Phthalazone连接的1,2,3-三唑共轭物：体外分子对接研究、合成、体内抗增殖和抑制激酶活性。
Phthalazone tethered 1,2,3-triazole conjugates: In silico molecular docking studies, synthesis, in vitro antiproliferative, and kinase inhibitory activities.
发表日期：2023 Feb 14
作者：
Mohamed A Abdelgawad, Syed Nasir Abbas Bukhari, Arafa Musa, Mohammed Elmowafy, AbdElAziz A Nayl, Ahmed H El-Ghorab, Mohamed Sadek Abdel-Bakky, Hany A Omar, Nasser Hadal Alotaibi, Hossam M Hassan, Mohammed M Ghoneim, Rania B Bakr
来源：
BIOORGANIC CHEMISTRY
摘要：
新的邻苯二酮系1,2,3-三氮唑衍生物12-21通过铜(I)-催化的炔基化邻苯二酮1与官能化叠氮化物2-11的点击反应合成。利用不同光谱技术，如IR、1H、13C、2D HMBC和2D ROESY NMR、EI MS和元素分析，确认了新的邻苯二酮-1,2,3-三氮唑结构12-21。评估了分子杂交物12-21对四种癌细胞系——结肠直肠癌、肝母细胞瘤、前列腺癌、乳腺腺癌和正常细胞系WI38的抗增殖效力。衍生物12-21的抗增殖评估显示，化合物16、18和21的活性比抗癌药物多柔比星强。当与SI值范围从0.75到1.61的多柔比星相比，化合物16对所测细胞系的选择性（SI）在3.35到8.84之间。将衍生物16、18和21评估其对VEGFR-2的抑制活性，结果表明衍生物16与索拉非尼（IC50 = 0.116 µM）相比具有强效活性（IC50 = 0.123 µM）。化合物16干扰了MCF7的细胞周期分布，并使S期细胞的百分比增加了1.37倍。对有效衍生物16、18和21进行的体外分子对接证实了该口袋内稳定的蛋白质-配体相互作用。版权所有©2023 Elsevier Inc.
New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.Copyright © 2023 Elsevier Inc. All rights reserved.