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为了发现新型姜黄素类抗肿瘤先导化合物,通过1,3-偶极环加成反应合成了14个螺杂环单羰基姜黄素类似物.该反应利用无需加催化剂的“一锅煮”方法合成,具有环境友好的优点.所有化合物结构经ESI-MS、ESI-HRMS和1H NMR确认,通过X衍射确证B6的晶体结构为单斜晶系,该类化合物的合成具有良好的区域选择性和立体选择性.通过噻唑兰(MTT)法测定所有化合物对人胃癌细胞SGC-7901、神经胶质瘤细胞U251、人大细胞肺癌细胞株NCI-H460的增殖抑制活性,部分化合物表现出了较好的活性.其中B1、B6、B7和B11对三种肿瘤细胞均表现出较好的抗肿瘤活性,而对正常人肝细胞HL-7702显示了相对较低的细胞毒性.化合物B1和B7均能明显诱导凋亡相关蛋白含半胱氨酸的天冬氨酸蛋白水解酶3(caspase3)和多聚ADP-核糖聚合酶(PARP)的活化,诱导肿瘤细胞发生凋亡.所合成的螺杂环单羰基姜黄素类似物为新型的抗肿瘤化合物,该类化合物可能在靶向抗肿瘤药物研发方面具有较好的研究前景.
In order to find a novel curcuminoid antitumor lead compound, 14 spiroheterocyclic monocarbonylcurcumin analogues were synthesized by 1,3-dipolar cycloaddition.The reaction was performed using the “one-pot” method without catalyst addition , Which has the advantage of environment friendliness.The structures of all the compounds were confirmed by ESI-MS, ESI-HRMS and 1H NMR. The crystal structure of B6 was confirmed to be monoclinic by X-ray diffraction. The synthesis of these compounds showed good regioselectivities and three- Selectivity.The inhibitory activity of all compounds on the proliferation of human gastric cancer cell line SGC-7901, glioma cell line U251 and human large cell lung cancer cell line NCI-H460 was determined by MTT assay, and some compounds showed good activity .B1, B6, B7 and B11 showed good antitumor activity against all three kinds of tumor cells, but showed relatively low cytotoxicity to normal human hepatocyte HL-7702.Compounds B1 and B7 were significantly induced Apoptosis of tumor cells was induced by the activation of caspase 3 and poly ADP-ribose polymerase (PARP) involved in apoptosis-related proteins, including spiroheterocyclic monocarbonyl Curcumin analogues are new Of the anti-tumor compounds, which may have better research prospects in the development of targeted anti-tumor drugs.