[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds H1–H18 against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound H12 exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC₅₀ values of 9.47, 9.58 and 13.1 μM, respectively, which were more potent than that of the positive drug 5-Fu. In addition, compound H12 could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound H12 exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound 12 induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, H12, might be a valuable hit compound for the development of anticancer agents.

中文翻译：

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[1,2,4]三唑并[1,5-a]嘧啶吲哚衍生物通过抑制ERK信号通路对胃癌细胞MGC-803的设计、合成和生物学评价

[1,2,4]三唑并[1,5- a ]嘧啶和吲哚骨架广泛用于设计抗癌剂。因此，本工作采用分子杂交策略设计合成了一系列[1,2,4]三唑并[1,5- a ]嘧啶吲哚衍生物。测试了目标化合物H1 – H18对三种人类癌细胞系 MGC-803、HCT-116 和 MCF-7 的抗增殖活性。其中，化合物H12对 MGC-803、HCT-116 和 MCF-7 细胞的抗增殖活性最强，IC ₅₀值分别为 9.47、9.58 和 13.1 μM，比阳性药物5更有效。 -傅。此外，复合H12可以剂量依赖性地抑制MGC-803细胞的生长和集落形成。化合物H12对 ERK 信号通路具有显着抑制作用，导致 ERK1/2、c-Raf、MEK1/2 和 AKT 的磷酸化水平降低。此外，化合物12诱导细胞凋亡和 G2/M 期阻滞，并调节 MGC-803 细胞中的细胞周期相关蛋白和凋亡相关蛋白。总之，我们在此报告 [1,2,4]三唑并[1,5- a ]嘧啶吲哚衍生物，通过抑制 ERK 信号通路和最活跃的化合物H12用作抗癌剂，可能是一个有价值的打击用于开发抗癌剂的化合物。