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

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.

DOI: 10.1016/j.bmc.2015.10.045

Cite this paper

@article{Tapadar2015ASR, title={A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities.}, author={Subhasish Tapadar and Shaghayegh Fathi and Idris O Raji and Wilson Omesiete and James Richard Kornacki and Sandra C. Mwakwari and Masanori Miyata and Kazunori Mitsutake and Jian-Dong Li and Milan Mrksich and Adegboyega K. Oyelere}, journal={Bioorganic & medicinal chemistry}, year={2015}, volume={23 24}, pages={7543-64} }