School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China.
Eur J Med Chem. 2019 Dec 1;183:111731. doi: 10.1016/j.ejmech.2019.111731. Epub 2019 Sep 25.
With the expectation to find out new anti-gastric cancer agents with high efficacy and selectivity, a series of novel tertiary sulfonamide derivatives were synthesized and the anti-cancer activity was studied in three selected cancer cell lines (MGC-803, PC-3, MCF-7) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells and were more potent than the positive control (5-Fu). The structure-activity relationship of tertiary sulfonamide derivatives was explored in this report. Among the tested compounds, compound 13g containing benzimidazole moiety showed the best anti-proliferation activities against MGC-803 cells (IC = 1.02 μM), HGC-27 cells (IC = 1.61 μM), SGC-7901 (IC = 2.30 μM) cells as well as the good selectivity between the cancer and normal cells. Cellular mechanism studies elucidated compound 13g inhibited the colony formation of gastric cancer cell lines. Meanwhile, compound 13g arrested cell cycle at G2/M phase and induced cell apoptosis. Mechanistically, compound 13g markedly decreased p-Akt and p-c-Raf expression, which revealed that compound 13g targeted gastric cancer cell lines via interfering with AKT/mTOR and RAS/Raf/MEK/ERK pathways. All the findings suggest that compound 13g might be a valuable lead compound for the anti-gastric cancer agents.
为了寻找高效、高选择性的新型抗胃癌药物，我们合成了一系列新型叔磺酰胺衍生物，并在三种选定的癌细胞系（MGC-803、PC-3、MCF-7）中进行了体外抗癌活性研究。一些合成的化合物能显著抑制这些测试癌细胞的增殖，且活性强于阳性对照（5-Fu）。本报告探讨了叔磺酰胺衍生物的构效关系。在测试的化合物中，含苯并咪唑结构的化合物 13g 对 MGC-803 细胞（IC=1.02 μM）、HGC-27 细胞（IC=1.61 μM）、SGC-7901 细胞的增殖抑制活性最好，对癌细胞和正常细胞的选择性也较好。细胞机制研究表明，化合物 13g 能抑制胃癌细胞系的集落形成。同时，化合物 13g 将细胞周期阻滞在 G2/M 期，并诱导细胞凋亡。机制上，化合物 13g 显著降低了 p-Akt 和 p-c-Raf 的表达，表明化合物 13g 通过干扰 AKT/mTOR 和 RAS/Raf/MEK/ERK 通路靶向胃癌细胞系。所有结果表明，化合物 13g 可能是一种有价值的抗胃癌药物先导化合物。
