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