2. Academic Validation
  3. Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

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.
Idris Raji 1,  Fatima Yadudu 1,  Emily Janeira 2,  Shaghayegh Fathi 1,  Lindsey Szymczak 3,  James Richard Kornacki 3,  Kensei Komatsu 4,  Jian-Dong Li 4,  Milan Mrksich 3,  Adegboyega K Oyelere 5
Affiliations

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.
PMID: 28057407 DOI: 10.1016/j.bmc.2016.12.032
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.

Figures