Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail

Novobiocin is a natural product that binds the Hsp90 C-terminus and manifests Hsp90 inhibitory activity. Structural investigations on novobiocin led to the development of both anti-cancer and neuroprotective agents. The varied pharmacological activity manifested by these novobiocin analogs prompted the investigation of structure function studies to identify these contradictory effects, which revealed that modifications to the amide side chain produce either anticancer or neuroprotective activity. Compounds that exhibit neuroprotective activity contain a short alkyl or cycloalkyl amide side chain. In contrast, anti-cancer agents contain five or more carbons, disrupt interactions between Hsp90 alpha and Aha1, and induce the degradation of Hsp90-dependent client proteins.