Total Synthesis of the Tridecasaccharide Motif from Angelica sinensis APS-1 II Polysaccharide with Anti-leukemia Activity and Structure–Activity Relationship Studies

Abstract

A polysaccharide APS-1 II from a medicinal plant Angelica sinensis represents an interesting therapeutic agent against leukemia. However, the synthetic accessibility of the highly branched and complex APS-1 II polysaccharide with multiple 1, 2-cis-glycosidic linkages remains a difficult task, impeding the in-depth structure-activity relationship biological studies and the development of carbohydrates-based therapeutics against leukemia. Here, we report the first chemical synthesis of tridecasaccharide repeating unit together with shorter sequences 4-mer, 6-mer and 9-mer from APS-1 II polysaccharide via one-pot orthogonal glycosylation strategy based on glycosyl ortho-(1-phenylvinyl)benzoates, which precluded the potential issues such as aglycone transfer associated with one-pot assembly with thioglycosides. The synthetic pathway also features the following aspects: 1) three contiguous and challenging 1, 2-cis-Fuc bonds were highly stereoselectively constructed via the newly developed stereoselective 1, 2-cis-fucosylation method; 2) several 1, 2-trans-glycosidic linkages were formed via neighboring group participation effect, while 1,2-cis-Glc linkage was stereoselectively assembled via N,N-dimethylformamide reagent modulation; 3) the final [1+1+2+9] one-pot assembly of the target tridecasaccharide via strategic utilizations of glycosyl N-phenyltrifluoroacetimidates, ortho-alkynylbenzoates and ortho-(1-phenylvinyl)benzoates. Biological studies revealed that human leukemia K562 and mouse L1210 cells could be effectively inhibited by tridecasaccharide repeating unit and nonasaccharide.