School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):74-84. doi: 10.1080/14756366.2020.1839446.
A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds ( and ) were also found to be potent anti-proliferative compounds with IC values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.
已经合成了一系列 3-取代喹啉羟肟酸，并评估了它们对人肺癌细胞系 (A549)、人结直肠癌细胞系 (HCT116) 和 HDAC 同工型 1、2、6 和 8 的影响。结果表明，喹啉 C3 取代有利于 HDAC6 的选择性。还发现两种化合物 ( 和 ) 对 A549 和 HCT116 细胞具有很强的增殖抑制活性，IC 值范围为 1.29 至 2.13 μM。这些化合物对其他 HDAC 同工型具有纳摩尔 IC 值的显著选择性。Western blot 分析显示，该系列化合物通过切割 caspase 3、8 和 9 激活凋亡半胱氨酸蛋白酶途径，并增加磷酸化 H2AX，从而以浓度依赖的方式诱导 DNA 双链断裂。流式细胞术分析还显示亚 G1 期细胞群的剂量依赖性增加。
