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

Citation
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
Citations number
33
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
44
Issue
16
Year of publication
2001
Pages
2661 - 2666
Database
ISI
SICI code
0022-2623(20010802)44:16<2661:TPAPAA>2.0.ZU;2-0
Abstract
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.