Bh. Wilmore et al., Thiazolidine prodrugs as protective agents against gamma-radiation-inducedtoxicity and mutagenesis in V79 cells, J MED CHEM, 44(16), 2001, pp. 2661-2666
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.