Total Syntheses and Biological Activities of Vinylamycin Analogues

Abstract

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.

Cyclic Depsipeptide BE‐43547A2: Synthesis and Activity against Pancreatic Cancer Stem Cells

“…From the results of an MTT assay, BE‐43547A 2 was the most effective at inhibiting the growth of Panc‐1 cells compared to the other derivatives. Xenograft zebrafish model experiments using Panc‐1 cells further demonstrated that BE‐43547A 2 shows higher anti‐pancreatic cancer activity than the compounds 2 , 2 a , and TBDPS‐ ent ‐vinylamycin (Figures S4 and S5). The significantly reduced inhibitory activities of 1 c , 2 , 2 a , and 2 b imply that both a double bond at C8−C9 and an S configuration at C15 are essential to maintain inhibitory activity against Panc‐1 cells.…”

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

“…Treatment of engrafted leukemic blasts from patient 4 reflected the poor response during the treatment coarse. Zebrafish have received more attention during the last decade as an embryonic model host for xenografts, with nine publications exploring engraftment of other leukemic blast cell types to date [21,24,25,36,[38][39][40][41]. The ALL-ZeFiX assay both provides proof-of-principle for BCP-ALL exgraftment and extends the clinical utility of drug testing in immunosuppressed zebrafish avatars with quantifiable endpoint analysis and a 5-day assay format.…”

Cyclic Depsipeptide BE‐43547A2: Synthesis and Activity against Pancreatic Cancer Stem Cells

“…From the results of an MTT assay,B E-43547A 2 was the most effective at inhibiting the growth of Panc-1 cells compared to the other derivatives. Xenograft zebrafish model experiments using Panc-1 cells further demonstrated that BE-43547A 2 shows higher antipancreatic cancer activity than the compounds 2, 2a,a nd TBDPS-ent-vinylamycin [14] (Figures S4 and S5). Thes ignificantly reduced inhibitory activities of 1c, 2, 2a,and 2b imply that both ad ouble bond at C8 À C9 and an S configuration at C15 are essential to maintain inhibitory activity against Panc-1c ells.…”