Disrupting microtubule dynamics has emerged as a promising strategy for cancer therapy. Novel trimethoxyanilino-substituted pyrimidine and quinazoline derivatives were designed and synthesized to serve as potent microtubule-inhibiting agents with anti-proliferative activity. Compound 2k demonstrates high efficacy against B16–F10 cancer cells at low nanomolar concentrations, with an IC50 of 0.098 ± 0.006 μM, which is comparable to colchicine. Mechanistic studies have revealed that 2k has the ability to inhibit microtubule protein polymerization in vitro, resulting in cell cycle arrest and apoptosis. Furthermore, 2k inhibits tumor cell migration and exhibits significant anti-tumor efficacy in a melanoma tumor model without causing obvious toxicity. In summary, the pyrimidine derivative 2k exhibits excellent anticancer activity and provides a new scaffold for the development of novel microtubule inhibitors, which deserves further in-depth research.

中文翻译：

---

新型嘧啶和喹唑啉类似物的设计、合成和抗肿瘤评价


破坏微管动力学已成为癌症治疗的一种有前途的策略。设计并合成了新型三甲氧基苯胺取代的嘧啶和喹唑啉衍生物，作为具有抗增殖活性的有效微管抑制剂。化合物 2k 在低纳摩尔浓度下对 B16-F10 癌细胞表现出高效，IC50 为 0.098 ± 0.006 μM，与秋水仙碱相当。机制研究表明，2k 具有在体外抑制微管蛋白聚合的能力，导致细胞周期停滞和细胞凋亡。此外，2k 抑制肿瘤细胞迁移，并在黑色素瘤肿瘤模型中表现出显着的抗肿瘤功效，而不会引起明显的毒性。综上所述，嘧啶衍生物 2k 表现出优异的抗癌活性，为新型微管抑制剂的开发提供了新的支架，值得进一步深入研究。