title: Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors.
abstract: Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, Wescoe Hall Drive, Malott 4070, Lawrence, KS, 66045-7563, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Byrd
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sanchez
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Hashim F
authors.initials: HF
authors.lastname: Motiwala
authors.affiliation: Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Boulevard,Stop 3016, Kansas City, Kansas, 66160, USA.
authors.forename: Weiya
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cohen
authors.affiliation: Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Boulevard,Stop 3016, Kansas City, Kansas, 66160, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Holzbeierlein
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, Wescoe Hall Drive, Malott 4070, Lawrence, KS, 66045-7563, USA. bblagg@ku.edu.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D049933:Aminocoumarins / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003374:Coumarins / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D049933:Aminocoumarins; D000970:Antineoplastic Agents; D003374:Coumarins; D018841:HSP90 Heat-Shock Proteins; D009675:Novobiocin; C030123:coumarin; C004628:coumermycin
keywords: C-terminal inhibitors; Hsp90; antitumor agents; luciferase refolding; medicinal chemistry