School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China.
Sci Rep. 2017 Oct 6;7(1):12788. doi: 10.1038/s41598-017-12912-4.
We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.
我们通过靶向微管蛋白秋水仙碱结合位点合成了一系列新型的β-内酰胺-叠氮衍生物作为口服有效的抗肿瘤药物，并研究了它们的构效关系（SAR）。其中，化合物 28 通过诱导 G2/M 期阻滞和细胞凋亡以及抑制上皮间质转化，对 MGC-803 细胞表现出最有效的抗增殖活性，IC 值为 0.106μM。28 通过与秋水仙碱结合位点结合，作为微管蛋白聚合的新型抑制剂发挥作用。SAR 分析表明，β-内酰胺-叠氮衍生物的β-内酰胺 C-3 位的一个氢原子对于其有效的抗增殖活性是必需的。化合物 28 在体内也能有效抑制裸鼠体内 MGC-803 异种移植肿瘤的生长，而不会导致体重明显下降。这些结果表明，化合物 28 是一种很有前途的口服有效的抗癌药物，具有进一步临床应用的潜力。
