Thermodynamic stability and anticancer activity of 2,3-unsaturated and 2,3-dideoxy O3 -betulin glycosides

Derivatization of natural compounds with proven cytotoxic properties is a widely employed strategy in the search for novel anticancer agents. This approach applies, among others, to betulin, a triterpenoid isolated from birch bark that exhibits pronounced antiproliferative and cytotoxic activities against various cancer cell lines. Herein, we report the stereoselective synthesis of 2,3-unsaturated O ³ -betulin glycosides, followed by regioselective hydrogenation to afford the corresponding 2,3-dideoxy analogs. The conformations of the synthesized glycosides and their influence on the stereoselectivity of the Ferrier rearrangement, as well as on antitumor activity, are discussed. Cytotoxicity studies of the synthesized O ³ -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 significantly enhances its activity against MCF7 cells. This improvement is accompanied by high selectivity of the active compounds. Structure-activity relationship (SAR) analysis leads to the conclusion that the enhanced activity is associated with the absence of a terminal hydroxymethyl group. Microscopic images of MCF7 cells treated with the synthesized glycosides show vacuolization, membrane blebbing, and apoptotic disintegration.