title: Design, synthesis, and biological evaluation of ring-constrained novobiocin analogues as hsp90 C-terminal inhibitors.
abstract: Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not induce the pro-survival heat shock response. Structural investigations on novobiocin have elucidated some structure-activity relationships and several promising compounds. On the basis of structure-activity relationships and computational studies, a library of ring-constrained novobiocin analogues was designed, synthesized, and evaluated in antiproliferative assays. Results obtained from these studies provide insights into the Hsp90 C-terminal binding site, and new analogues that were developed manifest low micromolar to mid-nanomolar antiproliferative activity resulting from Hsp90 inhibition.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7563, United States.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Garg
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7563, United States.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7563, United States.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
keywords: Heat shock protein 90; Hsp90 C-terminal inhibitors; breast cancer; ring-constrained novobiocin analogues; structure−activity relationship