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

doi:10.1021/JM001104N

Paper

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

Published Apr 19, 2001 · I. Hutchinson, Mei-Sze Chua, Helen L. Browne

Journal of medicinal chemistry

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327

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4

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Abstract

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substituted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioisomeric 5- and 7-fluoro-benzothiazoles were formed from the established Jacobsen cyclization of precursor 3-fluoro-thiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these target compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently cytotoxic (GI(50) < 1 nM) in vitro in sensitive human breast MCF-7 (ER+) and MDA 468 (ER-) cell lines but inactive (GI(50) > 10 microM) against PC 3 prostate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dose-response relationship characteristically shown by the benzothiazole series against sensitive cell lines was exhibited by the 4- and 6-fluoro-benzothiazoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The most potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h) which, unlike the 6-fluoro isomer (10d), produces no exportable metabolites in the presence of sensitive MCF-7 cells. Induction of cytochrome P450 CYP1A1, a crucial event in determining the antitumor specificity of this series of benzothiazoles, was not compromised. 10h is currently the focus of pharmaceutical and preclinical development.

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Study Snapshot

Fluorinated 2-(4-aminophenyl)benzothiazoles show potent cytotoxic effects against sensitive human breast cancer cell lines, with the most potent broad spectrum agent being 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h).

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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

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