2. Academic Validation
  3. Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail

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

  • ACS Med Chem Lett. 2016 Jul 5;7(8):813-8. doi: 10.1021/acsmedchemlett.6b00224.
Suman Ghosh 1,  Yang Liu 2,  Gaurav Garg 1,  Mercy Anyika 1,  Nolan T McPherson 1,  Jiacheng Ma 1,  Rick T Dobrowsky 1,  Brian S J Blagg 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
  • 2 Department of Medicinal Chemistry, Fujian Medical University , Fuzhou, China 350004.
PMID: 27563408 DOI: 10.1021/acsmedchemlett.6b00224
Abstract

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 anti-cancer 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 Hsp90α and Aha1, and induce the degradation of Hsp90-dependent client proteins.

Keywords

Aha1; Hsp90; Hsp90α; anti-cancer; neuroprotection; novobiocin; structure−activity relationship.

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