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.