Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak-Bcl-xl Complex Reorganization in Bladder Cancer Cells
Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak-Bcl-xl Complex Reorganization in Bladder Cancer Cells
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酞嗪并[1,2-b]喹唑啉酮作为 p53 激活剂：膀胱癌细胞中的细胞周期停滞、凋亡反应和 Bak-Bcl-xl 复合物重组
DOI：
10.1021/acs.jmedchem.6b01769
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发表时间：
2017
影响因子：
7.3
通讯作者：
Gui-Fa Su
中科院分区：
文献类型：
--
作者：
Guo-Hai Zhang;Jing-Mei Yuan;Gang Qian;Chen-Xi Gu;Kai Wei;Dong-Liang Mo;Jiang-Ke Qin;Yan Peng;Zu-Ping Zhou;Cheng-Xue Pan;Gui-Fa Su
p53失活是癌症治疗无反应性的临床定义特征。因此，非常需要通过恢复p53功能来开发抗癌剂。1在本文中，发现合成的酞嗪并[1，2-B]喹唑啉酮作为膀胱癌细胞中的p53激活剂。10-溴-5-（2-二甲氨基-乙氨基）酞嗪并[1，2-B]喹唑啉-8-酮（5da）被认为是最有前途的候选药物，其抗癌活性和作用机制都很好。5da在低至6 mg/kg的剂量下对多种癌细胞系表现出很强的抗癌活性，并显著降低异种移植模型中的肿瘤生长。此外，5d可使细胞周期停滞在S/G2期，诱导细胞凋亡，改变细胞大小，并通过增加亚G1期细胞的比例导致细胞死亡。分子机制研究表明，5 d处理后，线粒体中磷酸化p53的积累导致巴克的构象激活，从而引起细胞凋亡，最终导致不可逆的癌细胞抑制。我们的研究为磷酸化p53依赖的喹唑啉酮类化合物的分子相互作用和抗癌机制提供了新的见解。
p53 inactivation is a clinically defined characteristic for cancer treatment-nonresponsiveness. It is therefore highly desirable to develop anticancer agents by restoring p53 function.1 Herein the synthesized phthalazino[1,2-b]quinazolinones were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as the most promising candidate in view of both its anticancer activity and mechanisms of action.5daexhibited strong anticancer activity on a broad range of cancer cell lines and significantly reduced tumor growth in xenograft models at doses as low as 6 mg/kg. Furthermore,5dacaused cell cycle arrest at S/G2 phase, induced apoptosis, changed cell size, and led to cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that accumulation of phospho-p53 in mitochondria after5datreatment resulted in conformational activation of Bak, thereby evoking cell apoptosis, finally leading to irreversible cancer cell inhibition. Our present studies furnish new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent quinazolinone compound.