Collective total synthesis of chartreusin derivatives and bioactivity investigations†

Abstract

Capitalizing on Hauser annulation and Yu glycosylation, the chemical synthesis of chartreusin-type aromatic polycyclic polyketide glycosides has been investigated, culminating in the successful establishment of chemical approaches toward chartreusin derivatives with intricate chemical structures but promising bioactivities. Based on the chemical synthesis strategy, the first and collective chemical syntheses of chartreusin, D329C, and elsamicins A and B have been accomplished. The chemical strategy was featured by two complementary routes to secure chartarin 10-O-monosaccharide glycosides, the key intermediates in chartreusin derivative synthesis, as well as the highly stereoselective construction of the difficult glycosidic linkages. Through the synthetic investigations, viable donors and acceptors of 3-C-methyl-branched sugars were determined for the first time. Moreover, facilitated by the established chemical synthetic strategy, the cytotoxic activities of chartreusin derivatives against human cancer cell lines were assessed and profound antineoplastic effects for chartreusin and elsamicins A and B were recorded. Based on RNA-seq analysis, the underlying working mechanisms against ES-2 cells were investigated, and the appended sugar chain-determined function mechanisms were disclosed.