title: Stereochemical survey of digitoxin monosaccharides: new anticancer analogues with enhanced apoptotic activity and growth inhibitory effect on human non-small cell lung cancer cell.
abstract: A stereochemically diverse array of monosaccharide analogues of the trisaccharide based cardiac glycoside natural product digitoxin has been synthesized using a de novo asymmetric approach. The analogues were tested for cytotoxicity against the NCI panel of 60 human cancer cell lines and in more detail against non-small cell human lung cancer cells (NCI-H460). The results were compared with digitoxin and its aglycone digitoxigenin. Three novel digitoxin monosaccharide analogues with β-d-digitoxose, α-l-rhamnose, and α-l-amicetose sugar moieties showed excellent selectivity and activity. Further investigation revealed that digitoxin α-l-rhamnose and α-l-amicetose analogues displayed similar anti-proliferation effects, but with at least 5-fold greater potency in apoptosis induction than digitoxin against NCI-H460. This study demonstrates the ability to improve the digitoxin anti-cancer activity by modification of the stereochemistry and substitution of the carbohydrate moiety of this known cardiac drug.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115.
authors.forename: Hua-Yu Leo
authors.initials: HY
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xin
authors.forename: Maoquan
authors.initials: M
authors.lastname: Zhou
authors.forename: Todd A
authors.initials: TA
authors.lastname: Stueckle
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.forename: George A
authors.initials: GA
authors.lastname: O'Doherty