Design, synthesis and in silico studies of new quinazolinone derivatives as antitumor PARP-1 inhibitors

Ramadan Sayed K.; Elrazaz Eman Z.; Abouzid Khaled A. M.; El-Naggar Abeer M.

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Design, synthesis and in silico studies of new quinazolinone derivatives as antitumor PARP-1 inhibitors

机译：作为抗肿瘤PARP-1抑制剂的新喹唑啉酮衍生物的设计，合成和硅研究

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Herein, we report an eco-friendly synthesis of a new series of quinazolinone-based derivatives as potential PARP-1 inhibitors. The 4-quinazolinone scaffold was utilized as a bioisostere to the phthalazinone core of the reference compound Olaparib. Most of the synthesized compounds displayed appreciable inhibitory activity against PARP1. Compound 12c showed inhibitory activity at IC50 = 30.38 nM comparable to Olaparib, which has IC50 = 27.89 nM. Cell cycle analysis was performed for compounds 12a and 12c, and both exhibited cell growth arrest at G2/M phase in the MCF-7 cell line. In addition, both compounds increased the programmed apoptosis compared to the control. Furthermore, molecular docking of the final compounds into the PARP-1 active site was executed to explore their probable binding modes. Also, a computational QSAR and in silico ADMET study was performed. The results of this study revealed that some of the newly synthesized compounds could serve as a new framework to discover new PARP-1 inhibitors with anti-cancer activity.

机译：在此，我们报告了一种环保合成的新系列基于喹唑啉基衍生物作为潜在的PARP-1抑制剂。 4-喹唑啉酮支架用作参考化合物奥拉帕里氏植物的生物偏见的生物纤维素核。大多数合成化合物对PARP1显示出明显的抑制活性。化合物12c在IC50 = 30.38nm的抑制活性与olaparib相当，其具有IC50 = 27.89nm。对化合物12a和12c进行细胞循环分析，并且在MCF-7细胞系中的G2 / M相显示细胞生长停滞。此外，与对照相比，两种化合物都增加了编程的细胞凋亡。此外，对最终化合物的分子对接进入PARP-1活性位点以探讨其可能的结合模式。此外，进行了计算QSAR和Silico备用备用研究。该研究的结果显示，一些新合成的化合物可以作为发现具有抗癌活动的新PARP-1抑制剂的新框架。

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《RSC Advances》 |2020年第49期|共18页
作者
Ramadan Sayed K.; Elrazaz Eman Z.; Abouzid Khaled A. M.; El-Naggar Abeer M.;
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Ain Shams Univ Fac Sci Dept Chem Cairo 11566 Egypt;

Ain Shams Univ Fac Sci Dept Pharmaceut Chem Cairo 11566 Egypt;

Ain Shams Univ Fac Sci Dept Pharmaceut Chem Cairo 11566 Egypt;

Ain Shams Univ Fac Sci Dept Chem Cairo 11566 Egypt;

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1. Design, synthesis and in silico studies of new quinazolinone derivatives as antitumor PARP-1 inhibitors [J] . Ramadan Sayed K., Elrazaz Eman Z., Abouzid Khaled A. M., RSC Advances . 2020,第49期

机译：作为抗肿瘤PARP-1抑制剂的新喹唑啉酮衍生物的设计，合成和硅研究
2. Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity [J] . Jie Zhou, Ming Ji, Haiping Yao, Organic & biomolecular chemistry . 2018,第17期

机译：喹唑啉-2,4（1H，3H）-二酮衍生物作为新型PARP-1 / 2抑制剂的发现：设计，合成及其抗肿瘤活性
3. Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment [J] . Le Yi, Gan Yiyuan, Fu Yihong, Trends in Ecology & Evolution . 2020,第1期

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4. Design, Synthesis and Biological Activity Study of Novel 2-(Pyrazol-5-yl)-2,3-dihydro-4(1H)-quinazolinone Derivatives [C] . Huibin Yang, Yunbo Cong, Haibo Yu, Proceedings of 4th international symposium on pesticides and environmental safety amp; 5th pan Pacific confernce on pesticide science amp; 8th international workshop on crop protection chemistry and regulatory harmonization . 2012

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6. Design synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment [O] . Yi Le, Yiyuan Gan, Yihong Fu, 2020

机译：喹唑啉酮衍生物作为EGFR抑制剂抗肿瘤治疗的设计合成和体外生物学评估
7. Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment [O] . Yi Le, Yiyuan Gan, Yihong Fu, 2020

机译：喹唑啉酮衍生物作为抗肿瘤治疗抑制剂的设计，合成和体外生物学评价

Design, synthesis and in silico studies of new quinazolinone derivatives as antitumor PARP-1 inhibitors

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