Abstract
Derivatization of natural compounds with established cytotoxic activity is a common strategy in development of new anticancer agents. This approach is exemplified by betulin, a triterpenoid from birch bark that exhibits pronounced antiproliferative effects against various cancer cell lines. We used the Ferrier rearrangement to synthesize 2,3-unsaturated O3-betulin glycosides, which were converted into 2,3-dideoxy analogs via regioselective hydrogenation. The conformations of the 2,3-unsaturated O3-betulin glycosides are analyzed in relation to the stereoselectivity of the Ferrier rearrangement. Cytotoxicity studies of the synthesized O3-betulin glycosides were performed against breast cancer cells (MCF7 cell line), prostate cancer cells (PC3 cell line), and human keratinocytes (HaCaT cell line). These reveal that glycosylation of betulin with 2,3-unsaturated and 2,3-dideoxy sugars derived from D-xylose, L-arabinose, and L-fucose clearly enhances its activity against MCF7 cells. This improvement is accompanied by high selectivity of the active compounds. Structure-activity relationship analysis leads to the conclusion that enhanced activity is associated with the absence of a terminal hydroxymethyl group. Microscopic images of MCF7 cells treated with the synthesized glycosides illustrate vacuolization, membrane blebbing, and apoptotic disintegration. Presented studies show the anticancer potential of some of the O3-betulin glycosides and provide insight into the stereoselectivity of the Ferrier rearrangement.