Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton

Sandra C. Mwakwari, William Guerrant, Vishal Patil, Shabana I. Khan, Babu L. Tekwani, Zachary A. Gurard-Levin, Milan Mrksich, Adegboyega K. Oyelere

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.

Original languageEnglish (US)
Pages (from-to)6100-6111
Number of pages12
JournalJournal of Medicinal Chemistry
Volume53
Issue number16
DOIs
StatePublished - Aug 26 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Mwakwari, S. C., Guerrant, W., Patil, V., Khan, S. I., Tekwani, B. L., Gurard-Levin, Z. A., Mrksich, M., & Oyelere, A. K. (2010). Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton. Journal of Medicinal Chemistry, 53(16), 6100-6111. https://doi.org/10.1021/jm100507q