Raji Idris, Yadudu Fatima, Janeira Emily, Fathi Shaghayegh, Szymczak Lindsey, Kornacki James Richard, Komatsu Kensei, Li Jian-Dong, Mrksich Milan, Oyelere Adegboyega K
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Bioorg Med Chem. 2017 Feb 1;25(3):1202-1218. doi: 10.1016/j.bmc.2016.12.032. Epub 2016 Dec 24.
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.
我们在此公开了一系列对组蛋白脱乙酰酶（HDAC）和环氧化酶（COX）具有强效抑制活性的化合物。这些化合物因其抗COX和抗HDAC活性而有效抑制癌细胞系的生长。虽然化合物2b显示出与塞来昔布相当的COX - 2选择性水平，但化合物11b在对COX - 2相对于COX - 1的选择性方面优于吲哚美辛。我们的先导化合物（2b、8、11b和17b）的一个重要观察结果是，相对于雄激素非依赖性前列腺癌细胞系（DU - 145），它们对雄激素依赖性前列腺癌细胞系（LNCaP）的细胞毒性增强。有趣的是，化合物2b和17b使LNCaP的细胞周期进程停滞在S期，而化合物8显示出G0/G1期停滞，类似于伏立诺他。相对于伏立诺他，这些化合物表现出肿瘤选择性细胞毒性，因为它们对健康细胞（VERO）具有低抗增殖活性；这一特性使其成为有吸引力的药物开发候选物。
