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

Asymmetric total synthesis of the cyclic depsipeptide BE-43547A(2) was achieved in 15 linear steps on a 350 mg scale in one batch. The synthesis features the highly diastereoselective construction of an alpha-hydroxy-beta-ketoamide through alpha-hydroxylation with a d.r. of up to 86:1. BE-43547A(2) 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-43547A(2) can abolish the tumorigenesis of Panc-1 cells. The anti-PCSC activity of BE-43547A(2) could make this depsipeptide scaffold a promising starting point for discovering new PCSC-targeting drugs.