A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities

Subhasish Tapadar, Shaghayegh Fathi, Idris Raji, Wilson Omesiete, James R. Kornacki, Sandra C. Mwakwari, Masanori Miyata, Kazunori Mitsutake, Jian Dong Li, Milan Mrksich, Adegboyega K. Oyelere*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti-inflammatory (IC50 88 nM) activity relative to SAHA.

Original languageEnglish (US)
Pages (from-to)7543-7564
Number of pages22
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number24
DOIs
StatePublished - Dec 15 2015

Keywords

  • Anti-cancer
  • Anti-inflammation
  • Histone deacetylase (HDAC)
  • Histone deacetylase inhibitors (HDACi)
  • NF-κB
  • NTHi
  • Non-peptide macrocyclic HDACi
  • Structure activity relationship study (SAR)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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