title: Design, synthesis and biological evaluation of biphenylamide derivatives as Hsp90 C-terminal inhibitors.
abstract: Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors. Structure-activity relationship studies produced new derivatives that inhibit the proliferation of breast cancer cell lines at nanomolar concentrations, which corresponded directly with Hsp90 inhibition.
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Garg
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Istituto di chimica del riconoscimento molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Antwan
authors.initials: A
authors.lastname: Girgis
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Lucas S
authors.initials: LS
authors.lastname: Franco
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA.
authors.forename: Swapnil
authors.initials: S
authors.lastname: Singh
authors.affiliation: Istituto di chimica del riconoscimento molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, USA. Electronic address: bblagg@ku.edu.
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* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; D018841:HSP90 Heat-Shock Proteins
keywords: Biphenyl; Breast cancer; Heat shock protein 90; Hsp90 C-Terminal inhibitors; Structure–activity relationship