Synthesis and Characterization of New Ethylenediamine Platinum(IV) Complexes Containing Lipophilic Carboxylate Ligands

A series of new ethylenediamine (en) platinum(IV) complexes of the type Pt(IV)enX2A2, with X2  = cyclobutane-1,1-dicarboxylato (CBDCA), dichloro or bis(decanoato) and A = acetato, dodecanoato, tetradecanoato, hexadecanoato, octadecanoato, adamantanecarboxylato (Ad) or 3α, 12α-diformoxy-5β-cholato (DFCA) were synthesized and characterized by elemental analysis, infrared and NMR (1H  and  13C) spectroscopic techniques. Previous platinum(IV) compounds were usually restricted to trans-dihydroxo or trans-dichloro platinum(IV) complexes. Recently trans-dicarboxylato platinum(IV) complexes with mainly acetate, trifluoracetate or short-chain carboxylate groups (<11 carbons) in the axial position have been described in the literature[1,2,3]. In this paper we report on the synthesis and characterization of a new class of ethylenediamine platinum(IV) compounds that have high lipophilic long-chain carboxylate ligands either in the axial or equatorial position. The platinum(IV) compounds with the lipophilic trans-carboxylate ligands in the axial position were prepared by acylation of the trans-dihydroxo platinum(IV) species using an acyl halide in the presence of pyridine. In contrast to previous publications[1] the yields were excellent (up to 94%!).

Introduction cis-Diamminedichlomplatinum(ll) (cisplatin, CDDP) is widely used to treat various types of human cancer. Although it is effective against testicular tumors, ovarian caminomas, bladder tumors and tumors of the head and neck, its use is limited by significant severe side-effects such as dose-dependent nephrotoxicity, ototoxicity, neurotoxicity, myelotoxicity, nausea and vomiting []. In an attempt to ovemome these limitations, it is desirable to develop new platinum-based anticancer drugs with a broader spectrum of activity, reduced toxicities and an improved clinical effectiveness. Both acceptance and quality of life of cancer patients receiving a platinum-based chemotherapy could be further enhanced by the development of orally administrable platinum complexes. One strategy to attain this could be to replace the labile chlom ligands in CDDP with other leaving groups e.g. bidentate dicarboxylates and/or to replace the non-leaving groups with bis(alkylamine), diamine or mixed ammine/amine ligands. Several second-generation platinum drugs have entered clinical trials over the last two decades[], such as diammine-(cyclobutane-1,1 -dicarboxylato)platinum(II) (carboplatin/ (1,1-diaminocyclohexane)oxalatoplatinum(ll) (oxaliplatin) In and the racemic mixture of cis-bis(neodecanoato)-trans-R,R-[8 1,2-diaminocyclohexaneplatinum(ll) (L-NDDP) entrapped in liposomes as drug carriers, ] Another promising strategy in the search for new platinum-based anticancer drugs could be to convert platinum(l I) compounds into their platinum(IV) analogues. Cis-dichloro-trans-dihydroxocis-bis(isopropylamine)platinum(IV) (CHIP) [] was the first platinum(IV) complex to enter clinical [1 trials. Tetraplatin ] a racemic mixture of the I-trans and d-trans isomers of tetrachloro-(1,2-diamino-cyclohexane)platinum(IV), was the second. Previous platinum(IV) compounds were usually restricted to the trans-dichlom-or trans-dihydroxoplatinum(IV) species. trans-Dicarboxylatoplatinum(IV) compounds have recently been described in the literature. This new class of complexes is very interesting with regard to the development of platinum anticancer drugs that can be orally administered. Clinical trials with bis(acetato)(ammine)dichlom(cyclohexylamine)platinum(IV) (JM216) started a short while ago. Preclinical work has shown that JM216 has comparable p.o. activity to i.v. administered cisplatin and carboplatin in a panel of four human ovarian caminoma xenogmfts in vivd ]. Furthermore, JM216 is well absorbed from the gastrointestinal tract and has toxic effects comparable to those of carboplatin []. Therefore we report here on the systematic synthesis of platinum(IV) compounds that have trans-carboxylate ligands in the axial position. The general formula of these platinum (IV) complexes is PtVenXA, with X cyclobutane-l,l-dicarboxylato (CBDCA), dichloro or bis(decanoato) and A acetato, dodecanoato, tetradecanoato, hexadecanoato, octadecanoato, adamantanecarboxylato (Ad) or 3(,12(-diformoxy-5-cholato (DFCA). The compound with the trans-acetate ligand was prepared by the general synthetic procedure: reaction of the trans-dihydmxoplatinum(IV) species with acetic anhydride. The yield was 93%. The new class of ethylenediamine platinum(IV) compounds with high lipophilic carboxylate ligands in the axial position was not prepared by the conventional synthetic pathway. In contrast to previous publications we used an acyl halide in the presence of pyridine with very good yields.

Materials and Methods
Chemicals Silversulfate, hydrogen peroxide and acetic anhydride were pumhased from Merck while ethylenediamine was obtained from Roth, cyclobutane-l,l-dicarboxylic acid from EGA and potassiumtetrachlomplatinate from Degussa. All chemicals obtained from commemial suppliers were used as received. Water was used bidistilled while the required acyl halides were prepared by reaction of the corresponding carboxylic acid with thionyl chloride. Workup was carried out by general methods.

Physical Measurements
Elemental analyses were performed in our own laboratories. R spectra were recorded in KBr pellets in the range of 400-4400 cmon a Bruker FS 66. NMR spectra were measured using a Bruker Ac 200 MHz spectrometer. NMR (H, C) spectra were measured in [D]DMSO, CDCI, [D] acetone or DO containing [D] acetone as reference. The Pt NMR spectrum was obtained in CDCI and referenced using an external sample of HPtCI in DO at 0.0 ppm.

Preparation of Platinum Complexes
The trans-dicarboxylatoplatinum(IV) compounds with chlom ligands in the equatorial position were synthesized as shown in Scheme 1.
PtOenCl. An aqueous solution of KPtCI4 ( After stirring overnight at room temperature, the mixture was gently refluxed for 6 hours. The suspension was cooled down to room temperature and 70 ml of water were added to hydrolize the excess of acyl halide. The product and the tetradecanoic acid were filtered, washed with water and dded in vacuo. The carboxylic acid was extracted with CHCI and the final product was dried under reduced pressure, ptVenCI(OCO(CH)CH) was obtained as a white solid.
Anal. Calc. see Table 1. Yield, 94%. All trans-dicarboxylatoplatinum(IV) complexes with chlom ligands in the equatorial position were prepared in a manner similar to the one described above. The elemental analyses and yields are listed in Table 1 PtenCl was prepared as described above and activated by reaction with an equimolar amount of silversulfate (reaction (1) and (5)). The platinum(ll) complexes with different leaving groups were produced by mixing Pten(SO4)(H20) with the in situ prepared sodium salts of the corresponding carboxylic acids (reaction (6)). The obtained platinum(ll) carboxylates were oxidized by hydrogen peroxide (reaction (7)). The trans-bis(acetato)platinum(IV) compound was prepared by reaction of the trans-dihydroxoplatinum(IV) species with acetic anhydride (reaction (Sa)), whereas the platinum(IV) complexes with the lipophilic carboxylate ligands in the axial position were synthesized by reaction of PtenX2(OH) with an acyl halide in the presence of pyridine (reaction (8b)). PtV)en(CBDCA)(OCO(CH)eCH)z The following trans-dicarboxylatoplatinum(IV) compounds with the cyclobutane-l,l-dicarboxylate ligand in the equatorial position were prepared in a manner similar to the one used in the case of ptVenCI(OCO(CH)CH). The elemental analyses and yields of these complexes are listed in Table 1 Pt(")en(SO)(HO) in 10 ml of bidistilled water. After stirring for 30 minutes at 60C, one hour at 45C and two days in the dark at room temperature, the whole mixture was extracted with CHCI.

Results and Discussion
We have synthesized a new class of ethylenediamine platinum(IV) complexes containing lipophilic long-chain carboxylate ligands. The structural features of these complexes of the type ptVenXA with X two chlom, two carboxylato or one bidentate dicarboxylato ligands and A carboxylato are illustrated in Figure 1. The compounds were characterized by elemental analysis, IR and, if soluble enough, by NMR spectroscopy. The results of the elemental analyses are listed in Table 1. The theoretical values are in good agreement with the actual findings. The IR spectroscopic data for the tmns-dicarboxylatoplatinum(IV) compounds is listed in Table 2. In general, Pt0enCl and ethylenediamine platinum(ll) compounds show two single sharp and resolvable N-H stretching absorptions. The platinum(IV) analogues with mixed dicarboxylate ligands showed one broad band whereas platinum(IV) complexes with chlom ligands in the equatorial and carboxylato ligands in the axial position displayed one single sharp peak in the region of 3204 cm - C NMR spectrum of Pt(V)enCl(Ad) and pt0V)en(OCO(CH)CH)(OCOCH) could be obtained. The C resonance of the carbonyl group of Pt(V)enCl(Ad) was observed at 186.5. Unfortunately, the C=O resonance of Pt(V)en(OCO(CH)CH)=(OCOCH) was too weak to be reported.
In conclusion, a series of new ethylenediamine platinum(IV) compounds containing lipophilic long-chain carboxylate ligands either in the axial or equatorial position have been synthesized and characterized. Moreover, the use of the unconventional synthetic pathway via an acyl halide produced yields up to 94%. The potentially useful trans-dicarboxylatoplatinum(IV) complexes will be tested with regard to their antitumor activity and oral administration possibilities.