Chemistry of ring-substituted 4-(benzothiazol-2-yl)phenylnitrenium ions from antitumor 2-(4-aminophenyl)benzothiazoles.

Ring-substituted derivatives of 2-(4-aminophenyl)benzothiazole, 1a, 1b-g, are under development as antitumor agents. One derivative, 1f, has reached phase 1 clinical trials as the prodrug 2f, Phortress (NSC 710305). These amines are activated by CYP450 1A1, apparently into hydroxylamines 8a-g that are likely metabolized into esters that ionize into nitrenium ions responsible for cellular damage. Previously we showed that 9a, the acetic acid ester of 8a, generates the long-lived (530 ns) nitrenium ion 11a by hydrolysis or photolysis in water. In this study, azide trapping shows that 9b-g generate 11b-g via rate-limiting N-O heterolysis. Ion lifetimes, estimated from azide/solvent selectivities, range from 250 to 1150 ns with identical lifetimes for 11a and 11f. Differences in biological activity of the amines are likely not due to differences in the chemistry of the cations but to differences in metabolic activation/deactivation of individual amines. Unlike the nitrenium ions, lifetimes of the esters are strongly dependent on the 3'-Me substituent. Esters containing 3'-Me (9b, 9f, 9g) have lifetimes of 5-10 s compared to 400-800 s for esters without 3'-Me (9a, 9c, 9d, 9e). This restricts 3'-Me esters to cells/tissues in which activation occurs, concentrating their effects in tumor cells if metabolism is restricted to those cells.