7'-substituted Benzothiazolothio- and Pyridinothiazolothio-purines As Potent Heat Shock Protein 90 Inhibitors.
From: Department of Medicinal Chemistry, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, California 92121, USA. lzhang@conformacorp.com
Journal of medicinal chemistry
- Publish Date: Aug 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 17
- Pages: 5352-62
- Medium: Print
- Language: English
- Citation (JAMA): Zhang Lin, Fan Junhua, Vu Khang, et al. 7'-substituted Benzothiazolothio- and Pyridinothiazolothio-purines As Potent Heat Shock Protein 90 Inhibitors.. J. Med. Chem. Aug 2006;49:5352-62
Abstract
We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7’-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a 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 N87 human 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).
Mesh Headings (Keywords): Animals, Binding Sites, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, HSP90 Heat-Shock Proteins, Humans, Mice, Mice, Nude, Molecular Structure, Purines, Stereoisomerism, Structure-Activity Relationship, Sulfhydryl Compounds, Time Factors, Xenograft Model Antitumor Assays
Check for Full Text / PubMed Unique Identifier (PMID): 16913725
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