Antitumor benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl)benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines

2-(4-Aminophenyl)benzothiazoles display potent and selective antitumor acti vity against inter alia breast, ovarian, colon, and renal cell lines, but t heir mechanism of action, though yet to be defined, may be novel. Metabolis m is suspected to play a central role in the mode of action of these benzot hiazoles since drug uptake and biotransformation were observed in sensitive cell lines (e.g., breast MCF-7 and MDA 468 cells) in vitro, whereas insens itive cell lines (e.g., prostate PC 3 cells) showed negligible uptake and b iotransformation. N-Acyl derivatives of the arylamines have been synthesize d, and in vitro studies confirm N-acetylation and oxidation as the main met abolic transformations of 2-(4-aminophenyl)benzothiazoles, with the predomi nant process being dictated by the nature of the 3'-substituent. The protot ype amine 3 underwent mainly N-acetylation in vitro, while 3'-substituted a nalogues 4 and 5 were primarily oxidized. N-Acetylation of 4 to 11 exerts a drastic dyschemotherapeutic effect in vitro, but acetylation of the haloge no congeners 5-7 gave acetylamines 12-14 which substantially retain selecti ve antitumor activity. In vivo pharmacokinetic studies in rats confirmed ra pid and exclusive N-acetylation of the 3'-methyl analogue 4, but less acety lation with the 3'-chloro analogue 5. Distinct expression patterns of N-ace tyltransferase NAT1 and NAT2 have been demonstrated in our panel of cell li nes.