Asymmetric total synthesis of the cyclic depsipeptide BE-43547A 2 was achieved in 15 linear steps on a350 mg scale in one batch. The synthesis features the highly diastereoselective construction of an a-hydroxy-b-ketoamide through ahydroxylation with ad .r.o fu pt o8 6:1. BE-43547A 2 significantly reduces the percentage of pancreatic cancer stem cells (PCSCs) in Panc-1 cell cultures,a nd dramatically reduces the tumorsphere-forming capability of Panc-1 cells.A ni nvivo tumor-initiation assay, ag old standardf or cancer stem cell assays,c onfirmed 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 ap romising starting point for discovering new PCSC-targeting drugs.Pancreatic cancer is one of the most refractory cancers and has an overall 5-year survival rate of only 1-4 %. [1] Pancreatic cancer stem cells (PCSCs) may play ak ey role in the carcinogenesis,m etastasis,a nd drug resistance of pancreatic cancer. [2] Forexample,CD24 + CD44 + ESA + pancreatic cancer cells,t he commonly recognized PCSCs,a re able to generate tumors in half of the tested mice with 100 cells injected, which demonstrated 100-fold higher tumorigenic potential than regular pancreatic cancer cells. [3] However,c ompounds targeting pancreatic cancer stem cells are still very rare.T he compounds with PCSC-selective activity that have entered clinical trials against pancreatic cancer are triptolide, AZD7762, and LDE225, which have modest PCSC selectivity. [4] Therefore,new types of compounds that can effectively target PCSCs are urgently needed.TheB E-43547 family,i solated from Streptomyces sp.,i s composed of cyclic depsipeptides that are structurally characterized by 4-amido-2,4-pentadienoate (APD) and a-hydroxy-b-ketoamide (Scheme 1). Preliminary biological assays of the BE-43547 family have indicated high cytotoxicity against various cancer cell lines. [5] Recently,P oulsen and coworkers made abreakthrough in designing the first synthetic route to the BE-43547 macrocyclic scaffold. [6] With their chemical synthesis of ent-BE-43547A 1 and the biosynthesis of the BE-43547 family,t hey determined the absolute configuration of BE-43547A 1 % A 2 and proposed that the originally reported 1 HNMR data for BE-43547A 1 and A 2 were incorrect. [6] Meanwhile they demonstrated that BE-43457A 1 and A 2 show significant hypoxia-selective growth inhibitory activity against human pancreatic cancer Panc-1 cells.Wealso confirmed hypoxia selectivity of BE-43547A 2 against MCF-7 and K562 cell lines (see Table S3 in the Supporting Information). Since intermittent [7] and sustained [8] hypoxia have been reported to induce cancer stem cell (CSC)-like properties resulting in the invasiveness and metastasis of pancreatic cancer cells,wespeculated that BE-43457s may target PCSCs. Forvalidation of the selectivity of BE-43457s towards PCSCs, ah ighly efficient synthetic route to provide sufficient BE-43457s is important. Herein, we report our total synthesis of BE-43547A 2 ,a long...
