Natural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3′-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor activity. Among them, compound 8b revealed 55.15% and 55.50% inhibition for Top1 and Top2 at 25 μM, as well as 0.16 and 0.13 μM IC₅₀ value for MGC-803 and SGC-7901 cells, respectively; compound 9a revealed 70.50% and 71.81% inhibition for Top1 and Top2 at 25 μM, as well as 0.22 and 0.27 μM IC₅₀ value for MGC-803 and SGC-7901 cells, respectively. The further biological evaluation showed that they could functionally induce apoptosis, significantly arrest the cell cycle at the G2/M phase, and markedly inhibit cell proliferation, migration and invasion. In addition, compound 9a performed a tumor inhibitory rate of 36.35% and showed no apparent toxicity in vivo. Overall, these optimized protocols will advance the progression of cancer chemotherapy and can be used to expand the options for screening therapeutic cancer drugs.

天然产物吴茱萸碱是药物发现中最受青睐的支架之一，适合衍生化，可快速进行结构优化和构效关系研究。本工作完成了对N14-3'-氟苯基取代吴茱萸碱支架的综合SAR研究，筛选出抗肿瘤活性高、对Top1和Top2有良好抑制作用的化合物。测试的吴茱萸碱衍生物表现出优异的广谱抗肿瘤活性。其中，化合物8b在25 μM时对Top1和Top2的抑制率为55.15%和55.50%，对MGC-803和SGC-7901细胞的IC ₅₀值分别为0.16和0.13 μM；化合物9a_{显示在 25 μM 时 Top1 和 Top2 的抑制率为 70.50% 和 71.81%，MGC-803 和 SGC-7901 细胞的 IC 50}值分别为 0.22 和 0.27 μM 。进一步的生物学评价表明，它们可以在功能上诱导细胞凋亡，显着阻滞细胞周期在G2/M期，并显着抑制细胞增殖、迁移和侵袭。此外，化合物9a的肿瘤抑制率为36.35%，在体内没有表现出明显的毒性。总体而言，这些优化方案将促进癌症化疗的进展，并可用于扩大筛选治疗性癌症药物的选择。