Identification and characterization of flavonoids as sialyltransferase inhibitors
Identification and characterization of flavonoids as sialyltransferase inhibitors
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DOI：
10.1016/j.bbrc.2009.03.082
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发表时间：
2009-05-08
影响因子：
3.1
通讯作者：
Suzuki, Takashi
中科院分区：
文献类型：
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作者：
Hidari, Kazuya I. P. J.;Oyama, Kin-ichi;Suzuki, Takashi
唾液酰转移酶生物合成唾液酰糖缀合物，参与许多生物学和病理过程。我们研究并鉴定了合成的类黄酮衍生物作为唾液基转移酶抑制剂。我们首先使用β -半乳糖苷α 2,6-唾液基转移酶1 （ST6Gal I）和β -半乳糖苷α 2,3-唾液基转移酶对54种化合物进行固相酶测定。几种化合物抑制唾液基转移酶活性，而不考虑唾液基连锁反应。其中2个化合物对ST6Gal I具有抑制活性，IC50值均小于10 μ m，通过结构-抑制活性关系确定了黄酮类化合物的3个特征特征。首先，活性需要C2-C3键之间的双键。其次，增加b环的亲水性显著增强了抑制作用。第三，在a环的羟基上引入疏水官能团增强了抑制活性。利用人ST6Gal I进行的动力学分析表明，化合物具有混合抑制机制。综上所述，所鉴定的黄酮类化合物可用于控制唾液酸的细胞表达。(C) 2009爱思唯尔公司版权所有。
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 beta-galactoside alpha 2,6-sialyltransferase 1 (ST6Gal I) and beta-galactoside alpha 2,3-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 mu M. 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. (C) 2009 Elsevier Inc. All rights reserved.