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

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.

Heat shock protein 90; Hsp90 C-terminal inhibitors; breast cancer; ring-constrained novobiocin analogues; structure−activity relationship.