含α,β-烯酮片段的喹啉类化合物的合成及抗肿瘤活性

Synthesis and antitumor activity evaluation of quinoline derivatives containing α,β-enone fragments

目的设计并合成新型喹啉类化合物,并研究其体外抗肿瘤细胞增殖和对拓扑异构酶的抑制活性。方法以苯胺、乙酰乙酸乙酯、溴化苄、芳香酮为原料,经过Conrad-Limpach合成、Williamson合成、氧化、羟醛缩合等反应合成一系列目标化合物。采用MTT法测试目标化合物体外对人肝癌细胞Hep G2、肺癌细胞A549、前列腺癌细胞LNCaP的抗增殖活性;通过拓扑异构酶介导的DNA松散实验考察目标化合物对拓扑异构酶的抑制活性。结果与结论合成了30个未见文献报道的新型喹啉类化合物,其结构经~1H-NMR、^(13)C-NMR、MS谱确证;化合物Ⅱ1在50μmol·L^(-1)时对拓扑异构酶Ⅱ具有较强的抑制活性;大部分目标化合物对所测试的3种肿瘤细胞表现出较强的细胞毒活性。构效关系研究表明,取代基对化合物的抗增殖活性具有较大的影响,在苄基的对位引入氟原子化合物的活性最好。

Quinoline and chalcone derivatives have been reported to have various bioactivities, especially antitumor activity. In this study, a series of quinoline containing chalcone derivatives were designed and synthesized. The structures of the target compounds were identified by ^1H-NMR, ^13C-NMR and MS spectra. The antiproliferative activities in three human tumor cell lines were tested by MTT assay, and the topoisomerase inhibitory activities of target compounds were tested by topoisomerase mediated DNA relaxation assay. The results indicated that compound Ⅱ 1 displayed potent Topo Ⅱ inhibition activity at 50 μmol· L^ -1. Most compounds showed strong cytotoxicties against HepG2, A549, LNCaP cancer cells. The structure-activity relationships studies indicated that changing the substituents dramatically impact the cytotoxicties. The compounds showed the best cytotoxic activities when the fluorine substituent is introduced to the para-position of the benzene ring.