Antitumor benzothiazoles. 14. Synthesis and in vitro biological propertiesof fluorinated 2-(4-aminophenyl)benzothiazoles

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substi tuted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioiso meric 5- and 7-fluorobenzothiazoles were formed from the established Jacobs en cyclization of precursor 3-fluorothiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these ta rget compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently c ytotoxic (GI(50) < 1 nM) in vitro in sensitive human breast MCF-7 (ER+) and MDA 468 (ER-) cell lines but inactive (GI(50) > 10 muM) against PC 3 prost ate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dos e-response relationship characteristically shown by the benzothiazole serie s against sensitive cell lines was exhibited by the 4- and 6-fluorobenzothi azoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The m ost potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-meth ylphenyl)-5-fluorobenzothiazole (10h) which, unlike the g-fluoro isomer (10 d), produces no exportable metabolites in the presence of sensitive MCF-7 c ells. Induction of cytochrome P450 CYP1A1, a crucial event in determining t he antitumor specificity of this series of benzothiazoles, was not compromi sed. 10h is currently the focus of pharmaceutical and preclinical developme nt.