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首页> 外文期刊>RSC Advances >Discovery of novel quinazolinones and their acyclic analogues as multi-kinase inhibitors: design, synthesis, SAR analysis and biological evaluation
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Discovery of novel quinazolinones and their acyclic analogues as multi-kinase inhibitors: design, synthesis, SAR analysis and biological evaluation

机译：发现新型喹唑啉酮及其作为多激酶抑制剂的无循环类似物：设计，合成，SAR分析和生物学评估

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摘要

This work deals with the design and synthesis of some novel 6-iodo-2-(pyridin-3/4-yl)-3-substituted quinazolin-4-one derivatives 8a-l, 10a-h, 13-18 in addition to certain acyclic analogues thereof viz. 9an and 12a-h. The molecular design strategy was based on structural analogy between the new compounds and reported quinazolines and their acyclic analogues. This design scheme led to the synthesis of 8 new intermediates and 58 new final quinazolinones. The target compounds were evaluated for their antitumor activity against a panel of nine cancer cell lines viz. breast cancer (MCF-7, MDAMB-231, MDAMB-435 and HS-578T), colon cancer (HT-29 and HCC-2998) and leukemia (CCRF-CEM, K-562 and HL-60). The quinazolinones 10a-h displayed exceptional antitumor activity and compounds 12a-h showed superior potency against MCF-7. These compounds were further subjected to in vivo study. Kinase inhibitory assay was also carried out to investigate the mechanism of action of the target compounds and they displayed the highest activity against ABL, ALK and c-RAF kinases. The 3-substituted quinazolinones 10a-h showed the highest kinase activity inhibitory potency against ABL, ALK and c-RAF with the most active compound in this study being the fluoro-3-pyridyl derivative 10a. These results are in compliance with the observed antitumor activity. Finally, a molecular modeling study was performed to interpret the potential molecular interactions of these chemotypes with the most responsive biomolecular target ABL.
机译：这项工作涉及一些新颖的6-Iodo-2-（Pyridin-3 / 4-基）-3取代的喹唑啉-4-一个衍生物8a-h，10a-h，13-18的设计和合成某些无循环类似物viz。 9an和12a-h。分子设计策略基于新化合物和报告的喹唑啉和其无循环类似物之间的结构类比。这种设计方案导致了8种新中间体和58个新的最终喹唑啉酮的合成。评估目标化合物，用于对九种癌细胞系VIZ面板进行抗肿瘤活性。乳腺癌（MCF-7，MDAMB-231，MDAMB-435和HS-578T），结肠癌（HT-29和HCC-2998）和白血病（CCRF-CEM，K-562和HL-60）。喹唑啉酮10A-H显示出优异的抗肿瘤活性和化合物12A-H表现出对MCF-7的卓越效力。这些化合物进一步进行体内研究。还进行激酶抑制测定以研究靶化合物的作用机理，它们对ABL，ALK和C-RAF激酶显示出最高的活性。 3取代的喹唑啉酮10A-H显示了在本研究中最活跃的化合物的含有最活跃的化合物的最高激酶活性抑制效力是氟-3-吡啶基衍生物10a。这些结果符合观察到的抗肿瘤活性。最后，进行分子建模研究以将这些趋化型的潜在分子相互作用与最敏感的生物分子靶ABL解释。

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  • 来源
    《RSC Advances》 |2016年第113期|共20页
  • 作者

    El Sayed Nehad A.; Eissa Amal A.; El Masry Ghada F.; Abdullah Mohamed M.; Arafa Reem K.;

  • 作者单位

    Cairo Univ Fac Pharm Dept Pharmaceut Chem Zainab 11562 Cairo Governora Egypt;

    Cairo Univ Fac Pharm Dept Pharmaceut Chem Zainab 11562 Cairo Governora Egypt;

    Cairo Univ Fac Pharm Dept Pharmaceut Chem Zainab 11562 Cairo Governora Egypt;

    Mapco Pharmaceut Ind Res Unit Balteim Egypt;

    Univ Sci &

    Technol Zewail City Sci &

    Technol Cairo 12588 Egypt;

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  • 正文语种 eng
  • 中图分类 化学;
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