1. Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase.
- Author
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Raji, Idris, Yadudu, Fatima, Janeira, Emily, Fathi, Shaghayegh, Szymczak, Lindsey, Kornacki, James Richard, Komatsu, Kensei, Li, Jian-Dong, Mrksich, Milan, and Oyelere, Adegboyega K.
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ANTIBODY-drug conjugates , *CYCLOOXYGENASES , *HISTONE deacetylase , *DOSAGE forms of drugs , *CANCER cells , *THERAPEUTICS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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