FLUORINATED 2-(4-AMINO-3-METHYLPHENYL)BENZOTHIAZOLES INDUCE CYP1A1 EXPRESSION, BECOME METABOLIZED, AND BIND TO MACROMOLECULES IN SENSITIVE HUMAN CANCER CELLS

Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess po-tent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In “sensitive ” cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabo-lism appears to be essential for its antiproliferative activity through DNA adduct formation. However, a biphasic dose-response relation-ship compromises its straightforward development as a chemother-apeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive cancer cells. One fluorinated benzothiazole, 2-(4-amino-methylphenyl)-5-flu-orobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiprolif-erative activity without a biphasic dose-response. The fluorinate