含苯并噻唑环的β-咔啉衍生物的合成及抗肿瘤活性

Synthesis and antitumor activity of novel β-carboline derivatives containing benzothiazole ring

为了寻找高效低毒的抗肿瘤药物,制备具有更好抗肿瘤活性的化合物,在前期研究基础上,设计并合成了10个苯并噻唑环取代的新型β-咔啉衍生物(Ⅶa-Ⅶj),通过核磁共振氢谱、核磁共振碳谱和高分辨质谱等方法确定了化合物的化学结构。采用噻唑蓝(MTT)法评估了目标化合物对肺癌细胞(A549)、胃癌细胞(BGC-823)、结肠癌细胞(CT-26)、肝癌细胞(Bel-7402)和乳腺癌细胞(MCF-7)的体外抑制活性,结果表明,大部分化合物都表现出了中度至强效的抗肿瘤活性,并且比其前一步中间体活性高。其中化合物Ⅶd对A549,BGC-823,Bel-7402和MCF-7显示出较好的抗肿瘤活性,IC50值分别为12.9±0.9、6.7±0.6、12.4±0.8和10.2±0.7μmol·L^(-1),其活性优于对照品顺铂。化合物Ⅶc对A549细胞的抑制作用效果优于顺铂2倍(IC50=15.8±2.4μmol·L^(-1)),其IC50值为7.7±0.5μmol·L^(-1),研究结果可为基于β-咔啉类结构的新型抗肿瘤药物分子设计提供重要参考。

In order to find efficient and low toxicity antitumor drugs, ten novel β-carboline derivatives containing benzothiazole ring were synthesized based on our previous studies. The chemical structure of the new synthesized compounds was established by ~1H NMR,13C NMR, and HRMS. Furthermore, the anticancer activities of all compounds were evaluated in vitro against A549, BGC-823, CT-6, Bel-7402, and MCF-7 cell lines by MTT assay. The results showed that most of the target compounds showed moderate to excellent cytotoxicity against the tested cell lines, superior to the intermediates Ⅵa-Ⅵj. Among them, compound Ⅶd showed the better antiproliferative activity against A549, BGC-823, Bel-7402, and MCF-7 cancer cell lines with IC50values of 12.9±0.9, 6.7±0.6, 12.4±0.8, and 10.2±0.7 μmol·L^(-1), respectively, and the activity was potent than positive cisplatin. In the cytotoxicity assay with A549 cells, compound Ⅶc showed two bolds higher cytotoxicity than cisplatin(IC50= 15.8±2.4 μmol·L^(-1)), with IC50values of 7.7±0.5 μmol·L^(-1). The research results in this paper provide useful reference for further design of novel anticancer agents based on the β-carboline fused benzothiazole scaffold.