Fu Xiang-Jing, Huang Jiao, Li Na, Liu Yun-He, Liu Qiu-Ge, Yuan Shuo, Xu Yan, Chen Yi-Fan, Zhao Yu-Xuan, Song Jian, Zhang Sai-Yang, Bai Yi-Ru
Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, 450018, China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
Eur J Med Chem. 2023 Oct 17;262:115883. doi: 10.1016/j.ejmech.2023.115883.
In this work, we utilized the N-benzylaryl derivative 9 as a lead compound and employed the molecular hybridization strategy by introducing cinnamoyl fragments to successfully design and synthesize 33 novel N-benzylaryl cinnamide derivatives 15a∼15 ag. The in vitro antiproliferative activities were explored, and the preliminary analysis and summary of their structure-activity relationship were conducted. The majority of the compounds demonstrated significant inhibitory potency on MGC-803, HCT-116 and KYSE450 cells with IC values below 0.5 μM. Among them, compound 15e (MY-1076) exhibited the most effective effect on the proliferative inhibition of MGC-803, SGC-7901, HCT-116 and KYSE450 cells with IC values of 0.019, 0.017, 0.020 and 0.044 μM, respectively, which is more potent than colchicine and the lead compound 9. Additionally, compound 15e (MY-1076) still exhibited significant inhibitory proliferation activity against 13 other types of tumor cells (IC values < 0.1 μM). Further studies revealed that compound 15e (MY-1076) could effectively inhibit tubulin polymerization by acting on the β-tubulin colchicine binding site, thereby disrupting microtubule network assembly and mitotic progression. Additionally, compound 15e (MY-1076) also demonstrated a notable inhibitory effect on the oncogenic protein YAP by inducing its degradation. Compound 15e (MY-1076) could dose-dependently induce G2/M phase arrest and cell apoptosis, effectively inhibit the colony formatting ability and cause morphological changes in MGC-803 and SGC-7901 cells. Compound 15e (MY-1076) exhibited significant regulatory effects on the expression levels of cell cycle and apoptosis-related proteins. Taken together, we here reported a novel N-benzylaryl cinnamide derivative 15e (MY-1076) as a tubulin polymerization inhibitor capable of promoting degradation of YAP, which held great potential as an anti-gastric cancer agent.
在本研究中，我们以N-苄基芳基衍生物9作为先导化合物，并采用分子杂交策略，引入肉桂酰片段，成功设计并合成了33种新型N-苄基芳基肉桂酰胺衍生物15a∼15ag。研究了它们的体外抗增殖活性，并对其构效关系进行了初步分析和总结。大多数化合物对MGC-803、HCT-116和KYSE450细胞表现出显著的抑制活性，IC值低于0.5μM。其中，化合物15e（MY-1076）对MGC-803、SGC-7901、HCT-116和KYSE450细胞的增殖抑制作用最为显著，IC值分别为0.019、0.017、0.020和0.044μM，比秋水仙碱和先导化合物9更具活性。此外，化合物15e（MY-1076）对其他13种肿瘤细胞仍表现出显著的抑制增殖活性（IC值<0.1μM）。进一步研究表明，化合物15e（MY-1076）可通过作用于β-微管蛋白秋水仙碱结合位点有效抑制微管蛋白聚合，从而破坏微管网络组装和有丝分裂进程。此外，化合物15e（MY-1076）还通过诱导致癌蛋白YAP降解对其表现出显著的抑制作用。化合物15e（MY-1076）可剂量依赖性地诱导G2/M期阻滞和细胞凋亡，有效抑制MGC-803和SGC-7901细胞的集落形成能力并引起形态变化。化合物15e（MY-1076）对细胞周期和凋亡相关蛋白的表达水平具有显著的调节作用。综上所述，我们在此报道了一种新型N-苄基芳基肉桂酰胺衍生物15e（MY-1076）作为一种能够促进YAP降解的微管蛋白聚合抑制剂，作为抗胃癌药物具有巨大潜力。
