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Bioorg Med Chem. 2015 Dec 15;23(24):7543-64. doi: 10.1016/j.bmc.2015.10.045. Epub 2015 Nov 2.

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

Author information

1
School of Chemistry and Biochemistry, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
2
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
3
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
4
School of Chemistry and Biochemistry, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA. Electronic address: aoyelere@gatech.edu.

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.

KEYWORDS:

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

PMID:
26585275
PMCID:
PMC4685012
DOI:
10.1016/j.bmc.2015.10.045
[Indexed for MEDLINE]
Free PMC Article

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