Total Syntheses and Biological Activities of Vinylamycin Analogues.

Authors :: Wang J
Kuang B
Guo X
Liu J
Ding Y
Li J
Jiang S
Liu Y
Bai F
Li L
Zhang Q
Zhu XY
Xia B
Li CQ
Wang L
Yang G
Chen Y
Source :: Journal of medicinal chemistry [J Med Chem] 2017 Feb 09; Vol. 60 (3), pp. 1189-1209. Date of Electronic Publication: 2017 Jan 20.
Publication Year :: 2017
Abstract: Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC <subscript>50</subscript> = 4.86 μM) and be unstable in plasma (t <subscript>1/2</subscript> = 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 <subscript>1/2</subscript> = 14.3 h), improved activity against K562 leukemia cells (IC <subscript>50</subscript> = 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.