title: Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines.
abstract: Hsp90 represents a promising target for the development of both anti-cancer and neuroprotective agents. Structure-activity relationship studies on novobiocin and novobiocin analogues, led to the development of KU-32 and recently, KU-596, as lead compounds for the potential treatment of neurodegenerative diseases. Similar to KU-32, we have demonstrated that upon replacement of the acetamide side chain present in KU-32 with a benzamide, this neuroprotective agent was transformed into a scaffold that manifests anti-proliferative activity. To assess structure-activity relationships for this new scaffold, a library of benzamide-containing novologues was prepared and evaluated against two breast cancer cell lines. Compound 14a manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation in a concentration-dependent manner.
authors: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors: Huiping
authors: H
authors: Zhao
authors: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors: Mercy
authors: M
authors: Anyika
authors: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors: Antwan
authors: A
authors: Girgis
authors: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States. Electronic address: bblagg@ku.edu.
authors: Brian S J
authors: BS
authors: Blagg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; C037689:benzamide
keywords: Breast cancer; Heat shock protein 90; Hsp90 inhibitors; Novobiocin analogues