Synthesis and Radioprotective Activity of New Organosilicon and Germanium Compounds

Silathiazolidine and metalladithioacetals (M = Si, Ge) have been prepared by the interaction of dialkyldichloro- or bis(diethylamino)dialkylsilanes and -germanes with 3-[N-(2- thioethyl)]amino-propanamide (WR-2529) and [1-thioethyl-2-(1-naphtylmethyl)]-2- imidazoline. The study of these compounds in the field of chemical radioprotection has shown a notable decrease in the toxicity and a rather large increase in the radioprotective activity of these new derivatives in comparison with the starting organic compounds.


Materials and methods
All manipulations were carried out under dry nitrogen. Solvents were freshly distilled from sodium/benzophenone before use. IR spectra were recorded on a Perkin-Elmer 1600FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on Bruker's AC 80 (80.13 MHz) and AC 200 (50.32 MHz) spectrometers; the multiplicity of the 13C NMR signals was determined by the APT technique and quoted (-) for CH3 and CH, (+) for CH2 and (Cquat) for quaternary carbon atoms. Mass spectra under electron impact (El) conditions at 70 [11] (1.60 g, 10.80 retool) in 50 ml of THF was added dropwise, a solution of bis(diethylamino)di-n-hexylsilane (3.70 g, 10.80 retool) in 50 ml of THF. The mixture was refluxed under nitrogen for 3 h. The volatile material was removed in vacuo to afford the compound 1 (3.57 g, 96 %).
Method D Bis(diethylamino)di-n-hexylsilane (2.00 g, 5.84 mmol) in 40 ml of THF was added dropwise with stirring to a suspension of HSCH2CH2NHCH2CH2C(O)NH2 (1.73 g, 11.67 mmol) in 70 ml of THF. The mixture was refluxed under nitrogen for 3 h. After cooling down to room temperature, the volatiles were removed under vacuum to afford 3 (2.02 g, 70 %).
Compounds 4-7 were prepared analogously from the appropriate dialkyldichlorometallane or bis(diethylamino)dialkylmetallane and 3-[N- 25.16 mmol) in 60 ml of dry toluene was mixed with a solution of ethylene sulfide (1.59 g, 26.45 mmol) (Aldrich-Chemical) in 40 ml of dry toluene (sealed tube, argon flushed). The reaction mixture was then heated (110C oven) for 15 h. After cooling 100 ml of cold diethyl ether was added with stirring to reaction mixture, and filtration to remove small amount of polyethylene sulfide. The solvent was removed under reduced pressure to give a yellow pasty product 8 (4.78 g, 74 %). #To a solution of 2-(1-naphthylmethyl)-2-imidazoline hydrochloride (Aldrich-Chemical) (30g, 121.58 mmol) in 30 ml of water was added with stirring a solution of NaOH 14 % (34.73 g). After extraction with toluene (500 ml), the organic layer dried on Na2SO4. Removal of solvent in vacuo and crystallization from THF/diethyl ether (1/9, 400 ml) gave 2-(1naphtylmethyl)-2-imidazoline in form of white crystals (21.31 g, 87 %).
Physicochemical data of derivatives 1-8 are reported in Table   Compound   Table II Gy greater dose. The injected dose of compound was equal to, three-quater, two-third, onehalf or one eighth of the LDo value which had been determined previously. The radioprotective effect was evaluated by the Dose Reduction Factor (DRF), which is the ratio between the LDo/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 LDso values were determined by probit analysis.

Results and discussion Silathiazolidine
Silathiazolidine has been prepared according to two methods of heterocyclisation already described in the litterature [1,12,13]. Method A The action of di-n-hexyldichlorosilane, in stoichiometric amounts, on 3-[N-(2thioethyl)]aminopropanamide in refluxing anhydrous THF in the presence of freshly distilled triethylamine gave by a cyclisation reaction, with elimination of hydrochloric acid from Si-CI and NH groups [13], the corresponding product, Scheme 1:
With the other sila-and germadithioacetals, derivatives 4-7, we have observed a low decrease of the toxicity but a good radioprotective activity by intraperitoneal administration in mice. For example: derivative 4: at LDo/2 50 mg.kg 1 this product protects 100 % and 80 % of mice when 4 was injected 15 and 90 minutes before irradiation. derivative 5: at LDo/2 50 mg.kg this product protects 100 % of mice when 5 was injected 15 and 90 minutes before irradiation. In the example shown, 50 % survival was also observed at LDo/8. Concerning the derivatives 6 and 7 we have noted a low toxicity and a notable increase of radioprotective activity: derivative 6: at LDo/1.6 50 mg.kg this product protects 100 % of mice when 6 was injected 15 and 90 minutes before irradiation, 90 % survival when 6 was injected 180 minutes before irradiation. At LD0/6.4 there was still 80 % survival and at LDso/1.6, 70 and 30 % survival at dose of 9.75 and 11.75 Gy. derivative 7: at LDo/2 75 mg.kg this product protects 90 and 100 % of mice when 7 was injected 15 and 90 minutes before irradiation. At LDo/8, 70 % survival when 7 was injected 15 minutes before irradiation.