title: Synthesis and biological evaluation of novobiocin analogues as potential heat shock protein 90 inhibitors.
abstract: Recent studies have shown that novobiocin (NB), a member of the coumermycin (CA) family of antibiotics with demonstrated DNA gyrase inhibitory activity, inhibits Heat shock protein 90 (HSP90) by binding weakly to a putative ATP-binding site within its C-terminus. To develop more potent HSP90 inhibitors that target this site and to define structure-activity relationships (SARs) for this class of compounds, we have synthesized twenty seven 3-amido-7-noviosylcoumarin analogues starting from NB and CA. These were evaluated for evidence of HSP90 inhibition using several biological assays including inhibition of cell proliferation and cell cycle arrest, induction of the heat shock response, inhibition of luciferase-refolding in vitro, and depletion of the HSP90 client protein c-erbB-2/HER-2/neu (HER2). This SAR study revealed that a substantial increase in biological activity can be achieved by introduction of an indole-2-carboxamide group in place of 4-hydroxy-isopentylbenzamido group at C-3 of NB in addition to removal/derivatization of the 4-hydroxyl group from the coumarin ring. Methylation of the 4-hydroxyl group in the coumarin moiety moderately increased biological activity as shown by compounds 11 and 13. Our most potent new analogue 19 demonstrated biological activities consistent with known HSP90-binding agents, but with greater potency than NB.
authors.affiliation: Southwest Center for Natural Products Research and Commercialization, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, AZ 85706, United States.
authors.forename: G M Kamal B
authors.initials: GM
authors.lastname: Gunaherath
authors.forename: Marilyn T
authors.initials: MT
authors.lastname: Marron
authors.forename: E M Kithsiri
authors.initials: EM
authors.lastname: Wijeratne
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: A A Leslie
authors.initials: AA
authors.lastname: Gunatilaka
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D009675:Novobiocin
keywords: 4-PP; 4-pyrrolidinopyridine; 4′,6-diamidino-2-phenylindole; Biological activity; DAPI; DCC; EDC; FITC; Heat shock protein 90 (HSP90); N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide; NBT/BCIP; Novobiocin analogues; PBA; PFA; PMSF; Structure–activity relationship; Synthesis; TNES; TTBS; a buffer solution containing tris, NaCl, EDTA, and SDS; dicyclohexylcarbodiimide; fluorescein isothiocyanate; formaldehyde in phosphate buffered saline with bovine albumin; nitro-blue tetrazolium chloride and 5-bromo-4-chloro-3′-indolyphosphate p-toluidine salt; phenylmethylsulfonyl fluoride; phosphate buffered saline with bovine albumin; tween 20 in tris buffered saline