N-glycosylation Of Digitoxigenin Using Synthetic 6-deoxy-,2,6-dideoxy-D-glucosyl And Their Partially Methylated Derivatives As Glycosyl Donors

Cardiac glycosides,a class of naturally occuring glycosides,have mainly used for treatment of heart failure and atrial arrhythmia in clinical for many years.Modern pharmacology study have found,cardiac glycoside also has the effect of selective inhibition of tumor cell proliferation and has a good research prospect.Structure-activity relationship studies have shown that the antitumor activity of cardiac glycosides is closely related to the C-3-sugar chains and it’s sugar’s type.Among them,deoxyglycans,especially 6-deoxysugars or 2,6-dideoxysugars,is a important features of the cardiac glycoside structure and has a significant effect on its antitumor activity.In order to systematically study structure-activity relationship(SAR)of the sugar-moeity in the cardiac glycoside compounds and their antitumor activity,then get high efficiency and low toxicity anticancer agents.First,ten 6-deoxy-and 2,6-dideoxy-D-glucosyl and their partially methylated derivatives were synthesized starting from methyl ?-D-glucopyranoside and 2-deoxyD-glucose a s glycosyl donors.Meanwhile,the methoxylamino-substituted digoxigenin(MeONdigitoxigenin)which obtained by acidic hydrolysis of commercially available digoxin,with its C-3 of ? and ? configuration respectively,were used as glycosyl acceptor.Then,a 22-member MeON-neoglycoside library of digoxigenin with novel structure,were successfully synthesized by neoglycosylation method.Finally,the induction of Nur77 expression and its translocation from the nucleus to cytoplasm together with cytotoxicity towards the NIH-H460 of these 22 MeON-neoglycosides were evaluated.The results showed that most of the compounds could induce the expression of Nur77 protein in NIH-H460 cells,and the structure-activity relationship study showed that the C-3 glycosyl was very important for their induction of Nur77 protein expression.At the same time,the study also found that MeON-neoglycosides(2b and 8b)could significant induce the expression of Nur77 and its translocation from the nucleus to cytoplasm.However,these compounds showed no inhibitory effects on the proliferation of cancer cells at the concentration of 50 nM,relative to the positive control drug digoxin,suggesting that they may not induce apoptosis of NIH-H460 cancer cells under this concentration.The potential biological function of Nur77 protein expression and translocation after induction of nuclear orphan receptor remains to be further studied.