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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.

SUBMITTER: Garg G

PROVIDER: S-EPMC4329597 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Design, synthesis, and biological evaluation of ring-constrained novobiocin analogues as hsp90 C-terminal inhibitors.

Garg Gaurav G Zhao Huiping H Blagg Brian S J BS

ACS medicinal chemistry letters 20141212 2

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 ...[more]

PMID: 25699150

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