Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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DOI：
10.1002/cbdv.201800502
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发表时间：
2019-04-01
影响因子：
2.9
通讯作者：
Nguyen-Hai Nam
中科院分区：
文献类型：
--
作者：
Doan Thanh Hieu;Duong Tien Anh;Nguyen-Hai Nam
本文介绍了各种系列的新型异羟肟酸的合成和生物活性的新的小分子靶向组蛋白去乙酰化酶的喹唑啉-4（3 H）-酮。生物学评价表明，这些异羟肟酸对三种人癌细胞系（SW 620，结肠癌; PC-3，前列腺癌; NCI-H23，肺癌）具有强效细胞毒性。就细胞毒性而言，大多数化合物显示出比SAHA（辛二酰苯胺异羟肟酸，伏立诺他）上级的细胞毒性。尤其是，发现N-羟基-7-（7-甲基-4-氧代喹唑啉-3（4 H）-基）庚酰胺（5 b）和N-羟基-7-（6-甲基-4-氧代喹唑啉-3（4 H）-基）庚酰胺（5c）（IC 50值，0.10-0.16m）的细胞毒性比SAHA（IC 50值为3.29-3.67m）高约30倍。在细胞毒性试验中，N-羟基-7-（4-氧代喹唑啉-3（4 H）-基）庚酰胺（5a; IC 50值为0.21- 0.38 m）的效力约为SAHA的10- 15倍。这些化合物还显示出相当的HDAC抑制效力，IC 50值在亚微摩尔范围内。分子对接实验表明，大多数化合物，如5 b和5c，严格结合HDAC 2的活性结合位点的结合亲和力远高于SAHA。
The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10-0.16m) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29-3.67m). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21-0.38m) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.