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

doi:10.1016/j.bmc.2015.10.045

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

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

18 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 language	English (US)
Pages (from-to)	7543-7564
Number of pages	22
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2015.10.045
State	Published - 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

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2015.10.045

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Tapadar, S., Fathi, S., Raji, I., Omesiete, W., Kornacki, J. R., Mwakwari, S. C., Miyata, M., Mitsutake, K., Li, J. D., Mrksich, M., & Oyelere, A. K. (2015). A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities. Bioorganic and Medicinal Chemistry, 23(24), 7543-7564. https://doi.org/10.1016/j.bmc.2015.10.045

@article{76e2e1745004458ba26ca026ecef9ea3,

title = "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.",

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

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

note = "Funding Information: This work was financially supported by NIH RO1 Grant R01CA131217 (A.K.O.), by Georgia Institute of Technology through Cullen-Peck fellowship (A.K.O.), and by NIH RO1 Grant RO1DC005843 (J.D.L.). We thank ACS division of Medicinal Chemistry for a travel award to Idris Raji. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

year = "2015",

month = dec,

day = "15",

doi = "10.1016/j.bmc.2015.10.045",

language = "English (US)",

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Tapadar, S, Fathi, S, Raji, I, Omesiete, W, Kornacki, JR, Mwakwari, SC, Miyata, M, Mitsutake, K, Li, JD, Mrksich, M & Oyelere, AK 2015, 'A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities', Bioorganic and Medicinal Chemistry, vol. 23, no. 24, pp. 7543-7564. https://doi.org/10.1016/j.bmc.2015.10.045

TY - JOUR

T1 - A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities

AU - Tapadar, Subhasish

AU - Fathi, Shaghayegh

AU - Raji, Idris

AU - Omesiete, Wilson

AU - Kornacki, James R.

AU - Mwakwari, Sandra C.

AU - Miyata, Masanori

AU - Mitsutake, Kazunori

AU - Li, Jian Dong

AU - Mrksich, Milan

AU - Oyelere, Adegboyega K.

N1 - Funding Information: This work was financially supported by NIH RO1 Grant R01CA131217 (A.K.O.), by Georgia Institute of Technology through Cullen-Peck fellowship (A.K.O.), and by NIH RO1 Grant RO1DC005843 (J.D.L.). We thank ACS division of Medicinal Chemistry for a travel award to Idris Raji. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 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.

AB - 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.

KW - Anti-cancer

KW - Anti-inflammation

KW - Histone deacetylase (HDAC)

KW - Histone deacetylase inhibitors (HDACi)

KW - NF-κB

KW - NTHi

KW - Non-peptide macrocyclic HDACi

KW - Structure activity relationship study (SAR)

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U2 - 10.1016/j.bmc.2015.10.045

DO - 10.1016/j.bmc.2015.10.045

M3 - Article

C2 - 26585275

AN - SCOPUS:84949514989

SN - 0968-0896

VL - 23

SP - 7543

EP - 7564

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 24

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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