Phenylalkyl isothiocyanate-cysteine conjugates as glutathione S-transferase stimulating agents.
To develop analogues of phenylalkyl isothiocyanate with less toxicity and better biological activity, two water-soluble phenylalkyl isothiocyanate-cysteine conjugates, S-[N-benzyl(thiocarbamoyl)]-L-cysteine (1) and S-[N-(3-phenylpropyl)(thiocarbamoyl)]-L-cysteine (2), were synthesized. The induction of increased activity of the detoxifying enzyme glutathione S-transferase by the conjugates and their parent compounds was determined and compared in several tissues of A/J mice. The biological evaluation revealed that the conjugates as GST enzyme inducers appeared to be less toxic and even more potent than the parent compounds in the mouse bladder. Compounds 1 was much more active than 2 in all the tissues examined, while their parent compounds showed an inverse order of activity. Thus, an increase in the alkyl chain length of the parent isothiocyanates or a decrease in the alkyl length of the conjugates could result in higher enzyme-inducing activity in the same compound series. Since a number of nitrosamines have been identified as prime bladder carcinogens and phenylalkyl isothiocyanates have been reported to inhibit a wide range of carcinogenic nitrosamines, the corresponding conjugates may serve as prodrugs to protect against nitrosamine-induced urinary bladder carcinogenesis once they are delivered to the target organ.
Zheng
G Q
GQ
LKT Laboratories Inc., Minneapolis, Minnesota 55413.
Kenney
P M
PM
Lam
L K
LK
D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005982:Glutathione Transferase / Q000096:biosynthesis*; D007700:Kinetics; D051379:Mice; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013861:Thiocyanates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D013859:Thiocarbamates; D013861:Thiocyanates; C072352:S-(N-(3-phenylpropyl)(thiocarbamoyl))-cysteine; C036482:S-(N-benzylthiocarbamoyl)cysteine; D005982:Glutathione Transferase; D003545:Cysteine