Total Syntheses and Biological Activities of Vinylamycin Analogues

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.