The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine , Tianjin 300457, People's Republic of China.
J Med Chem. 2017 Feb 9;60(3):1189-1209. doi: 10.1021/acs.jmedchem.6b01745. Epub 2017 Jan 20.
Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC = 4.86 μM) and be unstable in plasma (t = 0.54 h). A total of 24 vinylamycin analogues with modification of the OH group and chiral centers were generated via a combinatorial approach. The lead compound 1a was subsequently characterized as having the following: no antimicrobial activity, significantly higher plasma stability (t = 14.3 h), improved activity against K562 leukemia cells (IC = 0.64 μM), and up to 75% cell inhibition without significant toxicities in K562 cells xenograft zebrafish model. Furthermore, compound 1a maintained its activity against the breast cancer cell line MCF-7 under hypoxic conditions. In comparison, the activity of gemcitabine in the same hypoxic in vitro model of MCF-7 cells was 15-fold lower. Therefore, the present results demonstrate that 1a has great potential as an anticancer agent.
天然衍生的环二肽 vinylamycin 此前被报道具有抗生素活性。本文报道 vinylamycin 对 K562 白血病细胞具有活性（IC = 4.86 μM），但在血浆中不稳定（t = 0.54 h）。通过组合方法共生成了 24 种 vinylamycin 类似物，对 OH 基团和手性中心进行了修饰。先导化合物 1a 随后被表征为：无抗菌活性，显著提高了血浆稳定性（t = 14.3 h），对 K562 白血病细胞的活性（IC = 0.64 μM）提高，在 K562 细胞异种移植斑马鱼模型中没有明显毒性的情况下，细胞抑制率高达 75%。此外，化合物 1a 在缺氧条件下对乳腺癌细胞系 MCF-7 仍保持活性。相比之下，在 MCF-7 细胞相同的缺氧体外模型中，吉西他滨的活性低 15 倍。因此，本研究结果表明 1a 具有作为抗癌药物的巨大潜力。
