7'-Substituted Benzothiazolothio- and Pyridinothiazolothio-Purines as Potent Heat Shock Protein 90 Inhibitors

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• 作者：Lin Zhang ; Junhua Fan ; Khang Vu ; Kevin Hong ; Jean-Yves Le Brazidec ; Jiandong Shi ; Marco Biamonte ; David J. Busch ; Rachel E. Lough ; Roy Grecko ; Yingqing Ran ; John L. Sensintaffar ; Adeela Kamal ; Karen L
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 24, 2006
• 年：2006
• 卷：49
• 期：17
• 页码：5352 - 5362
• 全文大小：191K
• 年卷期：v.49,no.17(August 24, 2006)
• ISSN：1520-4804

文摘

We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a7'-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity ina Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice.In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H- purin-6-ylamine).