Solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity

Solid phase synthesis of 2-(substituted-phenyl)benzothiazoles and evaluation of their cytotoxicity and topoisomerase II inhibition activity are described. To investigate one possible mechanism of action of the cytotoxic activity of benzothiazoles, we synthesized 2-(substituted-phenyl)benzothiazoles and evaluated their ability to inhibit topoisomerase II activities. Solid phase combinatorial method using trityl resin was employed and benzothiazole derivatives with various substitution on 2′-, 3′-, or 4′-position of phenyl group were obtained in ca. 30 mg scale (7–96% yield). Most of the compounds synthesized exhibited topoisomerase II inhibitory activity at 100 μM. 2-(3-Amino-4-methylphenyl)benzothiazole showed high activity (IC 50 = 71.7 μM), comparable to etoposide (IC 50 = 78.4 μM).