Thiazolidine prodrugs as protective agents against gamma-radiation-inducedtoxicity and mutagenesis in V79 cells

Representatives of two classes of thiazolidine prodrug forms of the well-kn own radioprotective agents L-cysteine, cysteamine, and 2-[(aminopropyl)amin o]ethanethiol (WR-1065) were synthesized by condensing the parent thiolamin e with an appropriate carbonyl donor. Inherent toxicity of the prodrugs was assessed in V79 cells using a clonogenic survival assay. Protection agains t radiation-induced cell death was measured similarly after exposure to 0 - 8 Gy gamma (Cs-137) radiation. Antimutagenic activity was determined at th e hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. All thiazol idine prodrugs exhibited less toxicity than their parent thiolamines, somet imes dramatically so. Protection against radiation-induced cell death was o bserved for the 2-alkylthiazolidine, 2(R,S)-D-ribo-(1 ' ,2 ' ,3 ' ,4 ' -tet rahydroxybutyl)thiazolidine (RibCyst), which produced a protection factor a t 8 Gy of 1.8; the cysteine analogue, 2(R,S)-D-ribo-(1 ' ,2 ' ,3 ' ,4 ' -te trahydroxybutyl)thiazolidine-4(R)-carboxylic acid (RibCys), was less active . RibCyst also exhibited excellent antimutational activity, rivaling that o f WR-1065. The 2-oxothiazolidine analogues showed little activity in either determination under the conditions tested, perhaps due to their enhanced c hemical and biochemical stability.