Identification and characterization of flavonoids as sialyltransferase inhibitors |
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Authors: | Kazuya IPJ Hidari Kin-ichi Oyama Miho Nakayama Shiho Goto Kei-ichi Watanabe Takumi Furuta Toshiyuki Kan |
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Institution: | a Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, Japan and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan b Chemical Instrument Facility, Research Center for Material Science, Nagoya University, Japan c Department of Synthetic Organic and Medicinal Chemistry, University of Shizuoka, School of Pharmaceutical Sciences, Japan and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan d Graduate School of Information Science, Nagoya University, Japan |
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Abstract: | Sialyltransferases biosynthesize sialyl-glycoconjugates involved in many biological and pathological processes. We investigated and characterized synthetic flavonoid derivatives as sialyltransferase inhibitors. We first examined 54 compounds by solid-phase enzyme assay using β-galactoside α2,6-sialyltransferase 1 (ST6Gal I) and β-galactoside α2,3-sialyltransferase. Several compounds inhibited sialyltransferase enzyme activity regardless of sialyl-linkage reactions. Among them, two compounds showed inhibitory activity against ST6Gal I with IC50 values less than 10 μM. Three characteristic features of flavonoids were determined by structure-inhibitory activity relationships. First, a double bond between C2-C3 linkages is required for the activity. Second, increasing hydrophilic properties on the B-ring markedly augmented the inhibitory effect. Third, a hydrophobic functional group introduced on the hydroxyl groups of the A-ring enhanced the inhibitory activity. Kinetic analysis using human ST6Gal I indicated a mixed inhibition mechanism of the compounds. In conclusion, the flavonoids identified could be applied for control of cellular expression of sialic acid. |
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Keywords: | Flavonoid Sialyltransferase inhibitor |
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