Dung Do T M, Huan Nguyen V, Cam Do M, Hieu Dao C, Hai Pham-The, Huong Le-Thi-Thu, Kim Jisung, Choi Jeong E, Kang Jong S, Han Sang-Bae, Nam Nguyen-Hai
Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Vietnam.
School of Medicine and Pharmacy, Hanoi National University, Hanoi, Vietnam.
Med Chem. 2018;14(8):831-850. doi: 10.2174/1573406414666180528111749.
Histone deacetylases (HDAC) enzymes are emerging as potential targets for cancer treatments. In this study, several series of novel hydroxamic acids incorporating 1-((1H- 1,2,3-triazol-4-yl)methyl)-3-substituted-2-oxoindolines were explored.
The compounds were designed using Autodock Vina program, then synthesized and evaluated in vitro and in silico for their inhibitory activity against HDACs. The cytotoxicity was measured by SRB method. The enzyme inhibitory effects of the compounds were evaluated by the fluorescent assay.
Biological evaluation showed that these hydroxamic acids were generally cytotoxic against four human cancer cell lines (SW620, colon; PC-3, prostate; AsPC-1, pancreas; NCI-H23, lung). Several compounds, e.g. 7g, 11c, and 11g, displayed up to 10-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. The synthesized compounds were also comparably potent to SAHA in inhibiting HDAC2. In particular, compound 11c displayed potential inhibitory effects against HDAC1, HDAC2, HDAC6, and HDAC8 with comparable or slightly higher potency than SAHA. Docking results on four class I and IIB isoenzymes indicated that these compounds tightly bound to HDACs at the active site with binding affinities much higher than that of SAHA. Finally, chemo-informatics approaches were employed to assess the pharmacokinetic and toxicity profiles of 7g and 11c. We identified degradation via phase II metabolism and toxicity two of the most serious problems that need further optimization.
Taking altogether our findings are encouraging and current hydroxamate derivatives are worth being considered as potential HDAC inhibitors and could be useful for further research on the development of new anti-cancer agents.
组蛋白脱乙酰酶（HDAC）作为癌症治疗的潜在靶点正逐渐崭露头角。在本研究中，探索了一系列新型异羟肟酸，其包含1-((1H-1,2,3-三唑-4-基)甲基)-3-取代-2-氧代吲哚啉。
使用Autodock Vina程序设计化合物，然后进行合成，并在体外和计算机模拟中评估其对HDAC的抑制活性。通过SRB法测量细胞毒性。通过荧光测定法评估化合物的酶抑制作用。
生物学评价表明，这些异羟肟酸对四种人类癌细胞系（SW620，结肠；PC-3，前列腺；AsPC-1，胰腺；NCI-H23，肺）通常具有细胞毒性。几种化合物，例如7g、11c和11g，在细胞毒性方面比SAHA（辛二酰苯胺异羟肟酸，伏立诺他）表现出高达10倍的效力。合成的化合物在抑制HDAC2方面也与SAHA具有相当的效力。特别地，化合物11c对HDAC1、HDAC2、HDAC6和HDAC8显示出潜在的抑制作用，其效力与SAHA相当或略高。对四种I类和IIB类同工酶的对接结果表明，这些化合物在活性位点与HDAC紧密结合，结合亲和力远高于SAHA。最后，采用化学信息学方法评估7g和11c的药代动力学和毒性概况。我们确定通过II期代谢降解和毒性是两个最严重的问题，需要进一步优化。
总体而言，我们的研究结果令人鼓舞，当前的异羟肟酸衍生物值得被视为潜在的HDAC抑制剂，并可能有助于进一步研究开发新的抗癌药物。
