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J Med Chem. 2017 Feb 9;60(3):1189-1209. doi: 10.1021/acs.jmedchem.6b01745. Epub 2017 Jan 20.

Total Syntheses and Biological Activities of Vinylamycin Analogues.

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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.
School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, People's Republic of China.
Hunter Biotechnology, Inc., F1A, building 5, no. 88 Jiangling Road, Binjiang Zone, Hangzhou, Zhejiang Province 310051, People's Republic of China.


Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC50 = 4.86 μM) and be unstable in plasma (t1/2 = 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 (t1/2 = 14.3 h), improved activity against K562 leukemia cells (IC50 = 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.

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