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. BE the best: Total synthesis of the cyclic depsipeptide BE‐43547A2 was achieved in 15 linear steps. BE‐43547A2 was shown to reduce the percentage of cancer stem cells in pancreatic cancer cell cultures by 21‐fold. In a tumorsphere‐formation assay, the number of tumorspheres formed in the BE‐43547A2‐treated group was about 46‐fold less than that in the doxycycline‐treated group. A murine tumor‐initiation assay confirmed that BE‐43547A2 can abolish tumorigenesis.