D. Zanini et R. Roy, SYNTHESIS OF NEW ALPHA-THIOSIALODENDRIMERS AND THEIR BINDING-PROPERTIES TO THE SIALIC-ACID SPECIFIC LECTIN FROM LIMAX-FLAVUS, Journal of the American Chemical Society, 119(9), 1997, pp. 2088-2095
Carbohydrate-protein binding interactions can be greatly amplified usi
ng the cluster or multivalent effect. In previous studies, sialylated
multibranched L-lysine dendrimers were found to be patent inhibitors o
f the hemagglutination of human erythrocytes by Influenza viruses. In
order to further the understanding of multivalency and its role in car
bohydrate-protein interactions, glycoconjugates with differing carbohy
drate densities, conformations, and interglycosidic spacings must be p
repared. The synthesis and biological testing of structurally similar
divergent and tethered alpha-sialodendrimers are presented herein. alp
ha-Thiosialoside-containing dendrimers scaffolded on an orthogonally p
rotected 3,3'-iminobis(propylamine) core were efficiently prepared via
Cbz-protecting group and HOBt/DIC coupling strategies. The potential
of these sialodendrimers to cross-link and precipitate Limax flavus le
ctin (LFA) was confirmed by turbidimetric analysis. When tested in enz
yme-linked lectin inhibition assays using human al-acid glycoprotein (
orosomucoid) as coating antigen and horseradish peroxidase-labeled LFA
for detection di- (31), tetra- (32), octa- (33), and hexadecavalent (
34) divergent dendrimers Showed IC50 values of 176, 11.8, 206, and 425
nM while the tethered structures with valencies of four (14), six (20
), eight (25), and twelve (30) exhibited IC50 values of 58.7, 16.9, 17
.5, and 8.22 nM, respectively. These data represent 3.5 (34) to 182 (3
0) fold increases in inhibitory potential over monovalent -deoxy-D-gly
cero-alpha-D-galacto-2-nonulopyranosyl azide used as a standard (IC50
1500 nM). The tethered alpha-sialodendrimers appeared to have structur
al organizations more suitable than the divergent dendrimers for the s
olid phase inhibition of the binding of human al-acid glycoprotein to
LFA. All alpha-sialodendrimers are currently being evaluated as inhibi
tors of human erythrocyte hemagglutination by Influenza viruses.