The hydrolysis and alkylation activities of S-(2-haloethyl)-L-cysteine analogs--evidence for extended half-life.
A series of S-(2-haloethyl)-L-cysteine derivatives, which are analogs of the proposed glutathione half-mustard metabolites of dihaloethanes, were synthesized and studied with respect to their hydrolysis and alkylation rates in aqueous solution. The trend of relative hydrolysis rates, Br greater than Cl much greater than F, paralleled their respective leaving group abilities; however, a dramatic rate increase was seen at pH 8 versus pH's 6 or 4. Hydrolysis of S-(2-chloroethyl)-L-cysteine analogs, where the ionizable groups were blocked (carboxyl esterified and/or N-acetylated), revealed that the amine moiety was responsible for the increased hydrolysis of mustard gas (beta, beta'-dichlorodiethyl sulfide) gave similar results with S-(2-chloroethyl)-L-cysteine, a finding which is consistent with the reaction intermediate being a highly charged species. The alkylation rates with 4-(p-nitrobenzyl)-pyridine were not affected by blocking the ionizable groups. A mechanism of internal cyclization is proposed to explain the accelerated alkaline hydrolysis rates noted with S-(2-haloethyl)-L-cysteines but not with the N-acetylated analogs (mercapturic acids). This scheme proposes the formation of 3-(thiomorpholine)-carboxylic acid as an alternative pathway to the generally accepted hydrolysis reaction. This compound and not S-(2-hydroxyethyl)-L-cysteine was the identified product following pH 10 hydrolysis. Increased hydrolysis half-time of amine-blocked cysteine analogs versus parent cysteine analogs may exist with S-(2-haloethyl)-glutathione derivatives which may explain the substantial nucleic acid alkylation seen with S-(2-haloethyl) derivatives of glutathione.
D000478:Alkylation; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D009150:Mustard Compounds / Q000138:chemical synthesis / Q000378:metabolism; D012996:Solutions
D009150:Mustard Compounds; D012996:Solutions; D003545:Cysteine