Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

Idris Raji; Fatima Yadudu; Emily Janeira; Shaghayegh Fathi; Lindsey Szymczak; James Richard Kornacki; Kensei Komatsu; Jian-Dong Li; Milan Mrksich; Adegboyega K Oyelere

doi:10.1016/j.bmc.2016.12.032

Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

Bioorg Med Chem. 2017 Feb 1;25(3):1202-1218. doi: 10.1016/j.bmc.2016.12.032. Epub 2016 Dec 24.

Authors

Affiliations

¹ School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
² Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
³ Departments of Chemistry and Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
⁴ Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, USA.
⁵ School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA. Electronic address: aoyelere@gatech.edu.

Abstract

We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Celecoxib / chemical synthesis
Celecoxib / chemistry
Celecoxib / pharmacology*
Cell Cycle / drug effects
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyclooxygenase Inhibitors / chemical synthesis
Cyclooxygenase Inhibitors / chemistry
Cyclooxygenase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Indomethacin / chemical synthesis
Indomethacin / chemistry
Indomethacin / pharmacology*
Models, Molecular
Molecular Structure
Prostaglandin-Endoperoxide Synthases / metabolism*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Cyclooxygenase Inhibitors
Histone Deacetylase Inhibitors
Prostaglandin-Endoperoxide Synthases
Histone Deacetylases
Celecoxib
Indomethacin

Abstract

Publication types

MeSH terms

Substances

Grants and funding