NOVEL DENDRITIC ALPHA-SIALOSIDES - SYNTHESIS OF GLYCODENDRIMERS BASEDON A 3,3'-IMINOBIS(PROPYLAMINE) CORE

The cluster or multivalent effect has been recognized as an effective means by which to increase binding interactions between carbohydrates and proteins. In fact, it has been demonstrated that sialylated multib ranched L-lysine dendrimers were potent inhibitors of hemagglutination of human erythrocytes by Influenza viruses. In a continuation of thes e studies, the synthesis of novel glycodendrimers with even valencies from 2 to 16 and ending with equidistant thiosialoside residues is des cribed. These symmetrical dendrimers were more readily characterized b y standard NMR spectral techniques than previously reported nonsymmetr ical dendrimers of this general type. The synthesis of the dendritic c ore was based on the regioselective protection of the primary amines o f 3,3'-iminobis(propylamine) (4) using benzyl cyanoformate. The result ing secondary amine 5 was alkylated with tert-butyl bromoacetate to pr ovide divalent core structure 6 with Cbz protected amines and acid pro tected tert-butyl ester. Sequential deprotection by trifluoroacetolysi s or hydrogenation afforded acid 7 or diamine 8 as key precursors, res pectively. The two fragments were coupled using HOBt/DIC strategy to p rovide Cbz-protected dendrimers with valencies of 2, 4, 8, and 16 in t he first, second, third, and fourth generations, respectively, in reas onable to good yields (42-82%). Cbz-protected precursors were efficien tly transformed into N-chloroacetylated dendrimers by hydrogenolysis a nd treatment of the resulting amines with chloroacetic anhydride (82-9 1%). N-Chloroacetylated dendrimers were then treated with an excess of 2-thiosialic acid derivative 3 to give fully protected sialodendrimer s in 76-96% yields. Deprotection of sialodendrimers under Zemplen cond itions followed by methyl ester saponification and purification by gel permeation chromatography afforded symmetrical dendritic alpha-thiosi alosides 21, 23, 25, and 27 in fair yields (47-58%). These novel sialo dendrimers, in keeping with their design, are currently being evaluate d as inhibitors of human erythrocyte hemagglutination by Influenza vir uses.