable and versatile building blocks for the biocombinatorial synthesis using a living cell. In addition, a strong and specific inhibition of β-galactosidase (bovine liver) was found for dodecyl 5a-carba-β-D-galactopyranoside (143).

Figure 21: Structures of carba-β-D-glycosides 142 and 143.

In addition, more complex carbaglycosides have interesting biological activities. Synthetic carbaxylosides of coumarins, that is, (+)-144 or (−)-144, have significant potential as oral antithrombotic agents [295], and a 5a-carba analogue of glucotropaeolin, (±)-145, was shown to display a good inhibition power [296] against myrosinase, the only known enzyme found in nature that can cleave a thiolinked glucose [297] (Figure 22).

Figure 22: Structures of carbaglycosides 144 and 145.

4.2.5. Carbanucleotides

Some synthetic carbasugar-nucleotide displayed biological activity as glycosyltransferase inhibitors. For instance, uridine-5′-(5a-carba-α-D-galactopyranosyl diphosphate) 146 (Figure 23), the carbocyclic analogue of UDP-galactose, exhibits inhibitory activity of β-(14) galactosyltransferase from bovine milk [298].

Figure 23: Structure of carbanucleotides 146 and 147.

On the other hand, the carbocyclic analogue of GDP-fucose, consisting of 5a-carba-β-L-fucopyranose 147 [299], was found to be a competitive inhibitor of fucosyltransferases, key enzymes in the biosynthesis of the Lewis-x determinant. Interestingly, the carbafucose analogue 147 showed a value similar to that observed for the GDP-fucose indicating that the ring oxygen of fucose is not critical for the recognition of GDP-Fuc by the enzyme, although it is essential for the transfer to occur [300].

4.2.6. Aminocarbasugars

Aminocarbasugars [301] are the most important and appealing carbapyranose derivatives from a biological standpoint.

(1) Valienamine, Validamine, Hydroxyvalidamine, Valiolamine, and Derivatives. Simple aminocarbasugars such as valienamine (31), validamine (32), hydroxyvalidamine (33), and valiolamine (34) appeared to be active against several sugar hydrolases [302, 303]. Valienamine, validamine, and hydroxyvalidamine were reported as microbial oligosaccharide α-glucosidase inhibitors [304–307]. The α-galacto-, β-gluco-, and α-mannovalidamine analogues 148–150 (Figure 24) have been prepared and their glycosidase activity was tested [308–310]. These compounds, however, displayed moderate activity as glycosidase inhibitors when compared with α-gluco-validamine. Conversely, valiolamine (34) has more potent α-glucosidase inhibitory activity against porcine intestinal sucrase, maltase, and isomaltase than the rest of the aminocarbasugars [311].

Figure 24: Structures of α-galacto-, β-gluco-, and α-mannovalidamine analogues (148–150) and voglibose (48).

This is why series of N-substituted valiolamines were synthesized, resulting in the preparation of the glycohydrolase inhibitor voglibose (48) [312–314]. Voglibose was launched as an antidiabetic agent in 1994 to improve postprandial hyperglycemia in diabetes mellitus [315–318]. Voglibose inhibits disaccharidases competitively, suppressing the elevation of the blood glucose concentration after oral sucrose, maltose, or starch administration, but not after oral glucose, fructose, or lactose intake.

Moreover, carbocyclic analogues of glycosylamides [319], which contain the 5a-carba-D-hexopyranose residues (Figure 25), have also been synthesized. 5a-Carba-β-glucopyranosyl and 5a-carba-β-galactopyranosyl amides 151 and 152 have been shown to be potent immunomodulators, comparable to the true sugars [320], suggesting that the glycolipid analogues may provide appropriate model compounds for biochemical studies in glycolipid chemistry.

Figure 25: 5a-Carba-β-glucopyranosyl and 5a-carba-β-galactopyranosyl amides.

On the other hand, the glycosidase inhibitory effects of 1,2-bis-epi-valienamine 153 and 1-epi-2-acetamido-2-deoxy-valienamine 154 (Figure 25) have been investigated. 1,2-Bis-epi-valienamine 153 acts as a β-mannosidase [321] inhibitor whereas 2-acetamido-2-deoxy-1-epi-valienamine 154 has been shown [322] to inhibit various β-hexosaminidases, enzymes involved in the hydrolysis of terminal N-acetyl-D-hexosamine residues in N-acetyl-β-D-hexosaminides [323–325].

A series of N-linked carbocyclic analogues of glycosylceramides, structurally related to glycosphingolipids and glycoglycerolipids, have also been synthesized by replacing the sugar residue with either saturated [326] (155, 156, Figure 26) or unsaturated [327] (157, 158, Figure 26) 5a-carba-D-gluco- or 5a-carba-D-galactopyranoses, respectively. Compounds 155 and 156 are mild immunomodulators and possess a mild inhibitory activity against gluco- and galactocerebrosidases, whereas the unsaturated gluco-157 and galacto-158 analogues were shown to be very potent and specific of gluco- and galactocerebrosidase inhibitors, respectively, thus showing the critical role played by the C4 configuration for specificity in inhibition.

Figure 26: N-linked carbocyclic analogues of glycosylceramides 155–158.

Various N-alkyl- and N,N-dialkyl-β-valienamines were synthesized and tested as glycosylases inhibitors [328–331]. For instance, N-benzylation of valienamine improves significantly their inhibitory activity toward α-glucosidases [332]. In this way, 91 pure N-alkylated valienamines 159 (Figure 27) prepared using solid-phase synthesis methodology are new β-glucosidase inhibitors that are generally more potent than valienamine [333].

Figure 27: Alkylated valienamine derivatives, spiroaziridines 160, spiroazirinas 161, cyclopentylamine derivative 162, and bicyclo[4.1.0]heptane derivatives 163 and 164.

On the other hand, the spiroaziridines and spirodiaziridines 160 and 161 were prepared and evaluated as glycosidase inhibitors against β-glucosidases from almonds, β-glucosidase from Caldocellum saccharolyticum, and α-glucosidase from yeast with poor results compared with cyclopentylamine 162 (Figure 27) [334].

Two isomeric bicyclo[4.1.0]heptane 163 and 164 (Figure 27) have been synthesized and evaluated against α-galactosidase enzymes from coffee bean and E. coli [335]. The activity of the glycosyl hydrolase family GH27 enzyme (coffee bean) was competitively inhibited by the 1R,6S-amine with a value of 0.541 μM. The E. coli  α-galactosidase exhibited a much weaker binding interaction with the 1R,6S-amine (IC₅₀ = 80 μM). The diastereomeric 1S,6R-amine bound weakly to both galactosidases (coffee bean, IC₅₀ = 286 μM, and E. coli, IC₅₀ = 2.46 mM).

N-Octyl-β-valienamine derivative 165 (Figure 28) is a potent specific inhibitor of β-glucocerebrosidades (IC₅₀ = 3 × 10−8 M). In contrast, galactose derivative 166 did not show any improvement in potency. Additionally, it was later demonstrated that 165 and 166 are potent competitive inhibitors of human β-glucosidase and human β-galactosidase, respectively.

Figure 28: N-Octyl-β-valienamine derivatives.

These activities suggest that carbasugar derivatives 165 and 166 work as chemical chaperones [112, 336–338] to accelerate transport and maturation of mutant forms of enzyme proteins and therefore may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases [339–351]. It should be opportune at this point to clarify the concept of chemical chaperone [352–354]. Pharmacological or molecular chaperone therapy is among the newest therapeutic ideas for lysosomal storage diseases. Lysosomes are enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective, because of a mutation, the large molecules accumulate within the cell, eventually killing it. Pharmacological chaperones are small molecules that specifically bind to and stabilize the functional form or three-dimensional shape of a misfolded protein in the endoplasmic reticulum (ER) of a cell. When misfolded due to a genetic mutation, the enzyme is unable to adopt the correct functional shape and, in consequence, the enzyme activity is reduced. The binding of the chaperone molecule helps the protein fold into its correct three-dimensional shape. Pharmacological chaperone therapy is in early-stage clinical trials for disease such as Fabry (a rare genetic lysosomal storage disease. Fabry disease can cause a wide range of systemic symptoms such as pain, kidney complications, high blood pressure, cardiomyopathy, fatigue, vertigo, nausea, diarrhea, etc.) and Gaucher type I (a genetic disorder in which glucocerebroside accumulates in cells and certain organs). The disorder is characterized by bruising, fatigue, anemia, low blood platelet count, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages (mononuclear leukocytes).

In the search for different sugar hydrolase inhibitors, 5a-carba-α-DL-fucopyranosyl amine [355, 356] ((±)-167) and 5a-carba-β-L-fucopyranosylamine (168) [357] were prepared. These compounds have been shown to be strong inhibitors of α-L-fucosidase. α-Fucosidase inhibitors are interesting because they are potential candidates for cancer and HIV drugs, due to their inhibitory effect on the extracellular matrix secreted fucosidases [358]. Different N-substituted derivatives of (±)-169 were prepared. The inhibitory activity was increased by incorporation of alkyl and phenylalkyl groups into the amino function of the parent (±)-167. The change of the N-alkyl substituents, from ethyl on 169a to nonyl on 169e, improved the inhibitory power. The n-octyl derivate (169d) was found to be the strongest inhibitor of α-L-fucosidase (bovine kidney) more potent ( μm) than deoxynojirimycin ( μm), the most powerful mammalian α-L-fucosidase inhibitor identified [359]. In a similar manner, chemical modifications of 168 generated N-substituted derivatives (±)-170a–g, which were found to be very strong β-galactosidase as well as β-glucosidase inhibitors with no specificity associated with the 4-epimeric structures. This inhibitory activity appeared attributable to D-enantiomers exclusively, that is, N-alkyl-6-deoxy-5a-carba-β-D-galactopyranosylamines (D-170) [360] (Figure 29).

Figure 29: Carbafucopyranosyl amines 167–170.

Carbasugar derivatives have also been envisaged to play roles in elucidating and controlling other biological events that involve sugar moieties. This includes the synthesis of analogues of enzyme substrates, which were modified by replacing part of their structures with carbasugar units and which were expected to be used in the elucidation of the mode of action of sugar transferases [361]. These analogues have been recognized as good substrates, thus showing that the ring oxygen in the acceptor is not involved in the specific recognition by the enzyme. For instance, bovine β-(14)-galactosyltransferase was tested with α-galacto- (171), α- and β-manno- (172 and 173), and α- and β-gluco- (174 and 175) 2-acetamido-2-deoxy-5a-carba-DL-hexopyranoses [362]. Of these compounds, only 174 and 175 behave as galactosyl acceptors. The reactions afforded disaccharides 176 and 177, but half of the material remained unreacted, suggesting that only the D-enantiomers behaved as acceptors. These results indicate that the ring oxygen atom is not used for specific recognition by bovine β-(14)-galactosyltransferase (Figure 30).

Figure 30: Carbasugars as sugar transferases.

(2) Validamycins, Salbostatin, Acarbose, Amylostatins, Adiposins, Oligostatins, Trestatins, and Related Compounds. Validamycins 35–42 and salbostatin (54) have been reported to be mechanistically unique fungicide agents [363–367]. Validamycin A (35), the most active compound of the complex, is a fungicide that inhibits trehalases, enzymes that carry out the degradation of the nonreducing disaccharide trehalose [368–370] in plants, insects, and fungi as well as enhancing trehalose accumulation in transgenic plants. It is widely used in rice-producing countries in Asia to control sheath blight disease of the rice plants caused by the fungus Rhizoctonia solani [371–385].

Validamycin A is able to control the spread of the pathogen by inhibiting specifically the hyphal (a long, branching filamentous structure of a fungus, oomycete, or actinobacterium [386]) extension without affecting the specific growth rate. This means validamycin A is effective against Pellicularia sasakii and Rhizoctonia solani in plants but only decreases their virulence instead of exhibiting a fungicidal effect [387–390]. Further extensive studies on the mechanism of action of validamycin in controlling the hyphal extension have been carried out by several research groups, and that seems to be related to the antitrehalase activity [391–393] of the carbadisaccharide validoxylamine (43) [394]. For the purpose of developing more potent trehalase inhibitors, several pseudotrehalosamines, such as 178 and 179, as well as dicarba analogues of trehalose, 180–182, composed of valienamine, validamine, and valiolamine moieties, were synthesized and they have been shown to possess strong inhibitory activity against trehalase (Figure 31) [395–397].

Figure 31: Carbasugars 178–182 with antitetrahalase activity.

Many members of the carbaoligosaccharidic group, for example, acarbose (46), amylostatins (50), adiposins (51), oligostatins (52), and trestatins (53), are known to display potent α-glucosidase inhibitory effects. Among these active metabolites, acarbose is of considerable pharmacological interest. In addition to its α-glucosidase activity, acarbose also displays potent inhibitory activity against sucrase, maltase, dextrinase, and glucoamylase. This pronounced inhibitory effect has resulted in its use as a clinical drug for the treatment of type II non-insulin-dependent diabetes and, in some countries, prediabetes in order to enable patients to better control blood sugar contents while living with starch-containing diets. It is a starch blocker and inhibits α-glucosidase, an intestinal enzyme that releases glucose from larger carbohydrates. Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. Interestingly, individual members of different series of carbaoligosaccharides deactivate α-amylase and sucrase quite differently. Thus, whereas amylase inhibition is maximum with homologues of four and five glucose units, the greatest sucrase inhibition is caused by acarbose containing two glucose residues [398].

Adiposins (51) have exhibited potent inhibitory activities against α-glucoside hydrolases, such as salivary and pancreatic α-amylases, and intestinal disaccharidases, such as sucrase, maltase, and isomaltase [399]. They have also showed antimicrobial activities against some Gram-positive bacteria, Gram-negative bacteria, some anaerobic bacteria, and some phytopathogenic fungi and also showed a synergistic effect on the antibacterial activity with some maltooligosaccharides [122].

Oligostatins (52) not only exhibited strong α-amylase inhibitory activity but also are active against Gram-negative bacteria, while Gram-positive bacteria are not affected [400].

The acarviosin, which is the core structure of acarbose and related carbaoligosaccharides α-amylase inhibitors, is responsible for their glycosidase inhibitory activities since the valienamine portion mimics the glucopyranosyl cation intermediate at the active site for hydrolysis of α-glucosides in the acarviosin moiety. Subsequently, several chemically modified acarviosin analogues, 183–188, have been prepared and their glycosidase inhibitory activities were tested [132, 401–403]. The results showed that the 4-amino-4,6-dideoxy moiety could be replaced by other simple structures, such as 1,6-anhydrohexoses, without losing its inhibitory power against α-glucosidase. However, modification of the valienamine portion, in order to mimic each substrate structure, did not result in any inhibitory activity against the targeted enzyme; see, for instance, compounds 187 and 188 for β-glucosidase and α-mannosidase activities, respectively (Figure 32).

Figure 32: Acarviosin analogues 183–188.

Carbatrisaccharide 189, an analogue of the “trimannosyl core” which frequently occurs in biologically important glycoconjugates [404, 405], was found [406] to be fully active as an acceptor for N-acetylglucosaminyltransferase-V, with both the enzyme isolated from hamster kidney and the one cloned from rat kidney. The kinetic parameters were functionally equivalent with those of the true trisaccharide. A preparative glycosylation reaction was performed using 189 as the acceptor with the cloned rat kidney enzyme. A tetrasaccharide formed by the addition of a Glc pNAc residue (190) was the sole product detected (Scheme 22).

Scheme 22: Carbatrisaccharides 189 and 190.

Fucosyl- and sialyltransferases are involved in the synthesis of sialyl Lewis-x, one of the most important blood group antigens, which is a tumor-associated tetrasaccharide, and ligand of E-selectin-mediated inflammatory extravasation of granulocytes and monocytes [407, 408]. Fucosyl- and sialyltransferases are involved in the last steps of the biosynthesis of Lewis oligosaccharide antigens by transferring α-fucopyranosyl residues [409–412]. Therefore, an area of interest is the design of potential inhibitors of these enzymes involved in the assembly of the sialyl Lewis-x structure. In the search for inhibitors of the biosynthesis of Lewis oligosaccharide antigens, the synthesis of carbasugar analogues of the disaccharide fragment highlighted in Figure 33 was carried out by Ogawa et al. [413, 414]. They prepared ether- and imine-linked N-acetyl--carba-β-lactosaminides and -isolactosaminides and tested them against fucosyltransferases. Biological assays showed that compounds 191a and 191b (Figure 33) are acceptor substrate for human-milk α-(13/4)-fucosyltransferase with kinetic parameters comparable to those observed for standard true disaccharides. Small-scale enzymatic synthesis was carried out by treatment of 191a and 191b with GDP-fucose and milk fucosyltransferase which resulted in the conversion into the corresponding trisaccharides (by fucosylation at O3).

Figure 33: Carbasugars disaccharide analogues as inhibitors of fucosyl- and sialyltransferases.

Interestingly, compounds 192a and 192b were neither acceptors nor inhibitors for milk fucosyltransferase, suggesting that α-(14) transfer is not possible. The milk preparation contains a mixture of two different [α-(13/4)- and α-(13)-] fucosyltransferase enzymes. These enzymes were separated, and it was shown that both forms utilized compounds 191a and 191b as acceptor substrates, whereas 192a and 192b were not appropriate acceptors. This was the first demonstration of a specific substrate for α-(13)-fucosyltransferase.

In contrast with these results, screening carried out on isomeric octyl 5a-carba-β-lactosaminide (193b) and isolactosaminide (194b) (where the carbasugar unit is at the reducing end) showed that both compounds were good substrates for α-(13)-fucosyltransferase V (human recombinant, Spodoptera frugiperda) as well as α-(23)-(N) sialyltransferase (rat, recombinant, Spodoptera frugiperda) when compared to the parent compounds 193a and 194a [415].

The inhibitory activity of four new carbadisaccharides (ether-linked methyl -carba-β-lactoside (195a) and imine-linked methyl -carba-β-lactoside (195b), methyl N-acetyl--carba-β-lactosaminide (195c), and methyl N-acetyl--carba-β-isolactosaminide (196)) toward rat recombinant α-(23)-sialyl and rat liver α-(26)-sialyltransferases with the presence of 4-methylumbelliferyl-labeled Lac-NAc as an acceptor substrate was evaluated [416]. Compounds 195a, 195b, and 196 showed more inhibition for α-(23)-sialyltransferase than for α-(26)-sialyltransferase. In addition, the enzyme-inhibition assays showed that compound 195b possesses potent and specific inhibitory activity toward rat recombinant α-(23)-sialyltransferase. Moreover, compounds 195b ( μM) and 196 ( μM) presented IC₅₀ values similar to that for the acceptor ( μM) toward α-(23)-sialyltransferases, whereas compound 195c displayed less inhibition ( μM). Surprisingly, compound 195c, which was expected to inhibit both enzymes, did not show any appreciable inhibition toward any of them. The authors concluded from this study that the imine function enhances affinity for sialyltransferases but that when two nitrogen atoms exist, the enzymes maintain an equilibrium of interaction between them. They also established that a carbagalactose residue in carbadisaccharides may bind to sialyltransferases but without the transfer of sialic acid.

(3) Pyralomicins. Pyralomicins 55–58 show activity against various bacteria, particularly strains of Micrococcus luteus, an opportunistic Gram-positive bacterium. The antibacterial activity of the pyralomicins appears to be dependent upon the number and the position of chlorine atoms within the molecules and the nature and methylation of the glycone [417]. That suggests a role for the cyclitol moiety in the antimicrobial activity.

5. Conclusions

More than four decades have already elapsed since the first synthesis of a carbocyclic analogue of a carbohydrate: a carbasugar. Because these compounds exhibit enhanced chemical stability, the prediction was that these new compounds could replace carbohydrates in their interaction with enzymes thus showing important biological properties. This prediction has been amply confirmed and several biologically active natural products containing carbasugars moieties have been discovered and their biosynthesis, synthesis, and biological properties were the subjects of extensive research. In addition, many synthetic analogues of these natural products have been synthesized in the search for improved biological properties. It seems fair to predict that the future holds considerable promise for advances in this area.

Disclosure

The present address of Silvia Roscales is Helmholtz-Zentrum Dresden-Rossendorf, Radiopharmaceutical and Chemical Biology Department, Bautzner Landstraße 400, 01328 Dresden, Germany.

Competing Interests

The authors declare that there are not competing interests regarding the publication of this paper.

Acknowledgments

One of the authors (Silvia Roscales) thanks Fundación Ramón Areces, Spain, for a postdoctoral fellowship.

References

J. L. de Paz and P. H. Seeberger, “Recent advances in carbohydrate microarrays,” QSAR and Combinatorial Science, vol. 25, no. 11, pp. 1027–1032, 2006.

M. Miljkovic, Carbohydrates: Synthesis, Mechanisms, and Stereoelectronic Effects, Springer, 2010.

R. V. Stick and S. J. Williams, Carbohydrates: The Essential Molecules of Life, Elsevier, New York, NY, USA, 2nd edition, 2009.

M. Sinnott, Ed., Carbohydrate Chemistry and Biochemistry: Structure and Mechanism, RSC, 1st edition, 2007, 2nd edition, 2013.

“Chemical reviews,” Carbohydrate Chemistry, vol. 10, no. 12, Edited by J. K. Bashkin, 2000

D. B. Werz and S. Vidal, Eds., Modern Synthetic Methods in Carbohydrate Chemistry. From Monosaccharides to Complex Glycoconjugates, John Wiley & Sons, New York, NY, USA, 2013.

P. Kovac, Ed., Carbohydrate Chemistry. Proven Synthetic Methods, vol. 1, CRC Press. Taylor & Francis Group, 2011.

G. van der Mare and J. Coreen, Eds., Carbohydrate Chemistry. Proven Synthetic Methods, vol. 2, CRC Press. Taylor & Francis Group, 2014.

R. Roy and S. Vidal, Eds., Carbohydrate Chemistry. Proven Synthetic Methods, vol. 3, CRC Press. Taylor & Francis Group, 2015.

Y. C. Lee and R. T. Lee, Eds., Recognition of Carbohydrates in Biological Systems. Part A: General Procedures, vol. 362 of Methods in Enzymology, Academic Press, New York, NY, USA, 2003.

Y. C. Lee and R. T. Lee, Eds., Recognition of Carbohydrates in Biological Systems. Part B: Specific Applications, vol. 363 of Methods in Enzymology, Academic Press, New York, NY, USA, 2003.

B. Wang and G. J. Boons, Eds., Carbohydrate Recognition. Biological Problems, Methods and Applications, Wileyohn Wiley & Sons, Bew York, NY, USA, 2011.

P. H. Seeberger and Ch. Rademacher, Eds., Carbohydrates as Drugs, vol. 12 of Topics in Medicinal Chemistry, Springer, 2014.

J. Jiménez-Barbero, J. Cañada, and S. Martín-Santamaría, Eds., Carbohydrates in Drug Design and Discovery, vol. 43, RSC: Drug Discovery Series, 2015.

R. A. Dwek and T. D. Butters, “Introduction: glycobiology—understanding the language and meaning of carbohydrates,” Chemical Reviews, vol. 102, no. 2, pp. 283–284, 2002.

H. Lis and N. Sharon, “Lectins: carbohydrate-specific proteins that mediate cellular recognition,” Chemical Reviews, vol. 98, no. 2, pp. 637–674, 1998.

V. L. Campo, V. Aragón-Leoneti, M. B. M. Teixeira, and I. Carvalho, “Carbohydrates and glycoproteins: cellular recognition and drug design,” New Developments in Medicinal Chemistry, vol. 1, pp. 133–151, 2010.

L. L. Kiessling and J. C. Grim, “Glycopolymer probes of signal transduction,” Chemical Society Reviews, vol. 42, no. 10, pp. 4476–4491, 2013.

Y.-L. Ruan, “Sucrose metabolism: gateway to diverse carbon use and sugar signaling,” Annual Review of Plant Biology, vol. 65, pp. 33–67, 2014.

K. Ljung, J. L. Nemhauser, and P. Perata, “New mechanistic links between sugar and hormone signalling networks,” Current Opinion in Plant Biology, vol. 25, pp. 130–137, 2015.

J. M. Rini and H. Leffler, “Carbohydrate recognition and signaling,” in Functioning of Transmembrane Receptors in Signaling Mechanism, R. Bradshaw and E. A. Dennis, Eds., Cell Signaling Collection, chapter 13, pp. 341–347, Academic Press, New York, NY, USA, 2011.

K. J. Doores, D. P. Gamblin, and B. G. Davis, “Exploring and exploiting the therapeutic potential of glycoconjugates,” Chemistry—A European Journal, vol. 12, no. 3, pp. 656–665, 2006.

K. M. Koeller and C. H. Wong, “The concept of ‘Medicinal Glycoscience’ was developed,” in Emerging Themes in Medicinal Glycoscience, vol. 18 of Nature Biotechnology, pp. 835–841, 2000.

S. J. Keding and S. J. Danishefsky, “Synthetic carbohydrate-based vaccines,” in Carbohydrate-Based Drug Discovery, C.-H. Wong, Ed., chapter 14, pp. 381–406, John Wiley & Sons, New York, NY, USA, 2003.

M.-L. Hecht, P. Stallforth, D. V. Silva, A. Adibekian, and P. H. Seeberger, “Recent advances in carbohydrate-based vaccines,” Current Opinion in Chemical Biology, vol. 13, no. 3, pp. 354–359, 2009.

L. Morelli, L. Poletti, and L. Lay, “Carbohydrates and immunology: synthetic oligosaccharide antigens for vaccine formulation,” European Journal of Organic Chemistry, vol. 2011, no. 29, pp. 5723–5777, 2011.

S. Bhatia, M. Dimde, and R. Haag, “Multivalent glycoconjugates as vaccines and potential drug candidates,” MedChemComm, vol. 5, no. 7, pp. 862–878, 2014.

S. J. Danishefsky and J. R. Allen, “From the laboratory to the clinic: a retrospective on fully synthetic carbohydrate-based anticancer vaccines,” Angewandte Chemie International Edition, vol. 39, no. 5, pp. 836–863, 2000.

“Part I: biosynthesis, structural diversity and sialoglycopathologies. Part II: tools and technique to identify and capture sialoglycans,” in Sialo Glyco Chemistry and Biology, R. Gerardy-Schahn, P. Delannoy, and M. von Itzstein, Eds., vol. 366-367 of Topics in Current Chemistry, Springer, Berlin, Germany, 2015.

M. Pudelko, J. Bull, and H. Kunz, “Chemical and chemoenzymatic synthesis of glycopeptide selectin ligands containing sialyl Lewis X structures,” ChemBioChem, vol. 11, no. 7, pp. 904–930, 2010.

N. Kaila and B. E. Thomas IV, “Design and synthesis of sialyl Lewisx mimics as E- and P-selectin inhibitors,” Medicinal Research Reviews, vol. 22, no. 6, pp. 566–601, 2002.

A. L. Majumder and B. B. Biswas, Eds., Biology of Inositols and Phosphoinositides, vol. 39 of Subcellular Biochemistry, Springer, New York, NY, USA, 2006.

A. Kukisis, “Laboratory techniques in biochemistry and molecular biology,” in Inositol Phospholipid Metabolism and Phosphatidyl Inositol Kimases, S. Pillai and P. C. Van der Viet, Eds., chapter 5, pp. 253–334, Elsevier, New York, NY, USA, 2003.

A. K. Menon, P. Orlean, T. Kinoshita, and F. Tamanoi, Eds., Glycosylphosphatidylinositols (GPI) Anchoring of Proteins, vol. 26 of The Enzimes, Elsevier, 2009.

GPI, Membrane Anchors. The Much Needed Link, Edited by J. A. Dangerfield, Ch. Metamer, Bentham, 2010.

I. Vilotijevic, S. Gutze, P. H. Seeberger, and D. V. Silva, “Chemical synthesis of GPI anchors and GPI anchored molecules,” in Modern Synthetic Methods in Carbohydrate Chemistry, D. B. Werz and S. Vidal, Eds., pp. 335–372, John Wiley & Sons, New York, NY, USA, 2014.

Ch. Zurzolo and K. Simons, “Glycosylphosphatidylinositol-anchored proteins. Membrane, organization and transport,” Biochimica et Biophysica Acta (BBA)—Biomembranes, vol. 1858, no. 4, pp. 632–639, 2016.

G. H. Boons and K. J. Hale, Organic Synthesis with Carbohydrates, Wiley-Blackwell, 2000.

M. M. K. Boysen, Ed., Carbohydrates Tools for Stereoselective Synthesis, John Wiley & Sons, Berlin, Germany, 2013.

P. Sears and C.-H. Wong, “Carbohydrate mimetics: a new strategy for tackling the problem of carbohydrate-mediated biological recognition,” Angewandte Chemie—International Edition, vol. 38, no. 16, pp. 2300–2324, 1999.

S. A. W. Gruner, E. Locardi, E. Lohof, and H. Kessler, “Carbohydrate-based mimetics in drug design: sugar amino acids and carbohydrate scaffolds,” Chemical Reviews, vol. 102, no. 2, pp. 491–514, 2002.

D. C. Koester, A. Holkenbrink, and D. B. Werz, “Recent advances in the synthesis of carbohydrate mimetics,” Synthesis, no. 19, Article ID E27110SS, pp. 3217–3242, 2010.

L. Cipolla and F. Peri, “Carbohydrate-based bioactive compounds for medicinal chemistry applications,” Mini-Reviews in Medicinal Chemistry, vol. 11, no. 1, pp. 39–54, 2011.

Joint Commission on Biochemical Nomenclature, “Nomenclature of carbohydrates,” Pure and Applied Chemistry, vol. 68, pp. 1919–2008, 1996.

O. Arjona, A. M. Gómez, J. C. López, and J. Plumet, “Synthesis and conformational and biological aspects of carbasugars,” Chemical Reviews, vol. 107, no. 5, pp. 1919–2036, 2007.

J. Plumet, A. M. Gómez, and J. C. López, “Synthesis of carbasugars based on ring closing metathesis: 2000–2006,” Mini-Reviews in Organic Chemistry, vol. 4, no. 3, pp. 201–216, 2007.

S. Jarosa, M. Nowogrodzki, M. Magdyca, and M. Potopnyk, “Carbobicyclic sugar mimics,” Journal of Carbohydrate Chemistry, vol. 37, pp. 303–325, 2012.

R. G. Soengas, J. M. Otero, A. M. Estévez et al., “An overview of key routes for the transformation of sugars into carbasugars and related compounds,” Carbohydrate Chemistry, vol. 38, pp. 263–302, 2012.

R. Lahiri, A. A. Ansari, and Y. D. Vankar, “Recent developments in design and synthesis of bicyclic azasugars, carbasugars and related molecules as glycosidase inhibitors,” Chemical Society Reviews, vol. 42, no. 12, pp. 5102–5118, 2013.

M. Bessières, F. Chevrier, V. Roy, and L. A. Agrofoglio, “Recent progress for the synthesis of selected carbocyclic nucleosides,” Future Medicinal Chemistry, vol. 7, no. 13, pp. 1809–1828, 2015.

P. Merino, Ed., Chemical Synthesis of Nucleoside Analogues, John Wiley & Sons, New York, NY, USA, 2013.

M. Adinolfi, M. M. Corsaro, C. De Castro et al., “Caryose: a carbocyclic monosaccharide from Pseudomonas caryophylli,” Carbohydrate Research, vol. 284, no. 1, pp. 111–118, 1996.

M. Adinolfi, M. M. Corsaro, C. De Castro et al., “Analysis of the polysaccharide components of the lipopolysaccharide fraction of Pseudomonas caryophylli,” Carbohydrate Research, vol. 284, no. 1, pp. 119–133, 1996.

M. Adinolfi, G. Barone, A. Iadonisi, L. Mangoni, and R. Manna, “Synthesis of caryose, the carbocyclic monosaccharide component of the lipopolysaccharide from pseudomonas caryophylli,” Tetrahedron, vol. 53, no. 34, pp. 11767–11780, 1997.

T. D. Brock, K. M. Brock, R. T. Belly, and R. L. Weiss, “Sulfolobus: a new genus of sulfur-oxidizing bacteria living at low pH and high temperature,” Archiv für Mikrobiologie, vol. 84, no. 1, pp. 54–68, 1972.

M. de Rosa, S. de Rosa, A. Gambacorta, L. Minale, and J. D. Bullock, “Chemical structure of the ether lipids of thermophilic acidophilic bacteria of the Caldariella group,” Phytochemistry, vol. 16, no. 12, pp. 1961–1965, 1977.

M. De Rosa, S. De Rosa, A. Gambacorta, and J. D. Bu'Lockt, “Structure of calditol, a new branched-chain nonitol, and of the derived tetraether lipids in thermoacidophile archaebacteria of the Caldariella group,” Phytochemistry, vol. 19, no. 2, pp. 249–254, 1980.

M. L. Bode, S. R. Buddoo, S. H. Minnaar, and C. A. du Plessis, “Extraction, isolation and NMR data of the tetraether lipid calditoglycerocaldarchaeol (GDNT) from Sulfolobus metallicus harvested from a bioleaching reactor,” Chemistry and Physics of Lipids, vol. 154, no. 2, pp. 94–104, 2008.

É. Untersteller, B. Fritz, Y. Bliériot, and P. Sinaÿ, “The structure of calditol isolated from the thermoacidophilic archaebacterium Sulfolobus acidocaldarius,” Comptes Rendus de l'Academie des Sciences—Series IIC-Chemistry, vol. 2, no. 7-8, pp. 429–433, 1999.

Y. Blériot, E. Untersteller, B. Fritz, and P. Sinaÿ, “Total synthesis of calditol: structural clarification of this typical component of Archaea order Sulfolobales,” Chemistry, vol. 8, no. 1, pp. 240–246, 2002.

T. W. Miller, B. H. Arison, and G. Albers Schonberg, “Isolation of a cyclitol antibiotic: 2,3,4,5-tetrahydroxycyclohexanemethanol,” Biotechnology and Bioengineering, vol. 15, no. 6, pp. 1075–1080, 1973.

J. Marco-Contelles, M. T. Molina, and S. Anjum, “Naturally occurring cyclohexane epoxides: sources, biological activities, and synthesis,” Chemical Reviews, vol. 104, no. 6, pp. 2857–2899, 2004.

C. Thebtaranonth and Y. Thebtaranonth, “Naturally occurring cyclohexene oxides,” Accounts of Chemical Research, vol. 19, no. 3, pp. 84–90, 1986.

J. Marco-Contelles, “Cyclohexane epoxides—chemistry and biochemistry of (+)-cyclophellitol,” European Journal of Organic Chemistry, no. 9, pp. 1607–1618, 2001.

Y. Kobayashi, Glycoscience, Chemistry and Chemical Biology, vol. 3, chapter 10.3, Springer, Berlin, Germany, 2001.

K. Tatsuta, “Total synthesis and chemical design of useful glycosidase inhibitors,” Pure and Applied Chemistry, vol. 68, no. 6, pp. 1341–1346, 1996.

S. Ogawa and M. Kanto, “Synthesis of bio-active compounds from cyclitol derivatives provided by bioconversion of myo-inositol,” Current Trends in Medicinal Chemistry, vol. 5, pp. 1–13, 2008.

B. Fraser-Reid and J. C. López, “Unsaturated sugars: a rich platform for methodological and synthetic studies,” Current Organic Chemistry, vol. 13, no. 6, pp. 532–553, 2009.

Y. Nobuji, C. Noriko, M. Takashi, U. Shigeru, A. Kenzon, and I. Michaki, “Novel herbicidal MK7607 and its manufacture with Curvularia,” Japanese Kokai Tokkyo Koho, JP, 06306000, 1994

A. Isogai, S. Sakuda, J. Nakayama, S. Watanabe, and A. Suzuki, “Isolation and structural elucidation of a new cyclitol derivative, streptol, as a plant growth regulator,” Agricultural and Biological Chemistry, vol. 51, no. 8, pp. 2277–2279, 1987.

P. Sedmera, P. Halada, and S. Pospisil, “New carbasugars from Streptomyces lincolnensis,” Magnetic Resonance in Chemistry, vol. 47, no. 6, pp. 519–522, 2009.

T. Yamada, M. Iritani, H. Ohishi et al., “Pericosines, antitumour metabolites from the sea hare-derived fungus Periconia byssoides. Structures and biological activities,” Organic and Biomolecular Chemistry, vol. 5, no. 24, pp. 3979–3986, 2007.

V. Usami, “Synthesis of marine-derived carbasugar pericosines,” Studies in Natural Products Chemistry, vol. 41, pp. 287–319, 2014.

P. Bayón and M. Figueredo, “The gabosine and anhydrogabosine family of secondary metabolites,” Chemical Reviews, vol. 113, no. 7, pp. 4680–4707, 2013.

D. H. Mac, S. Chandrasekhar, and R. Grée, “Total synthesis of gabosines,” European Journal of Organic Chemistry, no. 30, pp. 5881–5895, 2012.

M. Das and K. Manna, “Bioactive cyclohexenones: a mini review,” Current Bioactive Compounds, vol. 11, no. 4, pp. 239–248, 2015.

H. Chimura, H. Nakamura, T. Takita et al., “The structure of a glyoxalase I inhibitor and its chemical reactivity with SH-compounds,” The Journal of Antibiotics, vol. 28, no. 10, pp. 743–748, 1975.

S. Horii, T. Iwasa, and Y. Kameda, “Studies on validamycins, new antibiotics. V. Degradation studies,” The Journal of Antibiotics, vol. 24, no. 1, pp. 57–58, 1971.

S. Horii, T. Iwasa, E. Mizuta, and Y. Kameda, “Studies on validamycins, new antibiotics. VI. Validamine, hydroxyvalidamine and validatol, new cyclitols,” Journal of Antibiotics, vol. 24, no. 1, pp. 59–63, 1971.

Y. Kameda, N. Asano, M. Yoshikawa et al., “Valiolamine, a new α-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus,” The Journal of Antibiotics, vol. 37, no. 11, pp. 1301–1307, 1984.

Y. Kameda and S. Horii, “The unsaturated cyclitol part of the new antibiotics, the validamycins,” Journal of the Chemical Society, Chemical Communications, no. 12, pp. 746–747, 1972.

Y. Kameda, S. Horii, and T. Yamano, “Microbial transformation of validamycins,” Journal of Antibiotics, vol. 28, no. 4, pp. 298–306, 1975.

Y. Kameda, N. Asano, M. Teranishi, and K. Matsui, “New cyclitols, degradation of validamycin A by Flavobacterium saccharophilum,” Journal of Antibiotics, vol. 33, no. 12, pp. 1573–1574, 1980.

Y. Kameda, N. Asano, M. Teranishi, M. Yoshikawa, and K. Matsui, “New intermediates, degradation of validamycin a by Flavobacterium saccharophilum,” The Journal of Antibiotics, vol. 34, no. 9, pp. 1237–1240, 1981.

N. Asano, M. Takeuchi, K. Ninomiya, Y. Kameda, and K. Matsui, “Microbial degradation of validamycin A by Flavobacterium saccharophilum. Enzymatic cleavage of C-N linkage in validoxylamine A,” Journal of Antibiotics, vol. 37, no. 8, pp. 859–867, 1984.

S. Ogawa, Y. Miyamoto, and A. Nakajima, “Cleavage of the imino bonds of validoxylamine A derivatives with N-bromosuccinimide,” Chemistry Letters, pp. 725–728, 1989.

S. Ogawa, A. Nakajima, and Y. Miyamoto, “Cleavage of validoxylamine A derivatives with N-bromosuccinimide: preparation of blocked synthons useful for the construction of carba-oligosaccharides composed of imino linkages,” Journal of the Chemical Society, Perkin Transactions, vol. 1, no. 12, pp. 3287–3290, 1991.

H. Xu, J. Yang, L. Bai, Z. Deng, and T. Mahmud, “Genetically engineered production of 1,1′-bis-valienamine and validienamycin in Streptomyces hygroscopicus and their conversion to valienamine,” Applied Microbiology and Biotechnology, vol. 81, no. 5, pp. 895–902, 2009.

Y.-P. Xue, Y.-G. Zheng, and Y.-C. Shen, “Enhanced production of valienamine by Stenotrophomonas maltrophilia with fed-batch culture in a stirred tank bioreactor,” Process Biochemistry, vol. 42, no. 6, pp. 1033–1038, 2007.

Y.-S. Wang, Y.-G. Zheng, and Y.-C. Shen, “Isolation and identification of a novel valienamine-producing bacterium,” Journal of Applied Microbiology, vol. 102, no. 3, pp. 838–844, 2007.

T. Mahmud, “The C7N aminocyclitol family of natural products,” Natural Product Reports, vol. 20, no. 1, pp. 137–166, 2003.

T. Suami, “Synthesis of biologically active pseudo-oligosaccharides,” in Carbohydrates, H. Ogura, A. Hasegawa, and T. Suami, Eds., pp. 136–173, VCH, 1992.

T. Iwasa, H. Yamamoto, and M. Shibata, “Studies on validamycins, new antibiotics. I. Streptomyces hygroscopicus var. limoneus nov. var., validamycin-producing organism,” Journal of Antibiotics, vol. 23, no. 12, pp. 595–602, 1970.

T. Iwasa, E. Higashide, H. Yamamoto, and M. Shibata, “Studies on validamycins, new antibiotics. II. Production and biological properties of validamycins A and B,” Journal of Antibiotics, vol. 24, no. 2, pp. 107–113, 1971.

S. Horii, Y. Kameda, and K. Kawahara, “Studies on validamycins, new antibiotics. 8. Isolation and characterization of validamycins C,D,E and F.,” Journal of Antibiotics, vol. 25, no. 1, pp. 48–53, 1972.

Y. Kameda, N. Asano, K. Matsui, S. Horii, and H. Fukase, “Structures of minor components of the validamycin complex,” Journal of Antibiotics, vol. 41, no. 10, pp. 1488–1492, 1988.

Y. Kameda, N. Asano, T. Yamaguchi, K. Matsui, S. Horii, and H. Fukase, “Validamycin G and validoxylamine G, new members of the validamycins,” Journal of Antibiotics, vol. 39, no. 10, pp. 1491–1494, 1986.

N. Asano, Y. Kameda, K. Matsui, S. Horii, and H. Fukase, “Validamycin H, a new pseudo-tetrasaccharide antibiotic,” The Journal of Antibiotics, vol. 43, no. 8, pp. 1039–1041, 1990.

D. D. Schmidt, W. Frommer, B. Junge et al., “α-Glucosidase inhibitors—new complex oligosaccharides of microbial origin,” Naturwissenschaften, vol. 64, no. 10, pp. 535–536, 1977.

B. Junge, F.-R. Heiker, J. Kurz, L. Müller, D. D. Schmidt, and C. Wünsche, “Untersuchungen zur struktur des α-d-glucosidaseinhibitors acarbose,” Carbohydrate Research, vol. 128, no. 2, pp. 235–268, 1984.

U. Masharani and M. S. German, “Pancreatic hormones and diabetes mellitus,” in Greenspan's Basic & Clinical Endocrinology, D. G. Gardner and D. Shoback, Eds., chapter 17, McGraw-Hill Medical, 9th edition, 2011.

J. B. Buse, K. S. Polonsky, and Ch. F. Burant, “Type 2 diabetes mellitus,” in Williams Textbook of Endocrinology, S. Melmed, K. S. Polonsky, P. R. Larsen, and H. M. Kronenberg, Eds., section 7, chapter 31, Elsevier, 12th edition, 2012.

A. Kadziola, J.-I. Abe, B. Svensson, and R. Haser, “Crystal and molecular structure of barley α-amylase,” Journal of Molecular Biology, vol. 239, no. 1, pp. 104–121, 1994.

M. Machius, G. Wiegand, and R. Huber, “Crystal structure of calcium-depleted Bacillus licheniformisα-amylase at 2.2 Å resolution,” Journal of Molecular Biology, vol. 246, no. 4, pp. 545–559, 1995.

M. Hemker, A. Stratmann, K. Goeke et al., “Identification, cloning, expression, and characterization of the extracellular acarbose-modifying glycosyltransferase, AcbD, from Actinoplanes sp. strain SE50,” Journal of Bacteriology, vol. 183, no. 15, pp. 4484–4492, 2001.

E. Truscheit, W. Frommer, B. Junge, L. Muller, D. Schmidt, and W. Wingeder, “Chemistry and biochemistry of microbial α-glucosidase inhibitors,” Angewandte Chemie—International Edition, vol. 20, no. 9, pp. 744–761, 1981.

U. F. Wehmeier and W. Piepersberg, “Biotechnology and molecular biology of the α-glucosidase inhibitor acarbose,” Applied Microbiology and Biotechnology, vol. 63, no. 6, pp. 613–625, 2004.

U. F. Wehmeier, “The biosynthesis and metabolism of acarbose in Actinoplanes sp. SE 50/110: a progress report,” Biocatalysis and Biotransformation, vol. 21, no. 4-5, pp. 279–284, 2003.

H. Laube, “Acarbose. An update of its therapeutic use in diabetes treatment,” Clinical Drug Investigation, vol. 22, no. 3, pp. 141–156, 2002.

A. J. Scheen, “Clinical efficacy of acarbose in diabetes mellitus: a critical review of controlled trials,” Diabetes and Metabolism, vol. 24, no. 4, pp. 311–321, 1998.

H.-W. M. Breuer, “Review of acarbose therapeutic strategies in the long-term treatment and in the prevention of type 2 diabetes,” International Journal of Clinical Pharmacology and Therapeutics, vol. 41, no. 10, pp. 421–440, 2003.

S. Ogawa, M. Kanto, and Y. Suzuki, “Development and medical application of unsaturated carbaglycosylamine glycosidase inhibitors,” Mini-Reviews in Medicinal Chemistry, vol. 7, no. 7, pp. 679–691, 2007.

A. Bedekar, K. Shah, and M. Koffas, “Natural products for type II diabetes treatment,” Advances in Applied Microbiology, vol. 71, pp. 21–73, 2010.

J. L. Ríos, F. Francini, and G. R. Schinella, “Natural products for the treatment of type 2 diabetes mellitus,” Planta Medica, vol. 81, no. 12-13, pp. 975–994, 2015.

A. L. Harvey, “Plant natural products in anti-diabetic drug discovery,” Current Organic Chemistry, vol. 14, no. 16, pp. 1670–1677, 2010.

N. S. H. N. Moorthy, M. J. Ramos, and P. A. Fernandes, “Studies on α-glucosidase inhibitors development: magic molecules for the treatment of carbohydrate mediated diseases,” Mini-Reviews in Medicinal Chemistry, vol. 12, no. 8, pp. 713–720, 2012.

U. Ghani, “Re-exploring promising α-glucosidase inhibitors for potential development into oral anti-diabetic drugs: finding needle in the haystack,” European Journal of Medicinal Chemistry, vol. 103, pp. 133–162, 2015.

K.-I. Fukuhara, H. Murai, and S. Murao, “Amylostatins, other amylase inhibitors produced by Streptomyces diastaticus subsp. Amylostaticus No. 2476,” Agricultural and Biological Chemistry, vol. 46, no. 8, pp. 2021–2030, 1982.

K. Fukuhara, H. Murai, and S. Murao, “Isolation and structure-activity relationship of some amylostatins (F-1b fraction) produced by Streptomyces diastaticus subsp. Amylostaticus No. 9410,” Agricultural and Biological Chemistry, vol. 46, no. 7, pp. 1941–1945, 1982.

S. Namiki, K. Kangouri, T. Nagate, H. Hara, K. Sugita, and S. Omura, “Studies on the α-glucoside hydrolase inhibitor, adiposin. I. Isolation and physicochemical properties,” The Journal of Antibiotics, vol. 35, no. 9, pp. 1234–1236, 1982.

S. Namiki, K. Kangouri, T. Nagate, H. Hara, K. Sugita, and S. Omura, “Studies on the α-glucoside hydrolase inhibitor, adiposin. II. Taxonomic studies on the producing microorganism,” The Journal of Antibiotics, vol. 35, no. 9, pp. 1156–1159, 1982.

K. Kangouri, S. Namiki, T. Nagate, H. Hara, K. Sugita, and S. Omura, “Studies on the α-glucoside hydrolase inhibitor, adiposin. III. α-Glucoside hydrolase inhibitory activity and antibacterial activity in vitro,” The Journal of Antibiotics, vol. 35, no. 9, pp. 1160–1166, 1982.

S. Namiki, K. Kangouri, T. Nagate et al., “Studies on the α-glucoside hydrolase inhibitor, adiposin. IV. Effect of adiposin on intestinal digestion of carbohydrates in experimental animals,” Journal of Antibiotics, vol. 35, no. 9, pp. 1167–1173, 1982.

S. Ogawa, Y. Iwasawa, T. Toyokuni, and T. Suami, “Synthesis of adiposin-1, α-glucoside hydrolase inhibitor,” Chemistry Letters, vol. 12, no. 3, pp. 337–340, 1983.

S. Ogawa, Y. Iwasawa, T. Toyokuni, and T. Suami, “Synthesis of pseudooligosaccharidic glycosidase inhibitors. Part 1. Synthesis ofadiposin-1 and related compounds,” Carbohydrate Research, vol. 141, pp. 29–40, 1985.

S. Ogawa and Y. Shibata, “Total synthesis of acarbose andadiposin-2,” Journal of the Chemical Society, Chemical Communications, no. 9, pp. 605–606, 1988.

Y. Shibata and S. Ogawa, “Synthesis of pseudo-oligosaccharide glycosidase inhibitors. Part VII. Total synthesis of acarbose andadiposin-2,” Carbohydrate Research, vol. 189, pp. 309–322, 1989.

J. Itoh, S. Omoto, T. Shomura et al., “Oligostatins, new antibiotics with amylase inhibitory activity. I. Production, isolation and characterization,” Journal of Antibiotics, vol. 34, no. 11, pp. 1424–1428, 1981.

S. Omoto, J. Itoh, H. Ogino, K. Iwamatsu, N. Nishizawa, and S. Inouye, “Oligostatins, new antibiotics with amylase inhibitory activity. II. Structures of oligostatins C, D and E,” The Journal of Antibiotics, vol. 34, no. 11, pp. 1429–1433, 1981.

S. Ogawa, Y. Iwasawa, T. Toyokuni, and T. Suami, “Synthesis of a common structural unit of the antibiotic oligostatins,” Chemistry Letters, vol. 11, no. 11, pp. 1729–1732, 1982.

S. Ogawa, Y. Iwasawa, T. Toyokuni, and T. Suami, “Synthesis of a core structure of the antibiotic oligostatin,” Carbohydrate Research, vol. 144, no. 1, pp. 155–162, 1985.

Y. Shibata, Y. Kosuge, and S. Ogawa, “Synthesis and biological activities of methyl oligobiosaminide and some deoxy isomers thereof,” Carbohydrate Research, vol. 199, no. 1, pp. 37–54, 1990.

K. Watanabe, T. Furumai, M. Sudoh, K. Yokose, and H. B. Maruyama, “New α-amylase inhibitor, trestatins. IV. Taxonomy of the producing strains and fermentation of trestatin A,” Journal of Antibiotics, vol. 37, no. 5, pp. 479–486, 1984.

K. Yokose, K. Ogawa, T. Sano, K. Watanabe, H.-B. Maruyama, and Y. Suhara, “New α-amylase inhibitor, trestatins. I. Isolation, characterization and biological activities of trestatins A, B and C,” The Journal of Antibiotics, vol. 36, no. 9, pp. 1157–1165, 1983.

L. Vértesy, H.-W. Fehlhaber, and A. Schulz, “The trehalase inhibitor salbostatin, a novel metabolite from Streptomyces albus, ATCC 21838,” Angewandte Chemie—International Edition, vol. 33, no. 18, pp. 1844–1846, 1994.

T. Yamagishi, Ch. Uchida, and S. Ogawa, “Total synthesis of the trehalase inhibitor salbostatin,” Chemistry: A European Journal, vol. 1, pp. 634–636, 1996.

T. Yamagishi, Ch. Uchida, and S. Ogawa, “Total synthesis of trehalase inhibitor salbostatin,” Bioorganic & Medicinal Chemistry Letters, vol. 5, no. 5, pp. 487–490, 1995.

N. Kawamura, N. Kinoshita, R. Sawa et al., “Pyralomicins, novel antibiotics from Microtetraspora spiralis. I. Taxonomy and production,” The Journal of Antibiotics, vol. 49, no. 7, pp. 706–709, 1996.

N. Kawamura, R. Sawa, Y. Rakahashi et al., “Pyralomicins, new antibiotics from Actinomadura spiralis,” Journal of Antibiotics, vol. 48, no. 5, pp. 435–437, 1995.

N. Kawamura, R. Sawa, Y. Takahashi et al., “Pyralomicins, novel antibiotics from Microtetraspora spiralis. II. Structure determination,” Journal of Antibiotics, vol. 49, no. 7, pp. 651–656, 1996.

T. R. Kelly and R. L. Moiseyeva, “Total synthesis of the pyralomicinones,” Journal of Organic Chemistry, vol. 63, no. 9, pp. 3147–3150, 1998.

K. Tatsuta, M. Takahashi, and N. Tanaka, “The first total synthesis of pyralomicin 2c,” Tetrahedron Letters, vol. 40, no. 10, pp. 1929–1932, 1999.

K. Tatsuta, M. Takahashi, and N. Tanaka, “The first total synthesis of pyralomicin 1c,” Journal of Antibiotics, vol. 53, no. 1, pp. 88–91, 2000.

G. N. Jenkins and N. J. Turner, “The biosynthesis of carbocyclic nucleosides,” Chemical Society Reviews, vol. 24, no. 3, pp. 169–176, 1995.

R. J. Parry, “Investigations of the biosynthesis of aristeromycin,” in Secondary-Metabolite Biosynthesis and Metabolism, vol. 44 of Environmental Science Research, pp. 89–104, Springer, Berlin, Germany, 1992.

J. M. Hill, G. N. Jenkins, C. P. Rush et al., “Revised pathway for the biosynthesis of aristeromycin and neplanocin A from D-glucose in Streptomyces citricolor,” Journal of the American Chemical Society, vol. 117, no. 19, pp. 5391–5392, 1995.

R. J. Parry and Y. Jiang, “The biosynthesis of aristeromycin. Conversion of neplanocin A to aristeromycin by a novel enzymatic reduction,” Tetrahedron Letters, vol. 35, no. 52, pp. 9665–9668, 1994.

A. Gambacorta, A. Gliozzi, and M. De Rosa, “Archaeal lipids and their biotechnological applications,” World Journal of Microbiology and Biotechnology, vol. 11, no. 1, pp. 115–131, 1995.

A. Gambacorta, G. Caracciolo, D. Trabasso, I. Izzo, A. Spinella, and G. Sodano, “Biosynthesis of calditol, the cyclopentanoid containing moiety of the membrane lipids of the archaeon Sulfolobus solfataricus,” Tetrahedron Letters, vol. 43, no. 3, pp. 451–453, 2002.

N. Yamauchi, H. Ueoka, N. Kamada, and T. Murae, “Resemblance of carbocycle formation from carbohydrates between archaea and eucarya/eubacteria. Biosynthesis of calditol, the characteristic lipid-content molecule in Sulfolobus acidocaldarius,” Bulletin of the Chemical Society of Japan, vol. 77, no. 4, pp. 771–778, 2004.

N. Yamauchi, N. Kamada, and H. Ueoka, “The possibility of involvement of ‘cyclase’ enzyme of the calditol carbocycle with broad substrate specificity in Sulfolobus acidcaldarius, a typical thermophilic archaea,” Chemistry Letters, vol. 35, no. 11, pp. 1230–1231, 2006.

B. Nicolaus, A. Trincone, E. Esposito, M. R. Vaccaro, A. Gambacorta, and M. De Rosa, “Calditol tetraether lipids of the archaebacterium Sulfolobus solfataricus. Biosynthetic studies,” Biochemical Journal, vol. 266, no. 3, pp. 785–791, 1990.

D. Voet and J. G. Voet, “Citric acid cycle,” in Biochemistry, chapter 21, John Wiley & Sons, New York, NY, USA, 3rd edition, 2004.

J. M. Berg, J. L. Tymoczko, and L. Stryer, Biochemistry, W. H. Freeman, San Francisco, Calif, USA, 5th edition, 2002.

S. Singh, A. Anand, and P. K. Srivastava, “Regulation and properties of glucose-6-phosphate dehydrogenase: a review,” International Journal of Plant Physiology and Biochemistry, vol. 4, pp. 1–19, 2012.

H. W. Hofer and H. P. Bauer, “6-Phosphogluconolactonase,” Cell Biochemistry and Function, vol. 5, no. 2, pp. 97–99, 1987.

M. Rippa, S. Hanau, C. Cervellati, and F. Dallocchio, “6-Phosphogluconate dehydrogenase: structural symmetry and functional asymmetry,” Protein and Peptide Letters, vol. 7, no. 5, pp. 341–348, 2000.

W. T. Williamson and W. A. Wood, “D-Ribulose-5-phosphate3-epimerase,” Methods in Enzymology, vol. 9, pp. 605–608, 1966.

T. Wood, “Assay for D-ribose-5-phosphate ketol isomerase and D-ribulose-5-phosphate 3-epimerase,” Methods in Enzymology, vol. 41, pp. 63–66, 1975.

G. A. Kochetov and O. N. Solovjeva, “Structure and functioning mechanism of transketolase,” Biochimica et Biophysica Acta (BBA)—Proteins and Proteomics, vol. 1844, no. 9, pp. 1608–1618, 2014.

A. Ranoux and U. Hanefeld, “Improving transketolase,” Topics in Catalysis, vol. 56, no. 9-10, pp. 750–764, 2013.

R. Wohlgemuth, M. E. B. Smith, P. A. Dalby, and J. M. Woodley, “Transketolases,” in Encyclopedia of Industrial, M. C. Flickinger, Ed., vol. 7, pp. 4746–4752, John Wiley & Sons, New York, NY, USA, 2010.

T. Widlanski, S. L. Bender, and J. R. Knowles, “Dehydroquinate synthase: a sheep in wolf's clothing?” Journal of the American Chemical Society, vol. 111, no. 6, pp. 2299–2300, 1989.

A. Stratmann, T. Mahmud, S. Lee, J. Distler, H. G. Floss, and W. Piepersberg, “The AcbC protein from actinoplanes species is a C7-cyclitol synthase related to 3-dehydroquinate synthases and is involved in the biosynthesis of the α-glucosidase inhibitor acarbose,” The Journal of Biological Chemistry, vol. 274, no. 16, pp. 10889–10896, 1999.

S. Asamizu, P. Xie, C. J. Brumsted, P. M. Flatt, and T. Mahmud, “Evolutionary divergence of sedoheptulose 7-phosphate cyclases leads to several distinct cyclic products,” Journal of the American Chemical Society, vol. 134, no. 29, pp. 12219–12229, 2012.

K. M. Kean, S. J. Codding, S. Asamizu, T. Mahmud, and P. A. Karplus, “Structure of a sedoheptulose 7-phosphate cyclase: ValA from Streptomyces hygroscopicus,” Biochemistry, vol. 53, no. 26, pp. 4250–4260, 2014.

E. P. Carpenter, A. R. Hawkins, J. W. Frost, and K. A. Brown, “Structure of dehydroquinate synthase reveals an active site capable of multistep catalysis,” Nature, vol. 394, no. 6690, pp. 299–302, 1998.

K. M. Herrmann, “The shikimate pathway: early steps in the biosynthesis of aromatic compounds,” Plant Cell, vol. 7, no. 7, pp. 907–919, 1995.

R. Höfs, S. Schoppe, R. Thiericke, and A. Zeeck, “Biosynthesis of gabosines A, B, and C, carba sugars from Streptomyces cellulosae,” European Journal of Organic Chemistry, vol. 2000, no. 10, pp. 1883–1887, 2000.

S. Y. Liu and J. P. N. Rosazza, “Enzymatic conversion of glucose to UDP-4-keto-6-deoxyglucose in Streptomyces spp.,” Applied and Environmental Microbiology, vol. 64, no. 10, pp. 3972–3976, 1998.

C. J. Thibodeaux, C. E. Melançon, and H.-W. Liu, “Unusual sugar biosynthesis and natural product glycodiversification,” Nature, vol. 446, no. 7139, pp. 1008–1016, 2007.

M. Á. Fresneda, R. Alibés, J. Font, P. Bayón, and M. Figueredo, “How a diversity-oriented approach has inspired a new hypothesis for the gabosine biosynthetic pathway. A new synthesis of (+)-gabosine C,” Organic and Biomolecular Chemistry, vol. 11, no. 38, pp. 6562–6568, 2013.

R. Alibés, P. Bayón, P. De March, M. Figueredo, J. Font, and G. Marjanet, “Enantioselective synthesis and absolute configuration assignment of gabosine O. synthesis of (+)- and (-)-gabosine N and (+)- and (-)-epigabosines N and O,” Organic Letters, vol. 8, no. 8, pp. 1617–1620, 2006.

H. Dong, T. Mahmud, I. Tornus, S. Lee, and H. G. Floss, “Biosynthesis of the validamycins: identification of intermediates in the biosynthesis of validamycin A by Streptomyces hygroscopicus var. limoneus,” Journal of the American Chemical Society, vol. 123, no. 12, pp. 2733–2742, 2001.

S.-H. Lee, H. Choe, K. S. Bae, D.-S. Park, A. Nasir, and K. M. Kim, “Complete genome of Streptomyces hygroscopicus subsp. limoneus KCTC 1717 (=KCCM 11405), a soil bacterium producing validamycin and diverse secondary metabolites,” Journal of Biotechnology, vol. 219, pp. 1–2, 2016.

S. Lee and E. Egelkrout, “Biosynthetic studies on the α-glucosidase inhibitor acarbose in Actinoplanes sp.: glutamate is the primary source of the nitrogen in acarbose,” Journal of Antibiotics, vol. 51, no. 2, pp. 225–227, 1998.

M. K. Patterson Jr. and G. R. Orr, “Asparagine biosynthesis by the Novikoff Hepatoma. Isolation, purification, property, and mechanism studies of the enzyme system,” The Journal of Biological Chemistry, vol. 243, no. 2, pp. 376–380, 1968.

A. R. Tesson, T. S. Soper, M. Ciustea, and N. G. J. Richards, “Revisiting the steady state kinetic mechanism of glutamine-dependent asparagine synthetase from Escherichia coli,” Archives of Biochemistry and Biophysics, vol. 413, no. 1, pp. 23–31, 2003.

T. Mahmud, S. Lee, and H. G. Floss, “The biosynthesis of acarbose and validamycin,” Chemical Records, vol. 1, no. 4, pp. 300–310, 2001.

K. Arakawa, S. G. Bowers, B. Michels, V. Trin, and T. Mahmud, “Biosynthetic studies on the α-glucosidase inhibitor acarbose: the chemical synthesis of isotopically labeled 2-epi-5-epi-valiolone analogs,” Carbohydrate Research, vol. 338, no. 20, pp. 2075–2082, 2003.

T. Mahmud, I. Tornus, E. Egelkrout et al., “Biosynthetic studies on the α-glucosidase inhibitor acarbose in Actinoplanes sp.: 2-epi-5-epi-valiolone is the direct precursor of the valienamine moiety,” Journal of the American Chemical Society, vol. 121, no. 30, pp. 6973–6983, 1999.

A. M. Coghill and L. R. Garson, Eds., The ACS Style Guide: Effective Communication of Scientific Diphosphates Information, American Chemical Society, Washington, DC, USA, 3rd edition, 2006.

Q. Cui, W. S. Shin, Y. Luo, J. Tian, H. Cui, and D. Yin, “Thymidylate kinase: an old topic brings new perspectives,” Current Medicinal Chemistry, vol. 20, no. 10, pp. 1286–1305, 2013.

S. Lee, B. Sauerbrei, J. Niggemann, and E. Egelkrout, “Biosynthetic studies on the α-glucosidase inhibitor acarbose in Actinoplanes sp.: source of the maltose unit,” The Journal of Antibiotics, vol. 50, no. 11, pp. 954–960, 1997.

S. G. Bowers, T. Mahmud, and H. G. Floss, “Biosynthetic studies on the α-glucosidase inhibitor acarbose: the chemical synthesis of dTDP-4-amino-4,6-dideoxy-α-D-glucose,” Carbohydrate Research, vol. 337, no. 4, pp. 297–304, 2002.

U. F. Wehmeier and W. Piepersberg, “Enzymology of aminoglycoside biosynthesis-deduction from gene cluster,” in Complex Enzymes in Microbial Natural Products Biosynthesis. Part B.: Polyketides, Aminocoumarins and Carbohydrates, D. A. Howood, Ed., vol. 459 of Methods in Enzymology, chapter 19, p. 479, Elsevier, 2009.

H. Lodish, A. Berk, Ch. Kaiser et al., “Genes, genomics and chromosomes,” in Molecular Cell Biology, pp. 227–230, Freeman, 7th edition, 2013.

G. Yi, S.-H. Sze, and M. R. Thon, “Identifying clusters of functionally related genes in genomes,” Bioinformatics, vol. 23, no. 9, pp. 1053–1060, 2007.

R. Overbeek, M. Fonstein, M. D'Souza, G. D. Push, and N. Maltsev, “The use of gene clusters to infer functional coupling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 6, pp. 2896–2901, 1999.

J. Yang, H. Xu, Y. Zhang, L. Bai, Z. Deng, and T. Mahmud, “Nucleotidylation of unsaturated carbasugar in validamycin biosynthesis,” Organic and Biomolecular Chemistry, vol. 9, no. 2, pp. 438–449, 2011.

Ch.-S. Zhang, M. Podeschwa, O. Block, H.-J. Altenbach, W. Piepersberg, and U. F. Wehmeier, “Identification of a 1-epi-vañienol 7-kinase activity in the producer of acarbose, Actinoplanes sp. SE50/110,” FEBS Letters, vol. 540, no. 1–3, pp. 53–57, 2003.

C.-S. Zhang, A. Stratmann, O. Block et al., “Biosynthesis of the C7-cyclitol moiety of acarbose in Actinoplanes species SE50/110. 7-O-phosphorylation of the initial cyclitol precursor leads to proposal of a new biosynthetic pathway,” The Journal of Biological Chemistry, vol. 277, no. 25, pp. 22853–22862, 2002.

A. Stratmann, T. Mahmud, S. Lee, J. Distler, H. G. Floss, and W. Piepersberg, “The AcbC protein from Actinoplanes species is a C7-cyclitol synthase related to 3-dehydroquinate synthases and is involved in the biosynthesis of the α-glucosidase inhibitor acarbose,” Journal of Biological Chemistry, vol. 274, no. 16, pp. 10889–10896, 1999.

S. Wendler, V. Ortseifen, M. Persicke et al., “Carbon source dependent biosynthesis of acarviose metabolites in Actinoplanes sp. SE50/110,” Journal of Biotechnology, vol. 191, pp. 113–120, 2014.

D. E. Metzler, Biochemistry. The Chemical Reactions of Living Cells, vol. 1, Elsevier, 2nd edition, 2003.

P. M. Flatt, X. Wu, S. Perry, and T. Mahmud, “Genetic insights into pyralomicin biosynthesis in Nonomuraea spiralis IMC A-0156,” Journal of Natural Products, vol. 76, no. 5, pp. 939–946, 2013.

D. Schwarzer, R. Finking, and M. A. Marahiel, “Nonribosomal peptides: from genes to products,” Natural Product Reports, vol. 20, no. 3, pp. 275–287, 2003.

M. A. Marahiel, T. Stachelhaus, and H. D. Mootz, “Modular peptide synthetases involved in nonribosomal peptide synthesis,” Chemical Reviews, vol. 97, no. 7, pp. 2651–2673, 1997.

C. Khosla, R. S. Gokhale, J. R. Jacobsen, and D. E. Cane, “Tolerance and specificity of polyketide synthases,” Annual Review of Biochemistry, vol. 68, pp. 219–253, 1999.

H. Jenke-Kodama, A. Sandmann, R. Müller, and E. Dittmann, “Evolutionary implications of bacterial polyketide synthases,” Molecular Biology and Evolution, vol. 22, no. 10, pp. 2027–2039, 2005.

H. Lodish, L. Zipursky, P. B. Matsudaira, D. David, and J. Darnel, Molecular Definition of a Gene—Molecular Cell Biology, W. H. Freeman, San Francisco, Calif, USA, 2000.

G. J. Williams, “Engineering polyketide synthases and nonribosomal peptide synthetases,” Current Opinion in Structural Biology, vol. 23, no. 4, pp. 603–612, 2003.

C. R. Hutchinson, “Polyketide and non-ribosomal peptide synthases: falling together by coming apart,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 6, pp. 3010–3012, 2003.

M. E. Horsman, T. P. A. Hari, and Ch. N. Boddy, “Polyketide synthase and non-ribosomal peptide synthetase thioesterase selectivity: logic gate or a victim of fate?” Natural Product Reports, vol. 33, no. 2, pp. 183–202, 2016.

D. R. M. Smith, S. Grüschow, and R. J. Goss, “Scope and potential of halogenases in biosynthetic applications,” Current Opinion in Chemical Biology, vol. 17, no. 2, pp. 276–283, 2013.

T. Bureau, K. C. Lam, R. K. Ibrahim, B. Behdad, and S. Dayanandan, “Structure, function, and evolution of plant O-methyltransferases,” Genome, vol. 50, no. 11, pp. 1001–1013, 2007.

S. Singh, G. N. Phillips Jr., and J. S. Thorson, “The structural biology of enzymes involved in natural product glycosylation,” Natural Product Reports, vol. 29, no. 10, pp. 1201–1237, 2012.

A. Chang, S. Singh, G. N. Phillips, and J. S. Thorson, “Glycosyltransferase structural biology and its role in the design of catalysts for glycosylation,” Current Opinion in Biotechnology, vol. 22, no. 6, pp. 800–808, 2011.

H. Nothaft and C. M. Szymanski, “Protein glycosylation in bacteria: sweeter than ever,” Nature Reviews Microbiology, vol. 8, no. 11, pp. 765–778, 2010.

D. Calo, L. Kaminski, and J. Eichler, “Protein glycosylation in Archaea: sweet and extreme,” Glycobiology, vol. 20, no. 9, pp. 1065–1076, 2010.

W. S. Choi, X. Wu, Y.-H. Choeng et al., “Genetic organization of the putative salbostatin biosynthetic gene cluster including the 2-epi-5-epi-valiolone synthase gene in Streptomyces albus ATCC 21838,” Applied Microbiology and Biotechnology, vol. 80, no. 4, pp. 637–645, 2008.

G. E. McCasland, S. Furuta, and L. J. Durham, “Alicyclic carbohydrates. XXIX. The synthesis of a pseudo-hexose (2,3,4,5-tetrahydroxycyclohexanemethanol),” Journal of Organic Chemistry, vol. 31, no. 5, pp. 1516–1521, 1966.

T. Suami, S. Ogawa, M. Takata et al., “Synthesis of sweet tasting pseudo-β-fructopyranose,” Chemistry Letters, vol. 14, no. 6, pp. 719–722, 1985.

T. Suami, S. Ogawa, M. Takata, K. Yasuda, K. Takei, and A. Suga, “Pseudo-sugars. XIV. Synthesis of sweet-tasting pseudo-β-DL-fructopyranose,” Bulletin of the Chemical Society of Japan, vol. 59, no. 3, pp. 819–821, 1986.

S. Ogawa, Y. Uematsu, and S. Yoshida, “Synthesis and sweetness of pseudo-β-D and L-fructopyranose,” Journal of Carbohydrate Chemistry, vol. 6, no. 3, pp. 471–478, 1987.

J. M. Berg, J. L. Tymoczko, and L. Stryer, Biochemistry, chapter 8, section 8.5, Freeman, 5th edition, 2002.

U. Etxeberria, A. L. de la Garza, J. Campión, J. A. Martínez, and F. I. Milagro, “Antidiabetic effects of natural plant extracts via inhibition of carbohydrate hydrolysis enzymes with emphasis on pancreatic alpha amylase,” Expert Opinion on Therapeutic Targets, vol. 16, no. 3, pp. 269–297, 2012.

R. J. Parry, M. R. Burns, P. N. Skae, J. C. Hoyt, and B. Pal, “Carbocyclic analogues of D-ribose-5-phosphate: synthesis and behavior with 5-phosphoribosyl α-1-pyrophosphate synthetases,” Bioorganic and Medicinal Chemistry, vol. 4, no. 7, pp. 1077–1088, 1996.

J. H. Kim, D. Wolle, K. Haridas, R. J. Parry, J. L. Smith, and H. Zalkin, “A stable carbocyclic analog of 5-phosphoribosyl-1-pyrophosphate to probe the mechanism of catalysis and regulation of glutamine phosphoribosylpyrophosphate amidotransferase,” The Journal of Biological Chemistry, vol. 270, no. 29, pp. 17394–17399, 1995.

R. J. Parry and K. Haridas, “Synthesis of 1α-Pyrophosphoryl-2α,3α-dihydroxy-4β-cyclopentanemethanol-5-phosphate, a Carbocyclic Analog of 5-Phosphoribosyl-1-pyrophosphate (PRPP),” Tetrahedron Letters, vol. 34, no. 44, pp. 7013–7016, 1993.

J. A. Duley, J. Christodoulou, and A. P. M. de Brouwer, “The PRPP synthetase spectrum: what does it demonstrate about nucleotide syndromes?” Nucleosides, Nucleotides & Nucleic Acids, vol. 30, no. 12, pp. 1129–1139, 2011.

M. Tatibana, K. Kita, M. Taira et al., “Mammalian phosphoribosyl-pyrophosphate synthetase,” Advances in Enzyme Regulation, vol. 35, pp. 229–249, 1995.

S. Fujimori, “Genetic bases of gout and hyperuricemia. I. PRPP synthetase superactivity,” in Genetic Errors Associated with Purine and Pyrimidine Metabolism in Humans: Diagnosis and Treatment, Y. Moriwaki and T. Yamamoto, Eds., pp. 6–14, Research Signpost, Thiruvananthapuram, India, 2006.

United States Food, Drug Administration, and Guidance for Industry, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling, Clinical Pharmacology, 2006.

M. A. Becker, P. R. Smith, W. Taylor, R. Mustafi, and R. L. Switzer, “The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity,” Journal of Clinical Investigation, vol. 96, no. 5, pp. 2133–2141, 1995.

S. Mazurek, C. B. Boschek, and E. Eigenbrodt, “The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy,” Journal of Bioenergetics and Biomembranes, vol. 29, no. 4, pp. 315–330, 1997.

M. Sunamura, M. Oonuma, F. Motoi et al., “Gene therapy for pancreatic cancer targeting the genomic alterations of tumor suppressor genes using replication-selective oncolytic adenovirus,” Human Cell, vol. 15, no. 3, pp. 138–150, 2002.

J. R. K. Cairns and A. Esen, “β-Glucosidases,” Cellular and Molecular Life Sciences, vol. 67, no. 20, pp. 3389–3405, 2010.

K. Tatsuta, “Total synthesis and chemical design of useful glycosidase inhibitors,” in Carbohydrate Mimics, Y. Chapleur, Ed., pp. 283–305, John Wiley & Sons, New York, NY, USA, 1998.

W. W. Kallemeijn, M. D. Witte, T. Wennekes, and J. M. F. G. Aerts, “Mechanism-based inhibitors of glycosidases: design and applications,” Advances in Carbohydrate Chemistry and Biochemistry, vol. 71, pp. 297–338, 2014.

S. Atsumi, H. Iinuma, C. Nosaka, and K. Umezawa, “Biological activities of cyclophellitol,” The Journal of Antibiotics, vol. 43, no. 12, pp. 1579–1585, 1990.

S. Pengthaisong, C.-F. Chen, S. G. Withers, B. Kuaprasert, and J. R. Ketudat Cairns, “Rice BGlu1 glycosynthase and wild type transglycosylation activities distinguished by cyclophellitol inhibition,” Carbohydrate Research, vol. 352, pp. 51–59, 2012.

T. M. Gloster, R. Madsen, and G. J. Davies, “Structural basis for cyclophellitol inhibition of a β-glucosidase,” Organic & Biomolecular Chemistry, vol. 5, no. 3, pp. 444–446, 2007.

M. Nakata, C. Chong, Y. Niwata, K. Toshima, and K. Tatsuta, “A family of cyclophellitol analogs: synthesis and evaluation,” Journal of Antibiotics, vol. 46, no. 12, pp. 1919–1922, 1993.

V. W.-F. Tai, P.-H. Fung, Y.-S. Wong, and T. K. M. Shing, “Synthesis and glycosidase-inhibitory activity of cyclophellitol analogues,” Tetrahedron: Asymmetry, vol. 5, no. 7, pp. 1353–1362, 1994.

V. W.-F. Tai, P.-H. Fung, Y.-S. Wong, and T. K. M. Shing, “Kinetic studies on cyclophellitol analogues—mechanism-based inactivators,” Biochemical and Biophysical Research Communications, vol. 213, no. 1, pp. 175–180, 1995.

K.-Y. Li, J. Jiang, M. D. Witte et al., “Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors,” Organic & Biomolecular Chemistry, vol. 12, no. 39, pp. 7786–7791, 2014.

K. Tatsuta, Y. Niwata, K. Umezawa, K. Toshima, and M. Nakata, “Enantiospecific synthesis and biological evaluation of 1,6-epi-cyclophellitol,” Journal of Antibiotics, vol. 44, no. 4, pp. 456–458, 1991.

S. Atsumi, C. Nosaka, Y. Ochi, H. Iinuma, and K. Umezawa, “Inhibition of experimental metastasis by an α-glucosidase inhibitor, 1,6-epi-cyclophellitol,” Cancer Research, vol. 53, no. 20, pp. 4896–4899, 1993.

W. W. Kallemeijn, K.-Y. Li, M. D. Witte et al., “Novel activity-based probes for broad-spectrum profiling of retaining β-exoglucosidases in situ and in vivo,” Angewandte Chemie—International Edition, vol. 51, no. 50, pp. 12529–12533, 2012.

K.-Y. Li, J. Jiang, M. D. Witte et al., “Synthesis of cyclophellitol, cyclophellitol aziridine, and their tagged derivatives,” European Journal of Organic Chemistry, vol. 2014, no. 27, pp. 6030–6043, 2014.

L. I. Willems, T. J. M. Beenakker, B. Murray et al., “Synthesis of α- and β-galactopyranose-configured isomers of cyclophellitol and cyclophellitol aziridine,” European Journal of Organic Chemistry, vol. 2014, no. 27, pp. 6044–6056, 2014.

J. Jiang, T. J. M. Beenakker, W. W. Kallemeijn et al., “Comparing cyclophellitol N-alkyl and N-acyl cyclophellitol aziridines as activity-based glycosidase probes,” Chemistry, vol. 21, no. 30, pp. 10861–10869, 2015.

T. Suami and S. Ogawa, “Chemistry of carba-sugars (pseudo-sugars) and their derivatives,” Advances in Carbohydrate Chemistry and Biochemistry, vol. 48, pp. 21–90, 1990.

K. Kamata, M. Mitsuya, T. Nishimura, J.-I. Eiki, and Y. Nagata, “Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase,” Structure, vol. 12, no. 3, pp. 429–438, 2004.

C. Postic, M. Shiota, and M. A. Magnuson, “Cell-specific roles of glucokinase in glucose homeostasis,” Recent Progress in Hormone Research, vol. 56, pp. 195–217, 2001.

I. Miwa, H. Hara, J. Okuda, T. Suami, and S. Ogawa, “Inhibition of glucose-stimulated insulin release by pseudo-α- DL-glucose as a glucokinase inhibitor,” Biochemistry International, vol. 11, no. 6, pp. 809–816, 1985.

M. Kitaoka, S. Ogawa, and H. Taniguchi, “A cellobiose phosphorylase from Cellvibrio gilvus recognizes only the β-d-form of 5a-carba-glucopyranose,” Carbohydrate Research, vol. 247, pp. 355–359, 1993.

Y. Sugimoto, H. Suzuki, H. Yamaki, T. Nishimura, and N. Tanaka, “Mechanism of action of 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone, a SH inhibitory antitumor antibiotic, and its effect on drug-resistant neoplastic cells,” Journal of Antibiotics, vol. 35, no. 9, pp. 1222–1230, 1982.

C. F. M. Huntley, D. S. Hamilton, D. J. Creighton, and B. Ganem, “Reaction of COTC with glutathione: structure of the putative glyoxalase I inhibitor,” Organic Letters, vol. 2, no. 20, pp. 3143–3144, 2000.

D. Kamiya, Y. Uchihata, E. Ichikawa, K. Kato, and K. Umezawa, “Reversal of anticancer drug resistance by COTC based on intracellular glutathione and glyoxalase I,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 4, pp. 1111–1114, 2005.

F. Collu, L. Bonsignore, M. Casu, C. Floris, J. Gertsch, and F. Cottiglia, “New cytotoxic saturated and unsaturated cyclohexanones from Anthemis maritima,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 5, pp. 1559–1562, 2008.

E. Joseph, J. L. Eiseman, D. S. Hamilton et al., “Molecular basis of the antitumor activities of 2-crotonyloxymethyl-2-cycloalkenones,” Journal of Medicinal Chemistry, vol. 46, no. 1, pp. 194–196, 2003.

P. J. Thornalley, “Glyoxalase I—structure, function and a critical role in the enzymatic defence against glycation,” Biochemical Society Transactions, vol. 31, no. 6, pp. 1343–1348, 2003.

D. J. Creighton and D. S. Hamilton, “Brief history of glyoxalase I and what we have learned about metal ion-dependent, enzyme-catalyzed isomerizations,” Archives of Biochemistry and Biophysics, vol. 387, no. 1, pp. 1–10, 2001.

S. Mirza, L.-P. Molleyres, and A. Vasella, “Synthesis of a glyoxalase I inhibitor from Streptomyces griseosporeus Niida et Ogasawara,” Helvetica Chimica Acta, vol. 68, no. 4, pp. 988–996, 1985.

H. Takayama, K. Hayashi, and T. Koizumi, “Enantioselective total synthesis of Glyoxalase I inhibitor using asymmetric Diels-Alder reaction of a new chiral dienophile, (S)S-3-(3-triflouromethylpyrid-2-ylsulfinyl)acrylate,” Tetrahedron Letters, vol. 27, no. 45, pp. 5509–5512, 1986.

T. K. M. Shing and Y. Tang, “Enantiospecific synthesis of 2-crotonyloxy-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC) from quinic acid,” Journal of the Chemical Society, Chemical Communications, no. 4, p. 312, 1990.

C. F. M. Huntley, H. B. Wood, and B. Ganem, “A new synthesis of the glyoxalase-I inhibitor COTC,” Tetrahedron Letters, vol. 41, no. 13, pp. 2031–2034, 2000.

C. L. Arthurs, N. S. Wind, R. C. Whitehead, and I. J. Stratford, “Analogues of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC) with anti-tumor properties,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 2, pp. 553–557, 2007.

C. L. Arthurs, J. Raftery, H. L. Whitby, R. C. Whitehead, N. S. Wind, and I. J. Stratford, “Arene cis-dihydrodiols: useful precursors for the preparation of analogues of the anti-tumour agent, 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC),” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 21, pp. 5974–5977, 2007.

C. L. Arthurs, G. A. Morris, M. Piacenti et al., “The synthesis of 2-oxyalkyl-cyclohex-2-enones, related to the bioactive natural products COTC and antheminone A, which possess anti-tumour properties,” Tetrahedron, vol. 66, no. 46, pp. 9049–9060, 2010.

T. K. M. Shing, H. T. Wu, H. F. Kwok, and C. B. S. Lau, “Synthesis of chiral hydroxylated enones as potential anti-tumor agents,” Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 24, pp. 7562–7565, 2012.

C. L. Arthurs, K. F. Lingley, M. Piacenti et al., “(-)-Quinic acid: a versatile precursor for the synthesis of analogues of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC) which possess anti-tumour properties,” Tetrahedron Letters, vol. 49, no. 15, pp. 2410–2413, 2008.

P. M. Dowling, “Aminoglycosides and aminocyclitols,” in Antimicrobial Therapy in Veterinary Medicine, S. Giguère, J. F. Prescott, and P. M. Dowling, Eds., chapter 14, pp. 233–255, John Wiley & Sons, Hoboken, NJ, USA, 5th edition, 2013.

F. Kudo and T. Eguchi, “Aminoglycoside antibiotics: new insights into the biosynthetic machinery of old drugs,” The Chemical Record, vol. 16, no. 1, pp. 4–18, 2016.

N. M. Llewellyn and J. B. Spencer, “Biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics,” Natural Product Reports, vol. 23, no. 6, pp. 864–874, 2006.

E. Nango, T. Eguchi, and K. Kakinuma, “Active site mapping of 2-deoxy-scyllo-inosose synthase, the key starter enzyme for the biosynthesis of 2-deoxystreptamine. Mechanism-based inhibition and identification of lysine-141 as the entrapped nucleophile,” Journal of Organic Chemistry, vol. 69, no. 3, pp. 593–600, 2004.

D. Dykes and W. Waud, “Murine L1210 and P388 leukemias,” in Tumor Models in Cancer Research, B. Teicher, Ed., pp. 23–40, Humana Press, 2002.

A. Numata, M. Iritani, T. Yamada et al., “Novel antitumour metabolites produced by a fungal strain from a sea hare,” Tetrahedron Letters, vol. 38, no. 47, pp. 8215–8218, 1997.

R. S. Herbst, “Review of epidermal growth factor receptor biology,” International Journal of Radiation Oncology Biology Physics, vol. 59, no. 2, pp. 21–26, 2004.

J. J. Chanpoux, “DNA topoisomerases: structure, function, and mechanism,” Annual Review of Biochemistry, vol. 70, pp. 369–413, 2001.

G. Bach, S. Breiding-Mack, S. Grabley et al., “Secondary metabolites by chemical screening. 22. Gabosines, new carba-sugars from Streptomyces,” Liebigs Annalen der Chemie, pp. 241–250, 1993.

N. B. Javitt, “Hep G2 cells as a resource for metabolic studies: lipoprotein, cholesterol, and bile acids,” The FASEB Journal, vol. 4, no. 2, pp. 161–168, 1990.

Y.-Q. Tang, C. Maul, R. Höfs et al., “Gabosines L, N and O: new carba-sugars from streptomyces with DNA-binding properties,” European Journal of Organic Chemistry, no. 1, pp. 149–153, 2000.

A. Maier, C. Maul, M. Zerlin, S. Grabley, and R. Thiericke, “Biomolecular-chemical screening. A novel screening approach for the discovery of biologically active secondary metabolites. II. Application studies with pure metabolites,” The Journal of Antibiotics, vol. 52, no. 11, pp. 952–959, 1999.

K. Tatsuta, T. Tsuchiya, N. Mikami, S. Umezawa, H. Umezawa, and H. Naganawa, “KD16 U1, a new metabolite of Streptomyces. Isolation and structural studies,” Journal of Antibiotics, vol. 27, no. 8, pp. 579–586, 1974.

B. Winchester, “Role of α-D-mannosidases in the biosynthesis and catabolism of glycoproteins,” Biochemical Society Transactions, vol. 12, no. 3, pp. 522–524, 1984.

A. Vidyasagar and K. M. Sureshan, “Total synthesis and glycosidase inhibition studies of (-)-gabosine J and its derivatives,” European Journal of Organic Chemistry, vol. 2014, no. 11, pp. 2349–2356, 2014.

O. F. Smetanina, A. I. Kalinovskii, Y. V. Khudyakov et al., “Metabolites of the marine fungus Asperigillus varians KMM 4630,” Chemistry of Natural Compounds, vol. 41, no. 2, pp. 243–244, 2005.

K. Trisuwan, V. Rukachaisirikul, Y. Sukpondma et al., “Epoxydons and a pyrone from the marine-derived fungus Nigrospora sp. PSU-F5,” Journal of Natural Products, vol. 71, no. 8, pp. 1323–1326, 2008.

S. Qin, H. Hussain, B. Schulz, S. Draeger, and K. Krohn, “Two new metabolites, epoxydine A and B, from Phoma sp.,” Helvetica Chimica Acta, vol. 93, no. 1, pp. 169–174, 2010.

H. Kakeya, Y. Miyake, M. Shoji et al., “Novel non-peptide inhibitors targeting death receptor-mediated apoptosis,” Bioorganic & Medicinal Chemistry Letters, vol. 13, no. 21, pp. 3743–3746, 2003.

T. Mitsui, Y. Miyake, H. Kakeya, Y. Hayashi, H. Osada, and T. Kataoka, “RKTS-33, an epoxycyclohexenone derivative that specifically inhibits Fas ligand-dependent apoptosis in CTL-mediated cytotoxicity,” Bioscience, Biotechnology and Biochemistry, vol. 69, no. 10, pp. 1923–1928, 2005.

T. D. Gilmore, “Introduction to NF-κB: players, pathways, perspectives,” Oncogene, vol. 25, no. 51, pp. 6680–6684, 2006.

A. R. Brasier, “The NF-κB regulatory network,” Cardiovascular Toxicology, vol. 6, no. 2, pp. 111–130, 2006.

T. Saitoh, E. Suzuki, A. Takasugi et al., “Efficient synthesis of (±)-parasitenone, a novel inhibitor of NF-κB,” Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 18, pp. 5383–5386, 2009.

C.-H. Wang, H. T. Wu, H. M. Cheng et al., “Inhibition of glutathione S-Transferase M1 by new gabosine analogues is essential for overcoming cisplatin resistance in lung cancer cells,” Journal of Medicinal Chemistry, vol. 54, no. 24, pp. 8574–8581, 2011.

D. J. Giard, S. A. Aaronson, G. J. Todaro et al., “In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors,” Journal of the National Cancer Institute, vol. 51, no. 5, pp. 1417–1423, 1973.

L. S. Engel, E. Taioli, R. Pfeiffer et al., “Pooled analysis and meta-analysis of glutathione S-transferase M1 and bladder cancer: a HuGE review,” American Journal of Epidemiology, vol. 156, no. 2, pp. 95–109, 2002.

S. Ogawa, H. Aoyama, and T. Sato, “Synthesis of an ether-linked alkyl 5a-carba-β-D-glucoside, a 5a-carba-β-D-galactoside, a 2-acetamido-2-deoxy-5a-carba-β-D-glucoside, and an alkyl 5a′-carba-β-lactoside,” Carbohydrate Research, vol. 337, no. 21–23, pp. 1979–1992, 2002.

J. C. Becker, R. Houben, D. Schrama, H. Voigt, S. Ugurel, and R. A. Reisfeld, “Mouse models for melanoma: a personal perspective,” Experimental Dermatology, vol. 19, no. 2, pp. 157–164, 2010.

L. N. David and M. C. Michael, Lipids. Lehninger Principles of Biochemistry, W H Freeman, 4th edition, 2005.

I. Mocchetti, “Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophins,” Cellular and Molecular Life Sciences, vol. 62, no. 19-20, pp. 2283–2294, 2005.

V. Jeanneret, P. Vogel, P. Renaut, J. Millet, J. Theveniaux, and V. Barberousse, “Carbaxylosides of 4-ethyl-2-oxo-2H-benzopyran-7-yl as non-hydrolyzable, orally active venous antithrombotic agents,” Bioorganic and Medicinal Chemistry Letters, vol. 8, no. 13, pp. 1687–1688, 1998.

M. Lefoix, A. Tatibouët, S. Cottaz, H. Driguez, and P. Rollin, “Carba-glucotropaeolin: the first non-hydrolyzable glucosinolate analogue, to inhibit myrosinase,” Tetrahedron Letters, vol. 43, no. 16, pp. 2889–2890, 2002.

B. A. Halkier and J. Gershenzon, “Biology and biochemistry of glucosinolates,” Annual Review of Plant Biology, vol. 57, pp. 303–333, 2006.

H. Yuasa, M. M. Palcic, and O. Hindsgaul, “Synthesis of the carbocyclic analog of uridine 5′-(α-D-galactopyranosyl diphosphate) (UDP-gal) as an inhibitor of β(1→4)-galactosyltransferase,” Canadian Journal of Chemistry, vol. 73, no. 12, pp. 2190–2195, 1995.

S. Cai, M. R. Stroud, S. Hakomori, and T. Toyokuni, “Synthesis of carbocyclic analogs of guanosine 5′-(β-L-fucopyranosyl diphosphate) (GDP-fucose) as potential inhibitors of fucosyltransferases,” The Journal of Organic Chemistry, vol. 57, no. 25, pp. 6693–6696, 1992.

A. J. Norris, J. P. Whitelegge, M. J. Strouse, K. F. Faull, and T. Toyokuni, “Inhibition kinetics of carba- and C-fucosyl analogues of GDP-fucose against fucosyltransferase V: implication for the reaction mechanism,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 3, pp. 571–573, 2004.

L. Díaz and A. Delgado, “Medicinal chemistry of aminocyclitols,” Current Medicinal Chemistry, vol. 17, no. 22, pp. 2393–2418, 2010.

S. Ogawa and M. Kanto, “Design and synthesis of 5a-carbaglycopyranosylamime glycosidase inhibitors,” Current Topics in Medicinal Chemistry, vol. 9, no. 1, pp. 58–75, 2009.

X. Chen, Y. Fan, Y. Zheng, and Y. Shen, “Properties and production of valienamine and its related analogues,” Chemical Reviews, vol. 103, no. 5, pp. 1955–1977, 2003.

J.-F. Zhang, Y.-G. Zheng, and Y.-C. Shen, “Inhibitory effect of valienamine on the enzymatic activity of honeybee (Apis cerana Fabr.) α-glucosidase,” Pesticide Biochemistry and Physiology, vol. 87, no. 1, pp. 73–77, 2007.

Y.-G. Zheng, X.-P. Shentu, and Y.-C. Shen, “Inhibition of porcine small intestinal sucrase by valienamine,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 20, no. 1, pp. 49–53, 2005.

Y.-P. Xue, L.-Q. Jin, Z.-Q. Liu, J.-F. Zhang, and Y.-G. Zheng, “Purification and characterization of β-glucosidase from Reticulitermes flaviceps and its inhibition by valienamine and validamine,” African Journal of Biotechnology, vol. 7, no. 24, pp. 4595–4601, 2008.

Y. Zheng, X. Shentu, and Y. Shen, “Inhibition of porcine small intestinal sucrase by validamine,” Chinese Journal of Chemical Engineering, vol. 13, no. 3, pp. 429–432, 2005.

S. Ogawa, M. Oya, T. Toyokuni, N. Chida, and T. Suami, “Pseudo-sugars. VIII. Synthesis of DL-1-epivalidamine and related compounds,” Bulletin of the Chemical Society of Japan, vol. 56, no. 5, pp. 1441–1445, 1983.

S. Ogawa, M. Suzuki, and T. Tonegawa, “New synthesis of Penta-N,O-acetyl-DL-validamine and pseudo-2-amino-2-deoxy-α-DL-mannopyranose, and their uronate analogs,” Bulletin of the Chemical Society of Japan, vol. 61, no. 5, pp. 1824–1826, 1988.

Y. Kameda, K. Kawashima, M. Takeuchi, K. Ikeda, N. Asano, and K. Matsui, “Preparation and biological activity of manno- and galacto-validamines, new 5a-carba-glycosylamines as α-glycosidase inhibitors,” Carbohydrate Research, vol. 300, no. 3, pp. 259–264, 1997.

Y. Kameda, N. Asano, M. Yoshikawa et al., “Valiolamine, a new α-glucosidase inhibiting aminocyclitol. produced by Streptomyces hygroscopicus,” Journal of Antibiotics, vol. 37, no. 11, pp. 1301–1307, 1984.

S. Horii, H. Fukase, T. Matsuo, Y. Kameda, N. Asano, and K. Matsui, “Synthesis and α-D-glucosidase inhibitory activity of N-substituted valiolamine derivatives as potential oral antidiabetic agents,” Journal of Medicinal Chemistry, vol. 29, no. 6, pp. 1038–1046, 1986.

X. Chen, Y. Zheng, and Y. Shen, “Voglibose (Basen®, AO-128), one of the most important α-glucosidase inhibitors,” Current Medicinal Chemistry, vol. 13, no. 1, pp. 109–116, 2006.

A. S. Dabhi, N. R. Bhatt, and M. J. Shah, “Voglibose: an alpha glucosidase inhibitor,” Journal of Clinical and Diagnostic Research, vol. 7, no. 12, pp. 3023–3027, 2013.

H. Konya, T. Katsuno, T. Tsunoda et al., “Effects of combination therapy with mitiglinide and voglibose on postprandial plasma glucose in patients with type 2 diabetes mellitus,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. 6, pp. 317–325, 2013.

V. L. Campo, V. Aragão-Leoneti, and I. Carvalho, “Glycosidases and diabetes: metabolic changes, mode of action and therapeutic perspectives,” Carbohydrate Chemistry, vol. 39, pp. 181–203, 2013.

G. Derosa and P. Maffioli, “α-Glucosidase inhibitors and their use in clinical practice,” Archives of Medical Science, vol. 8, no. 5, pp. 899–906, 2012.

B.-H. Bin, J. Seo, S. H. Yang et al., “Novel inhibitory effect of the antidiabetic drug voglibose on melanogenesis,” Experimental Dermatology, vol. 22, no. 8, pp. 541–546, 2013.

O. Lockhoff, “Glycolipids as immunomodulators: syntheses and properties,” Angewandte Chemie—International Edition in English, vol. 30, no. 12, pp. 1611–1620, 1991.

H. Tsunoda, S.-I. Sasaki, T. Furuya, and S. Ogawa, “Pseudosugars, 36: synthesis of methyl 5′-carbamaltoses linked by imino, ether and sulfide bridges and unsaturated derivatives thereof,” Liebigs Annales, no. 2, pp. 159–165, 1996.

C. Ramstadius, O. Hekmat, L. Eriksson, H. Stålbrand, and I. Cumpstey, “β-Mannosidase and β-hexosaminidase inhibitors: synthesis of 1,2-bis-epi-valienamine and 1-epi-2-acetamido-2-deoxy-valienamine from d-mannose,” Tetrahedron Asymmetry, vol. 20, no. 6–8, pp. 795–807, 2009.

A. Scaffidi, K. A. Stubbs, R. J. Dennis et al., “A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of β-N-acetylglucosaminidases,” Organic and Biomolecular Chemistry, vol. 5, no. 18, pp. 3013–3019, 2007.

Y. Z. Frohwein and S. Gatt, “Isolation of β-N-acetylhexosaminidase, β-N-acetylglucosaminidase, and β-N-acetylgalactosaminidase from calf brain,” Biochemistry, vol. 6, no. 9, pp. 2775–2782, 1967.

S. C. Li and Y. T. Li, “Studies on the glycosidases of jack bean meal. 3. Crystallization and properties of beta-N-acetylhexosaminidase,” The Journal of Biological Chemistry, vol. 245, no. 19, pp. 5153–5160, 1970.

T. Liu, L. Chen, Q. Ma, X. Shen, and Q. Yang, “Structural insights into chitinolytic enzymes and inhibition mechanisms of selective inhibitors,” Current Pharmaceutical Design, vol. 20, no. 5, pp. 754–770, 2014.

H. Tsunoda and S. Ogawa, “Pseudosugars, 33. Synthesis of some 5a-carbaglycosylamides, glycolipid analogs of biological interests,” Liebigs Annalen der Chemie, no. 2, pp. 103–107, 1994.

H. Tsunoda, J.-I. Inokuchi, K. Yamagishi, and S. Ogawa, “Pseudosugars, 35. Synthesis of glycosylceramide analogs composed of imino-linked unsaturated 5a-carbaglycosyl residues: potent and specific gluco- and galactocerebrosidase inhibitors,” Liebigs Annalen, no. 2, pp. 279–284, 1995.

S. Ogawa, M. Ashiuraa, C. Uchida et al., “Synthesis of potent β-D-glucocerebrosidase inhibitors: N-alkyl-β-valienamines,” Bioorganic and Medicinal Chemistry Letters, vol. 6, no. 8, pp. 929–932, 1996.

S. Ogawa, T. Mito, E. Taiji, M. Jimbo, K. Yamagishi, and J.-I. Inokuchi, “Synthesis and biological evaluation of four stereoisomers of PDMP-analogue, N-(2-decylamino-3-hydroxy-3-phenylprop- 1-yl)-β-valienamine, and related compounds,” Bioorganic and Medicinal Chemistry Letters, vol. 7, no. 14, pp. 1915–1920, 1997.

S. Ogawa, Y. Kobayashi, K. Kabayama, M. Jimbo, and J.-I. Inokuchi, “Chemical modification of β-glucocerebrosidase inhibitor N-octyl-β-valienamine: synthesis and biological evaluation of N-alkanoyl and N-alkyl derivatives,” Bioorganic and Medicinal Chemistry, vol. 6, no. 10, pp. 1955–1962, 1998.

S. Horii, H. Fukase, T. Matsuo, Y. Kameda, N. Asano, and K. Matsui, “Synthesis and α-D-glucosidase inhibitory activity of N-substituted valiolamine derivatives as potential oral antidiabetic agents,” Journal of Medicinal Chemistry, vol. 29, no. 6, pp. 1038–1046, 1986.

Y. Kameda, N. Asano, M. Yoshikawa, K. Matsui, S. Horii, and H. Fukase, “N-substituted valienamines, α-glucosidase inhibitors,” Journal of Antibiotics, vol. 35, no. 11, pp. 1624–1626, 1982.

R. Łysek, C. Schütz, S. Favre et al., “Search for &-glucosidase inhibitors: new N-substituted valienamine and conduramine F-1 derivatives,” Bioorganic and Medicinal Chemistry, vol. 14, no. 18, pp. 6255–6282, 2006.

P. Kapferer, V. Birault, J.-F. Poisson, and A. Vasella, “Synthesis and evaluation as glycosidase inhibitors of carbasugar-derived spirodiaziridines, spirodiazirines, and spiroaziridines,” Helvetica Chimica Acta, vol. 86, no. 6, pp. 2210–2227, 2003.

Y. Wang and A. J. Bennet, “A potent bicyclic inhibitor of a family 27 α-galactosidase,” Organic and Biomolecular Chemistry, vol. 5, no. 11, pp. 1731–1738, 2007.

Y. Suzuki, S. Ogawa, and Y. Sakakibara, “Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities,” Perspectives in Medicinal Chemistry, vol. 2009, no. 3, pp. 7–19, 2009.

Y. Suzuki, “Chemical chaperone therapy for GM1-gangliosidosis,” Cellular and Molecular Life Sciences, vol. 65, no. 3, pp. 351–353, 2008.

Y. Suzuki, “β-Galactosidase deficiency: an approach to chaperone therapy,” Journal of Inherited Metabolic Disease, vol. 29, no. 2-3, pp. 471–476, 2006.

J. Matsuda, O. Suzuki, A. Oshima et al., “Chemical chaperone therapy for brain pathology in G M1-gangliosidosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15912–15917, 2003.

H. Lin, Y. Sugimoto, Y. Ohsaki et al., “N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1689, no. 3, pp. 219–228, 2004.

M. A. Hossain, K. Higaki, S. Saito et al., “Chaperone therapy for Krabbe disease: potential for late-onset GALC mutations,” Journal of Human Genetics, vol. 60, no. 9, pp. 539–545, 2015.

S. Kuno, K. Higaki, A. Takahashi, E. Nanba, and S. Ogawa, “Potent chemical chaperone compounds for GM1-gangliosidosis: N-substituted (+)-conduramine F-4 derivatives,” MedChemComm, vol. 6, no. 2, pp. 306–310, 2015.

Y. Suzuki, S. Ichinomiya, M. Kurosawa et al., “Therapeutic chaperone effect of N-Octyl 4-Epi-β-valienamine on murine GM1-gangliosidosis,” Molecular Genetics and Metabolism, vol. 106, no. 1, pp. 92–98, 2012.

S. Kuno, A. Takahashi, and S. Ogawa, “Transformation of quercitols into 4-methylenecyclohex-5-ene-1,2,3-triol derivatives, precursors for the chemical chaperones N-octyl-4-epi-β- valienamine (NOEV) and N-octyl-β-valienamine (NOV),” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 23, pp. 7189–7192, 2011.

Z. Luan, L. Li, H. Ninomiya et al., “The pharmacological chaperone effect of N-octyl-β-valienamine on human mutant acid β-glucosidases,” Blood Cells, Molecules, and Diseases, vol. 44, no. 1, pp. 48–54, 2010.

Y. Suzuki, S. Ichinomiya, M. Kurosawa et al., “Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities,” Perspectives in Medicinal Chemistry, vol. 3, pp. 7–19, 2009.

K. Lei, H. Ninomiya, M. Suzuki et al., “Enzyme enhancement activity of N-octyl-β-valienamine on β-glucosidase mutants associated with Gaucher disease,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1772, no. 5, pp. 587–596, 2007.

M. A. Hossain, K. Higaki, M. Shinpo et al., “Chemical chaperone treatment for galactosialidosis: effect of NOEV on β-galactosidase activities in fibroblasts,” Brain and Development, vol. 38, no. 2, pp. 175–180, 2016.

H. Suzuki, U. Ohto, K. Higaki et al., “Structural basis of pharmacological chaperoning for human β-galactosidase,” The Journal of Biological Chemistry, vol. 289, no. 21, pp. 14560–14568, 2014.

A. Takamura, K. Higaki, H. Ninomiya et al., “Lysosomal accumulation of Trk protein in brain of GM1—gangliosidosis mouse and its restoration by chemical chaperone,” Journal of Neurochemistry, vol. 118, no. 3, pp. 399–406, 2011.

Z. Luan, H. Ninomiya, K. Ohno et al., “The effect of N-octyl-β-valienamine on β-glucosidase activity in tissues of normal mice,” Brain and Development, vol. 32, no. 10, pp. 805–809, 2010.

G. Parenti, G. Andria, and K. J. Valenzano, “Pharmacological chaperone therapy: preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders,” Molecular Therapy, vol. 23, no. 7, pp. 1138–1148, 2015.

G. Parenti, M. Moracci, S. Fecarotta, and G. Andria, “Pharmacological chaperone therapy for lysosomal storage diseases,” Future Medicinal Chemistry, vol. 6, no. 9, pp. 1031–1045, 2014.

B. Winchester, A. Vellodi, and E. Young, “The molecular basis of lysosomal storage diseases and their treatment,” Biochemical Society Transactions, vol. 28, no. 2, pp. 150–154, 2000.

S. Ogawa, R. Sekura, A. Maruyama, H. Yuasa, and H. Hashimoto, “Synthesis and glycosidase inhibitory activity of 5a-carba-α-DL-fucopyranosylamine and -galactopyranosylamine,” European Journal of Organic Chemistry, vol. 2000, no. 11, pp. 2089–2093, 2000.

S. Ogawa, A. Maruyama, T. Odagiri, H. Yuasa, and H. Hashimoto, “Synthesis and biological evaluation of α-L-fucosidase inhibitors: 5a-carba-α-L-fucopyranosylamine and related compounds,” European Journal of Organic Chemistry, no. 5, pp. 967–974, 2001.

S. Ogawa, M. Watanabe, A. Maruyama, and S. Hisamatsu, “Synthesis of an α-fucosidase inhibitor, 5a-carba-β-L-fucopyranosylamine, and fucose-type α- and β-DL-valienamine unsaturated derivatives,” Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 5, pp. 749–752, 2002.

R. J. Bernacki, M. J. Niedbala, and W. Korytnyk, “Glycosidases in cancer and invasion,” Cancer and Metastasis Review, vol. 4, no. 1, pp. 81–101, 1985.

S. Ogawa, M. Mori, G. Takeuchi, F. Doi, M. Watanabe, and Y. Sakata, “Convenient synthesis and evaluation of enzyme inhibitory activity of several N-alkyl-, N-phenylalkyl, and cyclic isourea derivatives of 5a-Carba-α-DL-fucopyranosylamine,” Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 20, pp. 2811–2814, 2002.

S. Ogawa, S. Fujieda, Y. Sakata, M. Ishizaki, S. Hisamatsu, and K. Okazaki, “Synthesis and glycosidase inhibitory activity of some N-substituted 6-deoxy-5a-carba-β-dl- and L-galactopyranosylamines,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 20, pp. 3461–3463, 2003.

J. W. Gavin, S. T. Jon, and E. J. Toone, “Natural product glycosyltransferases: properties and applications,” Advances in Enzymology and Related Areas of Molecular Biology, vol. 76, pp. 55–119, 2009.

Y. Kajihara, H. Hashimoto, and S. Ogawa, “Galactosyl transfer ability of β-(1→4)-galactosyltransferase toward 5a-carba-sugars,” Carbohydrate Research, vol. 323, no. 1–4, pp. 44–48, 1999.

H. Qian, B. Hu, Z. Wang, X. Xu, and T. Hong, “Effects of validamycin on some enzymatic activities in soil,” Environmental Monitoring and Assessment, vol. 125, no. 1–3, pp. 1–8, 2007.

R. Ishikawa, K. Shirouzu, H. Nakashita, T. Teraoka, and T. Arie, “Control efficacy of validamycin A against Fusarium wilt correlated with the severity of phytotoxic necrosis formed on tomato tissues,” Journal of Pesticide Science, vol. 32, no. 2, pp. 83–88, 2007.

B. M. Naik, J. Priya, K. U. Solanky, L. Mahatma, B. P. Mehta, and A. N. Sabalpara, “Evaluation of newer fungicides for the management of foliar pathogens of banana,” Pestology, vol. 34, no. 10, pp. 40–43, 2010.

Y. H. Lee, C. W. Choi, S. H. Kim et al., “Chemical pesticides and plant essential oils for disease control of tomato bacterial wilt,” Plant Pathology Journal, vol. 28, no. 1, pp. 32–39, 2012.

J. P. Guirao-Abad, R. Sánchez-Fresneda, E. Valentín, M. Martínez-Esparza, and J.-C. Argüelles, “Analysis of validamycin as a potential antifungal compound against Candida albicans,” International Microbiology, vol. 16, no. 4, pp. 217–225, 2013.

S. Nwaka and H. Holzer, “Molecular biology of trehalose and the trehalases in the yeast Saccharomyces cerevisiae,” Progress in nucleic acid research and molecular biology, vol. 58, pp. 197–237, 1998.

A. Barraza and F. Sánchez, “Trehalases: a neglected carbon metabolism regulator?” Plant Signaling & Behavior, vol. 8, no. 7, Article ID e24778, 2013.

J. Müller, T. Boller, and A. Wiemken, “Trehalose and trehalase in plants: recent developments,” Plant Science, vol. 112, no. 1, pp. 1–9, 1995.

N. Tatun, O. Wangsantitham, J. Tungjitwitayakul, and S. Sakurai, “Trehalase activity in fungus-growing termite, Odontotermes feae (Isoptera: Termitideae) and inhibitory effect ofvalidamycin,” Journal of Economic Entomology, vol. 107, no. 3, pp. 1224–1232, 2014.

S. Lenka, G. Bhaktavatsalam, and B. Medhi, “Fungicidal control of sheath blight of rice,” Journal of Plant Protection and Environment, vol. 7, pp. 53–55, 2010.

V. Bhuvaneswari and S. K. Raju, “Efficacy of new fungicide of strobilurin group against rice sheath blight caused by Rhizoctonia solani,” Journal of Mycology and Plant Pathology, vol. 43, pp. 447–451, 2013.

O. Wakae and K. Matsuura, “Characteristics of validamycin as a fungicide for Rhizoctonia disease control. Review,” Journal of Plant Protection Research, vol. 8, pp. 81–92, 1975.

J. Serneels, H. Tournu, and P. Van Dijck, “Tight control of trehalose content is required for efficient heat-induced cell elongation in Candida albicans,” The Journal of Biological Chemistry, vol. 287, no. 44, pp. 36873–36882, 2012.

Z.-J. Wang, S. Ji, Y.-X. Si et al., “The effect of validamycin A on tyrosinase: inhibition kinetics and computational simulation,” International Journal of Biological Macromolecules, vol. 55, pp. 15–23, 2013.

Y. H. Lee, Y.-S. Cho, S. W. Lee, and J. K. Hong, “Chemical and biological controls of balloon flower stem rots caused by Rhizoctonia solani and Sclerotinia sclerotiorum,” Plant Pathology Journal, vol. 28, no. 2, pp. 156–163, 2012.

H. Berga and N. T. Tamb, “Use of pesticides and attitude to pest management strategies among rice and rice-fish farmers in the mekong delta, Vietnam,” International Journal of Pest Management, vol. 58, no. 2, pp. 153–164, 2012.

H. Li, H. Su, S. B. Kim et al., “Enhanced production of trehalose in Escherichia coli by homologous expression of otsBA in the presence of the trehalase inhibitor, validamycin A, at high osmolarity,” Journal of Bioscience and Bioengineering, vol. 113, no. 2, pp. 224–232, 2012.

K. Qian, T. Shi, T. Tang, S. Zhang, X. Liu, and Y. Cao, “Preparation and characterization of nano-sized calcium carbonate as controlled release pesticide carrier for validamycin against Rhizoctonia solani,” Microchimica Acta, vol. 173, no. 1-2, pp. 51–57, 2011.

M. Best, K. Koenig, K. McDonald, M. Schueller, A. Rogers, and R. A. Ferrieri, “Inhibition of trehalose breakdown increases new carbon partitioning into cellulosic biomass in Nicotiana tabacum,” Carbohydrate Research, vol. 346, no. 5, pp. 595–601, 2011.

A. Biswas and M. K. Bag, “Strobilurins in management of sheath blight disease of rice: a review,” Pestology, vol. 34, no. 4, pp. 23–26, 2010.

L.-Q. Jin and Y.-G. Zheng, “Inhibitory effects of validamycin compounds on the termites trehalase,” Pesticide Biochemistry and Physiology, vol. 95, no. 1, pp. 28–32, 2009.

M. López, N. A. Tejera, and C. Lluch, “Validamycin A improves the response of Medicago truncatula plants to salt stress by inducing trehalose accumulation in the root nodules,” Journal of Plant Physiology, vol. 166, no. 11, pp. 1218–1222, 2009.

R. P. Gibson, T. M. Gloster, S. Roberts et al., “Molecular basis for trehalase inhibition revealed by the structure of trehalase in complex with potent inhibitors,” Angewandte Chemie—International Edition, vol. 46, no. 22, pp. 4115–4119, 2007.

M. J. Madigan and J. Martinko, Eds., Brock Biology of Microorganisms, Prentice Hall, 11th edition, 2005.

T. Nioh and S. Mizushima, “Effect of validamycin on the growth and morphology of Pellicularia sasakii,” Journal of General and Applied Microbiology, vol. 20, no. 6, pp. 373–383, 1974.

M. Uyeda, A. Ikeda, T. Machimoto, and M. Shibata, “Effect of validamycin on production of some enzymes in Rhizoctonia solani,” Agricultural and Biological Chemistry, vol. 49, no. 12, pp. 3485–3491, 1985.

Y. Kido, T. Nagasato, and K. Ono, “Change in a cell-wall component of Rhizoctonia solani inhibited by validamycin,” Agricultural and Biological Chemistry, vol. 50, no. 6, pp. 1519–1525, 1986.

M. Uyeda, A. Ikeda, T. Ogata, and M. Shibata, “Effect of validamycin on β-D-glucan-degrading enzymes from Rhizoctonia solani,” Agricultural and Biological Chemistry, vol. 50, no. 7, pp. 1885–1886, 1986.

Y. Kameda, N. Asano, T. Yamaguchi, and K. Matsui, “Validoxylamines as trehalase inhibitors,” Journal of Antibiotics, vol. 40, no. 4, pp. 563–565, 1987.

N. Asano, M. Takeuchi, Y. Kameda, K. Matsui, and Y. Kono, “Trehalase inhibitors, validoxylamine A and related compounds as insecticides,” Journal of Antibiotics, vol. 43, no. 6, pp. 722–726, 1990.

R. Shigemoto, T. Okuno, and K. Matsuura, “Effects of validamycin A on the growth of and trehalose content in mycelia of Rhizoctonia solani incubated in a medium containing several sugars as the sole carbohydrate,” Annals of the Phytopathological Society of Japan, vol. 58, pp. 685–690, 1992.

N. Asano, T. Yamaguchi, Y. Kameda, and K. Matsui, “Effect of validamycins on glycohydrolases of Rhizoctonia solani,” Journal of Antibiotics, vol. 40, no. 4, pp. 526–532, 1987.

S. Ogawa, K. Sato, and Y. Miyamoto, “Synthesis and trehalase-inhibitory activity of an imino-linked dicarba-α,α-trehalose and analogues thereof,” Journal of the Chemical Society, Perkin Transactions 1, no. 6, pp. 691–696, 1993.

S. Ogawa, K. Nishi, and Y. Shibata, “Synthesis of a carba-sugar analog of trehalosamine, [(1S)-(1,2, 4 3,5)-2-amino-3,4-dihydroxy-5-hydroxymethyl-1-cyclohexyl] α-d-glucopyranoside, and a revised synthesis of its β anomer,” Carbohydrate Research, vol. 206, no. 2, pp. 352–360, 1990.

S. Ogawa and Y. Shibata, “Synthesis of biologically active pseudo-trehalosamine: [(1S)-(1,2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethyl-1-cyclohexyl] 2-amino-2-deoxy-α-d-glucopyranoside,” Carbohydrate Research, vol. 176, no. 2, pp. 309–315, 1988.

K.-I. Fukuhara, H. Murai, and S. Murao, “Isolation and structure-activity relationship of some amylostatins (F-1b fraction) produced by streptomyces diastaticus subsp. amylostaticus,” Agricultural and Biological Chemistry, vol. 46, no. 7, pp. 1941–1945, 1982.

S. Namiki, K. Kangouri, T. Nagate et al., “Studies on the α-glucoside hydrolase inhibitor, adiposin. IV. Effect of adiposin on intestinal digestion of carbohydrates in experimental animals,” Journal of Antibiotics, vol. 35, no. 9, pp. 1167–1173, 1982.

S. Omoto, J. Itoh, T. Shomura et al., “Oligostatins, new antibiotics with amylase inhibitory activity. I. Production, isolation and characterization,” Journal of Antibiotics, vol. 34, no. 11, pp. 1424–1428, 1981.

S. Ogawa, Y. Shibata, Y. Kosuge, K. Yasuda, T. Mizukoshi, and C. Uchida, “Synthesis of potent α-glucosidase inhibitors: Methyl acarviosin analogue composed of 1,6-anhydro-β-D-glucopyranose residue,” Journal of the Chemical Society, Chemical Communications, no. 20, pp. 1387–1388, 1990.

Y. Shibata, Y. Kosuge, T. Mizukoshi, and S. Ogawa, “Chemical modification of the sugar part of methyl acarviosin: synthesis and inhibitory activities of nine analogues,” Carbohydrate Research, vol. 228, no. 2, pp. 377–398, 1992.

S. Ogawa and D. Aso, “Chemical modification of the sugar moiety of methyl acarviosin: synthesis and inhibitory activity of eight analogues containing a 1,6-anhydro bridge,” Carbohydrate Research, vol. 250, no. 1, pp. 177–184, 1993.

S. Ogawa, S. Ogawa, and H. Tsunoda, “Chemical synthesis of glycosylamide and cerebroside analogs composed of carba sugars,” Methods in Enzymology, vol. 247, pp. 136–143, 1994.

S. Ogawa, S.-I. Sasaki, and H. Tsunoda, “Synthesis of carbocyclic analogues of the mannosyl trisaccharide: ether- and imino-linked methyl 3,6-bis(5a-carba-α-d-mannopyranosyl)-3,6-dideoxy-α-d-mannopyranosides,” Carbohydrate Research, vol. 274, pp. 183–196, 1995.

S. Ogawa, T. Furuya, H. Tsunoda, O. Hindsgaul, K. Stangier, and M. M. Palcic, “Synthesis of β-d-GlcpNAc-(1 → 2)-5a-carba-α-d-Manp-(1 → 6)-β-d-Glcp-O(CH₂)₇CH₃: a reactive acceptor analog for N-acetylglucosaminyltransferase-V,” Carbohydrate Research, vol. 271, no. 2, pp. 197–205, 1995.

S. I. Hakomori, “Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens,” Advances in Cancer Research, vol. 52, pp. 257–331, 1989.

H. Schachter, “Molecular cloning of glycosyltranferase genes,” in Molecular Glycobiology, M. Fukuda and O. Hindsgaul, Eds., pp. 86–162, IRL Press, New York, NY, USA, 1994.

J. P. Prieels, D. Monnom, M. Dolmans, T. A. Beyer, and R. L. Hill, “Co-purification of the Lewis blood group N-acetylglucosaminide alpha 1 goes to 4 fucosyltransferase and an N-acetylglucosaminide alpha 1 goes to 3 fucosyltransferase from human milk,” The Journal of Biological Chemistry, vol. 256, pp. 10456–10463, 1981.

B. A. Macher, E. H. Holmes, S. J. Swiedler, C. L. M. Stults, and C. A. Srnka, “Human α1–3 fucosyltransferases,” Glycobiology, vol. 1, no. 6, pp. 577–584, 1991.

T. de Vries, R. M. A. Knegtel, E. H. Holmes, and B. A. Macher, “Fucosyltransferases: structure/function studies,” Glycobiology, vol. 11, no. 10, pp. 119R–128R, 2001.

D. J. Becker and J. B. Lowe, “Fucose: biosynthesis and biological function in mammals,” Glycobiology, vol. 13, no. 7, pp. 41R–53R, 2003.

S. Ogawa, N. Matsunaga, and M. M. Palcic, “Synthesis of biological interest: ether linked octyl 5a-carba-β-lactosaminide and related compounds,” Carbohydrate letters, vol. 2, pp. 299–306, 1997.

S. Ogawa, N. Matsunaga, H. Li, and M. M. Palcic, “Synthesis of ether- and imino-linked octyl N-Acetyl-5a′-carba-β-lactosaminides and -isolactosaminides: acceptor substrates for α-()-fucosyltransferase, and enzymatic synthesis of 5a′-carbatrisaccharides,” European Journal of Organic Chemistry, no. 3, pp. 631–642, 1999.

S. Ogawa, K. Gamou, Y. Kugimiya, Y. Senba, A. Lu, and M. M. Palcic, “Synthesis of octyl N-acetyl-5a-carba-β-lactosaminide and-isolactosaminide: acceptor substrates for α1,3-fucosyltransferase V and α2,3-(N) sialyltransferase,” Carbohydrate Letters, vol. 3, no. 6, pp. 451–456, 2000.

K. Okazaki, S. Nishigaki, F. Ishizuka, Y. Kajihara, and S. Ogawa, “Potent and specific sialyltransferase inhibitors: imino-linked 5a′-carbadisaccharides,” Organic and Biomolecular Chemistry, vol. 1, no. 13, pp. 2229–2230, 2003.

N. Kawamura, N. Kinoshita, R. Sawa et al., “Pyralomicins, novel antibiotics from Microtetraspora spiralis. I. Taxonomy and production,” Journal of Antibiotics, vol. 49, no. 7, pp. 706–709, 1996.