Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, Iran.
School of Chemistry, College of Science, University of Tehran, Tehran, Iran.
Chem Biol Drug Des. 2018 Jul;92(1):1373-1381. doi: 10.1111/cbdd.13203. Epub 2018 May 18.
In this work, a wide range of novel quinazolin-4(3H)-one linked to 1,2,3-triazoles was designed, synthesized, and evaluated against a panel of three human breast (MDA-MB-231, MCF-7, T-47D), lung (A549), and prostate (PC3) cancer cell lines. Our results revealed that the anticancer activity of the synthesized compounds was selectively affected by the presence of methoxy group on the linker between quinazolinone and 1,2,3-triazole moieties. According to the calculated IC values, compounds 6q, 6w, and 6x showed good cytotoxicity against breast cancer cell lines even more effective than the reference drug, etoposide. Compounds 6q and 6u were found to be potent compounds against A549, non-small-cell lung cancer (NSCLC), comparing with erlotinib. Also, the morphological analysis by acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that potent compounds induced apoptosis in human cancer cell lines. Molecular docking studies were performed to clarify the inhibition mode of compounds 6g, 6u, 6w, and 6x over the EGFR active site. The most promising compounds, 6q and 6u, possessing 3-methoxy group were well oriented to the gatekeeper hydrophobic pocket of EGFR active site and interact well with Ala719, Val702, and Leu820 through hydrophobic interaction.
在这项工作中，设计、合成了一系列新型的喹唑啉-4(3H)-酮与 1,2,3-三唑相连的化合物，并对三种人乳腺癌（MDA-MB-231、MCF-7、T-47D）、肺癌（A549）和前列腺癌（PC3）细胞系进行了评估。我们的结果表明，合成化合物的抗癌活性选择性地受到连接喹唑啉酮和 1,2,3-三唑部分的连接子上甲氧基存在的影响。根据计算的 IC 值，化合物 6q、6w 和 6x 对乳腺癌细胞系表现出良好的细胞毒性，甚至比参考药物依托泊苷更有效。化合物 6q 和 6u 被发现对非小细胞肺癌（NSCLC）A549 具有很强的抑制作用，与厄洛替尼相比。此外，吖啶橙/溴化乙锭双重染色试验和流式细胞术分析的形态学分析表明，有效化合物诱导了人癌细胞系的细胞凋亡。进行了分子对接研究，以阐明化合物 6g、6u、6w 和 6x 在 EGFR 活性部位的抑制模式。具有 3-甲氧基的最有前途的化合物 6q 和 6u 很好地定向 EGFR 活性部位的守门员疏水口袋，并通过疏水相互作用与 Ala719、Val702 和 Leu820 很好地相互作用。
