Total Syntheses and Biological Activities of Vinylamycin Analogues

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• 作者：Jinghan Wang ; Beijia Kuang ; Xiaoqian Guo ; Jianwei Liu ; Yahui Ding ; Jiangnan Li ; Shende Jiang ; Ying Liu ; Fang Bai ; Luyuan Li ; Quan Zhang ; Xiao-Yu Zhu ; Bo Xia ; Chun-Qi Li ; Liang Wang ; Guang Yang ; Yue Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：1189-1209
• 全文大小：900K
• ISSN：1520-4804

文摘

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 (t_1/2 = 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 (t_1/2 = 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.