Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Yushan Road, Qingdao 266003, China.
Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
Bioorg Med Chem Lett. 2023 Jul 15;91:129370. doi: 10.1016/j.bmcl.2023.129370. Epub 2023 Jun 8.
Plinabulin is a promising microtubule destabilizing agent in phase 3 clinical stage for treating non-small cell lung cancer. However, the high toxicity and the poor water solubility of plinabulin limited its use and more plinabulin derivatives need to be explored. Here, two series of 29 plinabulin derivatives were designed, synthesized and evaluated for their anti-tumor effect against three types of cancer cell lines. Most of derivatives exerted obvious inhibition to the proliferation of the cell lines tested. Among them, compound 11c exerted stronger efficiency than plinabulin, and the reason might be the additional hydrogen bond between the nitrogen atom of the indole ring in compound 11c and Gln134 of β-tubulin. Immunofluorescence assay showed that compound 11c at 10 nM significantly disrupted tubulin structure. Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.
泊马度胺是一种有前景的微管蛋白稳定剂，处于治疗非小细胞肺癌的 3 期临床阶段。然而，泊马度胺的高毒性和较差的水溶性限制了其应用，需要探索更多的泊马度胺衍生物。在这里，设计、合成了两个系列的 29 个泊马度胺衍生物，并评估了它们对三种癌细胞系的抗肿瘤作用。大多数衍生物对测试的细胞系的增殖表现出明显的抑制作用。其中，化合物 11c 比泊马度胺表现出更强的效果，原因可能是化合物 11c 中吲哚环的氮原子与β-微管蛋白的 Gln134 之间形成了额外的氢键。免疫荧光分析表明，化合物 11c 在 10 nM 时可显著破坏微管结构。化合物 11c 还可显著诱导细胞周期 G2/M 期阻滞和凋亡，呈剂量依赖性。这些结果表明，化合物 11c 可能是一种有潜力的抗癌药物候选物，作为抗微管蛋白剂。
