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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1202-1218 |
| Number of pages | 17 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 25 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2017 |
Funding
This project was financially supported by NIH grants R01CA131217 (A.K.O.) and R21CA185690 (A.K.O.) and RO1DC005843 (J.D.L.). Emily Janeira was supported by the Research Experience for Undergraduates (REU) program (summer 2014) at Georgia Institute of Technology. J.D. Li is a Georgia Research Alliance Eminent Scholar in Inflammation and Immunity.
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Molecular Biology
- Biochemistry
- Clinical Biochemistry
- Pharmaceutical Science
- Organic Chemistry
