Tumor angiogenesis is closely associated with the metastasis and progression of non–small cell lung cancer (NSCLC), a highly vascularized solid tumor. However, novel therapeutics are lacking for the treatment of this cancer. Here, we developed a series of 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazol analogs (6a–6x) as tubulin colchicine-binding site inhibitors, aiming to find a novel promising drug candidate for NSCLC treatment. We first identified 2-(2-fluorophenyl)-3-(3,4,5-trimethoxybenzoyl)-5-(3-hydroxyazetidin-1-yl)-2H-1,2,3-triazole (6h) as a hit compound, which inhibited angiogenesis induced by NSCLC cells both in vivo and in vitro. In addition, our data showed that 6h could tightly bind to the colchicine-binding site of tubulin and inhibit tubulin polymerization. We also found that 6h could effectively induce G2/M cell cycle arrest of A549 and H460 cells, inhibit cell proliferation, and induce apoptosis. Furthermore, we showed 6h had the potential to inhibit the migration and invasion of NSCLC cells, two basic characteristics of tumor metastasis. Finally, we found 6h could effectively inhibit tumor progression in A549 xenograft mouse models with minimal toxicity. Taken together, these findings provide strong evidence for the development of 6h as a promising microtubule colchicine-binding site inhibitor for NSCLC treatment.

肿瘤血管生成与高度血管化的实体瘤非小细胞肺癌（NSCLC）的转移和进展密切相关。然而，缺乏治疗这种癌症的新疗法。在这里，我们开发了一系列 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-取代的 1,2,3-triazol 类似物 ( 6a–6x ) 作为微管蛋白秋水仙碱结合位点抑制剂，旨在寻找一种新的有前途的NSCLC治疗候选药物。我们首先将 2-(2-fluorophenyl)-3-(3,4,5-trimethoxybenzoyl)-5-(3-hydroxyazetidin-1-yl)-2 H -1,2,3-triazole ( 6h ) 鉴定为hit 化合物，在体内和体外均抑制 NSCLC 细胞诱导的血管生成。此外，我们的数据显示，6h能与微管蛋白的秋水仙碱结合位点紧密结合，抑制微管蛋白聚合。我们还发现6h可以有效诱导A549和H460细胞的G2/M细胞周期停滞，抑制细胞增殖，诱导细胞凋亡。此外，我们发现6h有可能抑制 NSCLC 细胞的迁移和侵袭，这是肿瘤转移的两个基本特征。最后，我们发现6h可以有效抑制 A549 异种移植小鼠模型中的肿瘤进展，且毒性最小。总之，这些发现为开发6h作为用于 NSCLC 治疗的有前途的微管秋水仙碱结合位点抑制剂提供了强有力的证据。