Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak–Bcl-xl Complex Reorganization in Bladder Cancer Cells,Journal of Medicinal Chemistry

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Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak–Bcl-xl Complex Reorganization in Bladder Cancer Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-15 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01769
Guo-Hai Zhang _{1,

2} , Jing-Mei Yuan ₁ , Gang Qian ₁ , Chen-Xi Gu ₁ , Kai Wei ₁ , Dong-Liang Mo ₁ , Jiang-Ke Qin ₁ , Yan Peng ₁ , Zu-Ping Zhou ₂ , Cheng-Xue Pan ₁ , Gui-Fa Su ₁

Affiliation

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. 5da exhibited 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, 5da caused 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 after 5da treatment 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.

中文翻译：

Phthalazino [1,2- b ]喹唑啉酮类作为p53激活剂：膀胱癌细胞的细胞周期阻滞，凋亡反应和Bak-Bcl-xl复合物的重组。

p53失活是癌症治疗无反应的临床定义特征。因此，非常需要通过恢复p53的功能来开发抗癌药。1在本文中，发现合成的酞菁[1,2- b ]喹唑啉酮是膀胱癌细胞中的p53激活剂。考虑到其抗癌活性和作用机理，10-Bromo-5-（2-二甲基氨基-乙基氨基）酞嗪[1,2 - b ]喹唑啉-8-一（5da）被认为是最有希望的候选者。5da在低至6 mg / kg的剂量下对多种癌细胞系均表现出强大的抗癌活性，并在异种移植模型中显着降低了肿瘤的生长。而且5da导致细胞周期停滞在S / G2期，诱导细胞凋亡，改变细胞大小，并通过增加亚G1细胞的比例导致细胞死亡。分子机制研究表明5da处理后线粒体中磷酸化p53的积累导致Bak的构象活化，从而引起细胞凋亡，最终导致不可逆的癌细胞抑制作用。我们目前的研究为依赖磷酸化p53的喹唑啉酮化合物的分子相互作用和抗癌机制提供了新的见解。

更新日期：2017-08-15

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