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

Asymmetric total synthesis of the cyclic depsipeptide BE-43547A₂ was achieved in 15 linear steps on a 350 mg scale in one batch. The synthesis features the highly diastereoselective construction of an α-hydroxy-β-ketoamide through α-hydroxylation with a d.r. of up to 86:1. BE-43547A₂ significantly reduces the percentage of pancreatic cancer stem cells (PCSCs) in Panc-1 cell cultures, and dramatically reduces the tumorsphere-forming capability of Panc-1 cells. An in vivo tumor-initiation assay, a gold standard for cancer stem cell assays, confirmed that BE-43547A₂ can abolish the tumorigenesis of Panc-1 cells. The anti-PCSC activity of BE-43547A₂ could make this depsipeptide scaffold a promising starting point for discovering new PCSC-targeting drugs.