Systematic syntheses of influenza neuraminidase inhibitors: a series of carbosilane dendrimers uniformly functionalized with thioglycoside-type sialic acid moieties.
In order to develop novel influenza sialidase inhibitors, we constructed a library of glycoclusters composed of twelve types of sialylated dendrimers with thioglycosidic linkage that are resistant to hydrolysis by the sialidases. These sialodendrimers were synthesized by condensation reaction between a thiosialoside modified on the aglycon terminal end by a thioacetyl group and twelve types of carbosilane dendrimers having brominated terminal ends under deacetylation conditions, and temporal re-protection was performed for purification. Removal of all protection of the glycodendrimers was accomplished by transesterification and subsequent saponification to provide corresponding water-soluble glycodendrimers in good yields. For investigation of the structure-activity relationship, dendrimer scaffolds having differences in number of the sugar moieties, such as 3-, 4-, 6- and 12-functionalized dendrimers, and in linkage patterns, such as normal aliphatic linkage, ether- and amide-linkages. Biological evaluations of these glycodendrimers showed that all of the ether- and amide-elongated compounds had inhibitory potencies for the influenza sialidases in the mM range, while compounds having normal aliphatic linkage did not have any activities except for a 12-functionalized compound.
Sakamoto
Jun-ichi
J
Division of Material Science, Graduate School of Science and Engineering, Saitama University, Sakura, Saitama 338-8570, Japan.
Koyama
Tetsuo
T
Miyamoto
Daisei
D
Yingsakmongkon
Sangchai
S
Hidari
Kazuya I P J
KI
Jampangern
Wipawee
W
Suzuki
Takashi
T
Suzuki
Yasuo
Y
Esumi
Yasuaki
Y
Nakamura
Takemichi
T
Hatano
Ken
K
Terunuma
Daiyo
D
Matsuoka
Koji
K
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology*; D007251:Influenza, Human / Q000188:drug therapy; D015394:Molecular Structure; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012821:Silanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013865:Thioglycosides / Q000737:chemistry; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D050091:Dendrimers; D012821:Silanes; D013865:Thioglycosides; D014764:Viral Proteins; C504072:carbosilane; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid