Antitumor Benzothiazoles. 26. 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a Simple Fluorinated 2-Arylbenzothiazole, Shows Potent and Selective Inhibitory Activity against Lung, Colon, and Breast Cancer Cell Lines

A series of new 2-phenylbenzothiazoles has been synthesized on the basis of the discovery of the potent and selective in vitro antitumor properties of 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (8n; GW 610, NSC 721648). Synthesis of analogues substituted in the benzothiazole ring was achieved via...

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Published in:	Journal of medicinal chemistry 2006-01, Vol.49 (1), p.179-185
Main Authors:	Mortimer, Catriona G, Wells, Geoffrey, Crochard, Jean-Philippe, Stone, Erica L, Bradshaw, Tracey D, Stevens, Malcolm F. G, Westwell, Andrew D
Format:	Article
Language:	eng
Subjects:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Benzothiazoles - chemical synthesis Benzothiazoles - chemistry Benzothiazoles - pharmacology Breast Neoplasms - drug therapy Cell Line, Tumor Cell Proliferation - drug effects Colonic Neoplasms - drug therapy Drug Screening Assays, Antitumor Humans In Vitro Techniques Lung Neoplasms - drug therapy Molecular Structure Stereoisomerism
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Summary:	A series of new 2-phenylbenzothiazoles has been synthesized on the basis of the discovery of the potent and selective in vitro antitumor properties of 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (8n; GW 610, NSC 721648). Synthesis of analogues substituted in the benzothiazole ring was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. Compounds were evaluated in vitro in four human cancer cell lines, and compound 8n was found to possess exquisitely potent antiproliferative activity (GI50 < 0.1 nM for MCF-7 and MDA 468). Potent and selective activity was also observed in the NCI 60 human cancer cell line panel. Structure−activity relationships established that the compound 8n stands on a pinnacle of potent activity, with most structural variations having a deactivating in vitro effect. Mechanistically, this new series of agents contrasts with the previously reported 2-(4-aminophenyl)benzothiazoles; compound 8n is not reliant on induction of CYP1A1 expression for antitumor activity.
ISSN:	0022-2623 1520-4804