Department of Medicinal Chemistry, College of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
J Med Chem. 2013 Feb 14;56(3):685-99. doi: 10.1021/jm301864s. Epub 2013 Jan 28.
A series of novel cyclopropylamide analogues of combretastatin-A4 (CA-4) were designed and synthesized. Most of them had significant in vitro antiproliferative activities, particularly for compounds 7i4, 7c4, 8a4, and 8c4. Moreover, compound 8c4 was also equally potent against paclitaxel resistant cancer cells. Interestingly, the novel cyclopropylamide analogues had different binding mechanisms from CA-4. Instead of inhibiting tubulin polymerization, these CA-4 derivatives were able to stimulate tubulin polymerization. Flow cytometry revealed that compound 8c4 arrested A549 cancer cells in the G2/M phase and resulted in cellular apoptosis. Further immunofluorescence assays revealed that compound 8c4 induced mitotic arrest in A549 cells through disrupting microtubule dynamics. In addition, compound 8c4 also effectively inhibited the tumor growth in the A549 xenograft model without causing significant loss of body weight. Compound 8c4 represents a novel class of microtubule-stabilizing agent and can be used as a promising lead for the development of new antitumor agents.
设计并合成了一系列新型的考布他汀 A4（CA-4）环丙酰胺类似物。它们中的大多数具有显著的体外增殖活性，特别是化合物 7i4、7c4、8a4 和 8c4。此外，化合物 8c4 对紫杉醇耐药的癌细胞也具有同等的抑制活性。有趣的是，这些新型的环丙酰胺类似物与 CA-4 具有不同的结合机制。这些 CA-4 衍生物不是抑制微管聚合，而是能够刺激微管聚合。流式细胞术显示，化合物 8c4 将 A549 癌细胞阻滞在 G2/M 期，并导致细胞凋亡。进一步的免疫荧光试验显示，化合物 8c4 通过破坏微管动力学诱导 A549 细胞的有丝分裂阻滞。此外，化合物 8c4 还能有效地抑制 A549 异种移植模型中的肿瘤生长，而不会导致体重明显下降。化合物 8c4 代表了一类新型的微管稳定剂，可作为开发新型抗肿瘤药物的有前途的先导化合物。
