title: Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail.
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.
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Suman
authors: S
authors: Ghosh
authors: Department of Medicinal Chemistry, Fujian Medical University , Fuzhou, China 350004.
authors: Yang
authors: Y
authors: Liu
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Gaurav
authors: G
authors: Garg
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Mercy
authors: M
authors: Anyika
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Nolan T
authors: NT
authors: McPherson
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Jiacheng
authors: J
authors: Ma
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Rick T
authors: RT
authors: Dobrowsky
authors: Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
authors: Brian S J
authors: BS
authors: Blagg
keywords: Aha1; Hsp90; Hsp90α; anti-cancer; neuroprotection; novobiocin; structure−activity relationship