TY - JOUR
T1 - Thiazolidine prodrugs as protective agents against γ-radiation-induced toxicity and mutagenesis in V79 cells
AU - Wilmore, B. H.
AU - Cassidy, P. B.
AU - Warters, R. L.
AU - Roberts, J. C.
PY - 2001/8/2
Y1 - 2001/8/2
N2 - Representatives of two classes of thiazolidine prodrug forms of the well-known radioprotective agents L-cysteine, cysteamine, and 2-[(aminopropyl)amino]ethanethiol (WR-1065) were synthesized by condensing the parent thiolamine with an appropriate carbonyl donor. Inherent toxicity of the prodrugs was assessed in V79 cells using a clonogenic survival assay. Protection against radiation-induced cell death was measured similarly after exposure to 0-8 Gy γ (137Cs) radiation. Antimutagenic activity was determined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. All thiazolidine prodrugs exhibited less toxicity than their parent thiolamines, sometimes dramatically so. Protection against radiation-induced cell death was observed for the 2-alkylthiazolidine, 2(R,S)-D-ribo-(1′,2′,3′,4′-tetrahydroxybutyl) thiazolidine (RibCyst), which produced a protection factor at 8 Gy of 1.8; the cysteine analogue, 2(R,S)-D-ribo-(1′,2′,3′,4′-tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid (RibCys), was less active. RibCyst also exhibited excellent antimutational activity, rivaling that of WR-1065. The 2-oxothiazolidine analogues showed little activity in either determination under the conditions tested, perhaps due to their enhanced chemical and biochemical stability.
AB - Representatives of two classes of thiazolidine prodrug forms of the well-known radioprotective agents L-cysteine, cysteamine, and 2-[(aminopropyl)amino]ethanethiol (WR-1065) were synthesized by condensing the parent thiolamine with an appropriate carbonyl donor. Inherent toxicity of the prodrugs was assessed in V79 cells using a clonogenic survival assay. Protection against radiation-induced cell death was measured similarly after exposure to 0-8 Gy γ (137Cs) radiation. Antimutagenic activity was determined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. All thiazolidine prodrugs exhibited less toxicity than their parent thiolamines, sometimes dramatically so. Protection against radiation-induced cell death was observed for the 2-alkylthiazolidine, 2(R,S)-D-ribo-(1′,2′,3′,4′-tetrahydroxybutyl) thiazolidine (RibCyst), which produced a protection factor at 8 Gy of 1.8; the cysteine analogue, 2(R,S)-D-ribo-(1′,2′,3′,4′-tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid (RibCys), was less active. RibCyst also exhibited excellent antimutational activity, rivaling that of WR-1065. The 2-oxothiazolidine analogues showed little activity in either determination under the conditions tested, perhaps due to their enhanced chemical and biochemical stability.
UR - http://www.scopus.com/inward/record.url?scp=0035797354&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035797354&partnerID=8YFLogxK
U2 - 10.1021/jm010162l
DO - 10.1021/jm010162l
M3 - Article
C2 - 11472218
AN - SCOPUS:0035797354
SN - 0022-2623
VL - 44
SP - 2661
EP - 2666
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -