7 選択的β-グリコシダーゼ阻害剤β-glycosylamidine誘導体の合成と応用(口頭発表の部)

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The inhibitors of glycosidases have attracted increasing research interest as chemotherapeutic agents and as useful molecular probes to understand the function of glycoproteins and the catalytic mechanism of glycosidases. The inhibitors of glycosidases have generally been designed to mimic the charge and/or the shape of the oxocarbenium ion-like transition-state or intermediate, but the incorporation of a nitrogen positive center into a sugar pyranose ring requires relatively long reaction sequence and often disrupts the structure of the sugar pyranose ring to affect the selectivity of inhibitors. We designed novel potent and selective glycosidase inhibitors, β-glycosylamines 1, 2 and 3, by incorporating a positive charge outside the sugar pyranose ring near C-1 so that the whole structure of the sugar moiety is maintained. The β-glycosylamidines 1-3 were readily synthesized without using protecting groups from the corresponding β-glycosylamine by reaction with the thioimidate in dry pyridine. Since the thioimidates are easily accessible from amides and nitriles, this synthetic route is a general method to accesss a variety of β-glucosylamidines with various glycon and aglycon structures. The β-glycosylamidines 1-3 strongly inhibited the corresponding β-glycosidase with Ki as low as 0.1 μM with substantial selectivity according to the glycon- and α-,β-specificities of glycosidases. Thus, β-Glu-amidine 1 selectively and competitively inhibited a β-glucosidase from A. niger with a Ki of less than 0.1 μM, but did not inhibit the α-glucosidases, α- and β-galactosidases, and β-xylosidase. Similarly, β-Gal-amidine 2 and β-Xyl-amidine 3 inhibited the corresponding β-glycosidase most potently, but showed little activity against α-glycosidases. We also synthesized and evaluated several β-glucosylamidine derivatives 1a-g with various aralkyl groups in the aglycon moiety. Most of them served as potent inhibitors of β-glucosidases with K_i of μM range, but substantial selectivity was observed among β-glucosidases such as mold and almond enzymes, according to the structure of the aglycon moiety. In some cases where a hydrophilic aglycon was involved, the selectivity reached as high as 10^6. The selective and easily accessible nature of β-glycosylamidines have employed to prepare an adsorbent for affinity chromatography of glucosidases by one-pot reaction of β-glucosylamine, iminothiolane-HCl and an affinity matrix with maleimide groups. A crude enzyme extract of tea leaves was passed through the column, and one of the β-glucosidase was selectively and quantitatively adsorbed onto the column. The adsorbed enzyme was eluted by glucose to give an almost pure β-glucosidase which showed a single band electrophoretically.
天然有機化合物討論会の論文
2001-09-01

7 選択的β-グリコシダーゼ阻害剤β-glycosylamidine誘導体の合成と応用(口頭発表の部)

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