Effect of five-membered sugar mimics on mammalian glycogen-degrading enzymes and various glucosidases

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• 作者：Yasuhiro Minami ; Chinami Kuriyama ; Kyoko Ikeda ; Atsushi Kato ; Kenji Takebayashi ; Isao Adachi ; George W.J. Fleet ; Aikkarach Kettawan ; Tadashi Okamoto ; Naoki Asano
• 关键词：Glycogen phosphorylase ; Amylo-1 ; 6-glucosidase ; Glucosidase ; Inhibitor ; Caco-2 cell
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 March 2008
• 卷：16
• 期：6
• 页码：2734-2740
• 文件大小：220 K

摘要

We investigated inhibitory activities of five-membered sugar mimics toward glycogen-degrading enzymes and a variety of glucosidases. 1,4-Dideoxy-1,4-imino-d-arabinitol (d-AB1) is known to be a potent inhibitor of glycogen phosphorylase. However, the structural modification of d-AB1, such as its enantiomerization, epimerization at C-2 and/or C-3, introduction of a substituent to C-1, and replacement of the ring nitrogen by sulfur, markedly lowered or abolished its inhibition toward the enzyme. The present work elucidated that d-AB1 was also a good inhibitor of the de-branching enzyme of glycogen, amylo-1,6-glucosidase, with a ICb>50b> value of 8.4 bc;M. In the present work, the de-sulfonated derivative of salacinol was isolated from the roots of Salacia oblonga and found to be a potent inhibitor of rat intestinal isomaltase with an ICb>50b> value of 0.64 bc;M. On the other hand, salacinol showed a much more potent inhibitory activity toward maltase in Caco-2 cell model system than its de-sulfonated derivative, with an ICb>50b> value of 0.5 bc;M, and was further a stronger inhibitor of human lysosomal border="0">-glucosidase than the derivative (ICb>50b> = 0.34 bc;M). This indicates that the sulfate in the side chain plays an important role in the specificity of enzyme inhibition.