title: Targeting the heat shock protein 90 dimer with dimeric inhibitors.
abstract: The design, synthesis, and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3 mm2, A549, and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent antiproliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ∼100 fold increase in antiproliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045-7563, USA.
authors.forename: Bhaskar Reddy
authors.initials: BR
authors.lastname: Kusuma
authors.forename: Laura B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.forename: George
authors.initials: G
authors.lastname: Vielhauer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Holzbeierlein
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D049933:Aminocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D019281:Dimerization; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D055503:Protein Multimerization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D049933:Aminocoumarins; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C004628:coumermycin