Influence of Sugar Amine Regiochemistry on Digitoxigenin Neoglycoside Anticancer Activity

The synthesis of a set of digitoxigenin neogluco/xylosides and corresponding study of their anticancer SAR revealed sugar amine regiochemistry has a dramatic effect upon activity. Specifically, this study noted sugar 3-amino followed 1 by 4-amino-substitution to be most advantageous where the solvent accessibility of the appended amine within neoglycoside-Na+,K+-ATPase docked models correlated with increased anticancer potency. This study presents a preliminary model for potential further warhead optimization in the context of antibody-directed steroidal glycosides and extends the demonstrated compatibility of aminosugars in the context of neoglycosylation.