Thiazolidine prodrugs as protective agents against gamma-radiation-induced toxicity and mutagenesis in V79 cells.
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 gamma ((137)Cs) 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.
Wilmore
B H
BH
Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Cassidy
P B
PB
Warters
R L
RL
Roberts
J C
JC
D000818:Animals; D016587:Antimutagenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003543:Cysteamine / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D005720:Gamma Rays; D008624:Mercaptoethylamines / Q000737:chemistry*; D009152:Mutagenicity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines
D016587:Antimutagenic Agents; D008624:Mercaptoethylamines; D011355:Prodrugs; D011837:Radiation-Protective Agents; C432702:RibCyst; D013402:Sugar Alcohols; D013844:Thiazoles; D053778:Thiazolidines; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D003543:Cysteamine; D003545:Cysteine