Design, synthesis, and biological evaluation of novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives as potential anticancer agents via PI3K inhibition
Design, synthesis, and biological evaluation of novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives as potential anticancer agents via PI3K inhibition
复制标题
通过 PI3K 抑制作为潜在抗癌剂的新型 6-(pyridin-3-yl) quinazolin-4(3H)-one 衍生物的设计、合成和生物学评价
DOI：
10.1016/j.bmc.2021.116346
复制
发表时间：
2021
影响因子：
3.5
通讯作者：
Yanhua Fan
中科院分区：
文献类型：
--
作者：
Huarong Yang;Qing Li;Mingzhi Su;Fang Luo;Yahua Liu;Daoping Wang;Yanhua Fan
PI 3 K/Akt通路的异常激活在大多数人类恶性肿瘤中被证实通过调节增殖、细胞周期和凋亡。因此，以PI 3 K/Akt通路为靶点的药物的发现和开发在抗肿瘤药物的开发中引起了研究者的极大兴趣。本论文设计并合成了15个6-（吡啶-3-基）喹唑啉-4（3 H）-酮衍生物。评价了所合成化合物的抗肿瘤活性，并探讨了其可能的作用机制。几个化合物对所测试的癌细胞包括人非小细胞肺癌（NSCLC）HCC 827、人神经母细胞瘤SH-SY 5 Y和肝细胞癌LM 3细胞显示出一定的增殖抑制活性。其中化合物7i和7 m对所有肿瘤细胞株的抑制活性最好，对肝癌细胞HCC 827的抑制活性更强，IC 50值分别为1.12 μM和1.20 μM。此外，7i和7 m对H7702细胞（人正常肝细胞）的抑制活性较低，IC 50值分别为8.66 μM和10.89 μM，比HCC 827细胞低近8倍。这些结果表明，化合物7i和7 m对肿瘤细胞具有一定的选择性。进一步的生物学研究表明，7i通过PI 3 K/Akt和caspase依赖的途径诱导肝癌细胞G2/M期阻滞和凋亡。总之，这些新的6-（吡啶-3-基）喹唑啉-4（3 H）-酮衍生物如化合物7i和7 m可能是开发潜在抗癌药物的先导化合物。
Abnormal activation of the PI3K/Akt pathway is demonstrated in most of human malignant tumors via regulation of proliferation, cell cycle, and apoptosis. Therefore, drug discovery and development of targeting the PI3K/Akt pathway has attracted great interest of researchers in the development of anticancer drugs. In this study, fifteen 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives were designed and synthesized. Anticancer activities of the synthetic compounds were evaluated and the potential mechanisms were explored. Several compounds showed certain proliferation inhibitory activity against the tested cancer cells including human non-small cell lung cancer (NSCLC) HCC827, human neuroblastoma SH-SY5Y and hepatocellular carcinoma LM3 cells. Among them, compound7iand7mshowed the best inhibitory activity against all the cancer cell lines and more active against HCC827 cells with IC50values of 1.12 μM and 1.20 μM, respectively. In addition,7iand7mshowed lower inhibitory activity against H7702 cells (human normal liver cells) with IC50values of 8.66 μM and 10.89 μM, respectively, nearly 8-fold lower than that in HCC827 cells. These results suggested that compounds7iand7mhad certain selectivity to tumor cells, compared to human normal cells. Further biological studies indicated7iinduced G2/M phase arrests and cell apoptosis of HCC827 cells via PI3K/Akt and caspase dependent pathway. Together, these novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives such as compound7iand7mmight be lead compounds for development of potential anti-cancer drugs.