Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors.
Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors.
复制标题
新型吲哚衍生物作为有效秋水仙碱结合位点抑制剂的血管生成和抗白血病活性
DOI：
10.1080/14756366.2022.2032688
复制
发表时间：
2022-12
影响因子：
5.6
通讯作者：
Duan Y
中科院分区：
文献类型：
--
作者：
Yao Y;Huang T;Wang Y;Wang L;Feng S;Cheng W;Yang L;Duan Y
从我们的内部文库中筛选化合物DYT-1作为先导化合物（抑制微管蛋白聚合：IC50=25.6µM，抗斑马鱼血管生成：IC50=38.4µM，抗K562和Jurkat增殖：IC50分别=6.2和7.9µM）。进一步的药物化学条件研究发现，基于微管蛋白和斑马鱼的实验，化合物29e（抑制微管蛋白聚合：IC50=4.8µM，抗斑马鱼血管生成：IC50=3.6µM）对多种白血病细胞系（IC50= 0.09-1.22µM），特别是诱导凋亡的K562细胞显示出显著的纳摩尔效价。分子对接、分子动力学（MD）模拟、放射性配体结合实验和细胞微管网络破坏结果表明，29e稳定地结合于秋水仙花碱微管蛋白位点。29e显著抑制HUVEC试管的形成、迁移和侵袭。斑马鱼异种移植在体内证实了抗血管生成的作用。29e还能显著阻断K562细胞在斑马鱼异种移植模型血管和周围组织中的增殖和转移。29e具有良好的物理化学性质和代谢稳定性，可以被认为是一种有效的抗血管生成和白血病的候选药物，与微管蛋白秋水仙碱位点结合。
The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09–1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.
登录
查看更多内容
影响因子：
2.7
作者：
Iftikhar, Sunniya;Khan, Sardraz;Saleem, Rahman Shah Zaib
通讯作者：
Saleem, Rahman Shah Zaib
影响因子：
20.3
作者：
Petit, Isabelle;Karajannis, Matthias A.;Rafii, Shahin
通讯作者：
Rafii, Shahin
影响因子：
5.6
作者：
Ruan Y;Kim HN;Ogana H;Kim YM
通讯作者：
Kim YM
影响因子：
6.7
作者：
Chen, Kun;Zhang, Ya-Liang;Zhu, Hai-Liang
通讯作者：
Zhu, Hai-Liang
影响因子：
7.7
作者：
Ki, Soo Mi;Kim, Ji Hyun;Lee, Ji Eun
通讯作者：
Lee, Ji Eun