A Review on the Radioprotective Activity of organogermanium and Organosilicon Compounds

The present review describes the work carried out during the last 20 years in the field of the radioprotective activity and toxicity of several classes of organosilicon and organogermanium compounds (i.e. metallathiazolidines, metalladithioacetals, metallatranes and germathianes).


Introduction
During the 20-year period between 1978 and 1998 the Dlgation Gnrale pour I'Armement and Dpartement de Chimie Pharmacologie, France, sponsored a coordinated antiradiation drug development program. The objective of this program was to develop a drug or combination of drugs with organometallated compounds which could be taken by military personnel or other populations to protect them from the effects of ionizing radiations in a nuclear weapons attack, medical treatments or, in general, all radiation exposition.
During the research program approximately 562 compounds were chemically synthesized and tested in mice for their radioprotective properties.
120 compounds of these derivatives are characterized by a dose reduction factor (DRF) between 1.3 and 1.75. The radioprotective activity and toxicity of several classes of organometallated derivatives (silathiazolidines, germathiazolidines, siladithioacetals, germadithioacetals, germatranes, silatranes and germylated sulfides) and their synthesis are reported.
All the biological tests have been performed in the Centre de Recherche du Service de Sant des Armies, La Tronche, France.
Compounds Method A The action of diorganosilicon and-germanium dichloride [3] (in stoichiometric amounts) on Nsubstituted cysteamine, methylcysteamine, N-(2-thioethyl)-l,3-diaminopropane and N-substituted cysteamine or methylcysteamine by naphthylmethylimidazoline in refluxing anhydrous tetrahydrofuran in the presence of freshly distilled triethylamine gave by a cyclisation reaction, with elimination of hydrochloric acid from M-CI and SH and NH [4] groups the corresponding products, The reaction of N-substituted cysteamine, methylcysteamine, N-(2-thioethyl)-l,3diaminopropane and N-substituted cysteamine or methylcysteamine by naphthylmethylimidazoline, in stoichiometric amounts, with the bis(diethylamino)dialkylsilanes or-germanes in anhydrous tetrahydrofuran resulted in the cleavage of M-N bonds by the NH and SH groups (a transamination reaction) [1,[3][4][5], forming the corresponding sila-and germathiazolidines in good yields, Scheme 2.
Method C The action of diorganosilicon and-germanium dichloride [3] on two equivalents of Nsubstituted cysteamine, methylcysteamine, N-(2-thioethyl)-l,3-diaminopropane, N-substituted cysteamine and methylcysteamine by naphthylmethylimidazoline and N-substituted naphthylmethylimidazoline in refluxing anhydrous tetrahydrofuran in the presence of freshly distilled triethylamine gave the acyclic derivatives, Scheme 3.         Male CD1 mice (Charles River, France), 25 g body weight, were used. The compounds were injected intraperitoneally 15, 90, 120 or 180 rain before irradiation. The irradiation dose was LD100/30 days for untreated mice (7.5, 7.75, 8, 8.25 or 8.3 Gy, according to the irradiation date) or a 2 Gy greater dose. When necessary, other irradiation doses (between 8.5-13.5 Gy were tested in order to evaluate the irradiation LD50/30 days of protected mice. The injected dose of the compound was equal to one-half or one-eighth of the LD50 value which had been determined previously. The radioprotective effect was evaluated by the Dose Reduction Factor (DRF), which is the ratio between the LD50/30 days of treated mice and that of control mice (between 6.5 and 6.75 Gy, according to the date). Irradiation was applied using a cobalt-60 source at the dose rate of 0.3-0.4 Gy.min -1 according to the date. During irradiation, animals were placed in a Plexiglass box with 30 cells in a homogeneous field, 28.5 x 28.5 cm in area. Dosimetry was checked with an ionisation chamber dosimeter. The different LD5o values were determined by probit analysis.

Conclusion
The objective of this work was to incorporate potentially radioprotective organic groups in organometallic structures such as metallathiazolidines, metalladithioacetals, metallatranes and germathianes so as to decrease their toxicity and increase their radioprotective activity.
Tables through Vl summarize the radiation protection obtained in mice after intraperitoneal administration in miglyol solution of the organosilylated and organogermylated derivatives described. Generally, these organometallic compounds have a lower toxicity and a radioprotective activity equal to or greater than that of the starting organic derivatives (namely cysteamine [19], methylcysteamine [10] and N-substituted cysteamine or methylcysteamine [6,9] and N-substituted naphthylmethylimidazoline [7,12]). We have to underline that in some cases this great radioprotective activity was obtained with organosilylated or organogermylated derivatives injected in lower doses, expressed in mmol fraction, than those used for starting organic compounds.
The analysis of the toxicity and powerful radioprotective effect of all compounds presented in Table shows that the metallathiazolidines have generally a good radioprotective activity and lower toxicity compared with starting organic derivatives.
-Derivative 1 (DRF 1.6; LD5o 800 mg.kg-1) at one-half of LD5o (the maximum tolerated dose, MTD) this product protects 93 % and 90 % of mice at 10 Gy 15 or 120 minutes after injection and 70 % survival at 12 Gy 15 minutes before irradiation. At one-eighth of the LD5o, there was a 16 % survival at a dose of 10 Gy.
-Derivative 2 (DRF 1.5; LD50 750 mg.kg-1) at one-half of LD5o 95 % and 89 % protection were obtained at doses of 10 and 12 Gy. At one-eighth of the LD5o, there was still 75 % survival at a dose of 10 Gy.
-Derivative 6 (DRF 1.6; LD50 600 mg.kg-1) at one-half of LDs0 100 % and 90 % survival were obtained at doses of 7.5 and 9.5 Gy and 50 % survival was observed at a dose of 7.5 Gy. At one-eighth of the LD5o, there was a 30 % survival at a dose of 7.5 Gy.
-Derivative 31 (DRF 1.5; LD5o 100 mg.kg-1) at one-half of LD5o 100 % protection was observed at a dose of 7.75 Gy. At one-eighth of the LD5o, there was still 50 % survival at a dose of 7.75 Gy.
-Derivative 42 (DRF 1.5; LD5o 800 mg.kg-1) at one-half of LD5o 100 % and 80 % survival were observed at a dose of 7.5 Gy. At one-eighth of the LD50, there was still 50 % survival at a dose of 7.5 Gy.
-Derivative 47 (DRF>1.6; LD5o 800 mg.kg-1) the administration of this product at of LD5o protects 100 % and 70 % of mice at a dose of 7.5 Gy and 90 % survival was obtained at a dose of 9.5 Gy.
At last, it is important to note the significant radioprotective activity of organogermylated sulfides 54 and 55 (DRF 1.5-1.6).
-Derivative ,54 (DRF 1.6; LD5o 1000 mg.kg-) at the MTD this product protects 100 % and 80 % of mice at doses of 7.5 and 9.5 Gy, it also protects 50 % of mice at a dose of 7.5 Gy.
In short, several organosilylated and organogermylated compounds present a good radioprotective activity compared with the starting organic derivatives due to the presence in these molecules of organometallic groups which increase the hydrosolubility and by the presence of organic ligands which increase the liposolubility and biological activity of these molecules, thereby favouring their passage through the cellular membranes.