Ling Yong, Guo Jing, Yang Qiuxing, Zhu Peng, Miao Jiefei, Gao Weijie, Peng Yanfu, Yang Jiaying, Xu Kun, Xiong Biao, Liu Gongqing, Tao Jinhua, Luo Lin, Zhu Qing, Zhang Yanan
School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China.
School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China.
Eur J Med Chem. 2018 Jan 20;144:398-409. doi: 10.1016/j.ejmech.2017.12.061. Epub 2017 Dec 20.
A series of novel β-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these β-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC values of 0.53-1.56 μM, which was considerably more potent than harmine (IC = 46.7-55.3 μM) and also three-to ten-fold lower than that of SAHA (IC = 4.48-6.26 μM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and α-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway.
设计并合成了一系列新型的基于β-咔啉的异羟肟酸酯衍生物12a-k，并在一系列体外实验中评估了它们的生物活性。这些β-咔啉衍生物中的几种不仅表现出优异的HDAC1/3/6抑制作用，还对五种人类癌细胞显示出显著的抗肿瘤活性。最有效的化合物12f对癌细胞系表现出最高的抗癌效力，IC值为0.53-1.56μM，其效力远高于哈尔明（IC = 46.7-55.3μM），也比SAHA（IC = 4.48-6.26μM）低三到十倍。免疫印迹分析表明，12f剂量依赖性地抑制组蛋白H3和α-微管蛋白的乙酰化，证实了其HDAC抑制作用。此外，12f通过浓度依赖性地抑制细胞周期相关蛋白CDK1和细胞周期蛋白B，使HepG2细胞在G2/M期显著停滞。有趣的是，12f还通过同时降低MMP2和MMP9的蛋白水平并抑制MAPK信号通路发挥强大的抗转移活性。
