Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase
| Autor: | Jian Dong Li, Adegboyega K. Oyelere, Kensei Komatsu, Idris O. Raji, Lindsey C. Szymczak, Shaghayegh Fathi, Emily Janeira, Milan Mrksich, James R. Kornacki, Fatima Yadudu |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Cell Survival Indomethacin Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Pharmacology Biochemistry Histone Deacetylases Article Cell Line Structure-Activity Relationship 03 medical and health sciences Drug Discovery LNCaP Humans Structure–activity relationship Cyclooxygenase Inhibitors Cytotoxicity Molecular Biology Cell Proliferation Dose-Response Relationship Drug Molecular Structure biology Chemistry Cell growth Cell Cycle Organic Chemistry Cell cycle Histone Deacetylase Inhibitors 030104 developmental biology Celecoxib Prostaglandin-Endoperoxide Synthases Cell culture biology.protein Molecular Medicine Cyclooxygenase Histone deacetylase Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic & Medicinal Chemistry. 25:1202-1218 |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect