title: Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.
abstract: Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 microM. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure-activity relationships were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, Kansas 66045-7563, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Burlison
authors.forename: Christopher
authors.initials: C
authors.lastname: Avila
authors.forename: George
authors.initials: G
authors.lastname: Vielhauer
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Lubbers
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Holzbeierlein
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D009675:Novobiocin