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Several new strategies have been introduced into the realm of synthetic carbohydrate chemistry during the period covered by this review. Regioselective glycosylation of lightly protected glycosyl acceptors has been applied successfully to the synthesis of molecules which are related to cell adhesion. Intramolecular reactions are becoming promising methods of obtaining the β-mannosides found in the core region of N-linked glycoproteins.

Due to high demand to access biologically important oligosaccharide structures, efficient and stereoselective synthetic methods are required. This article addresses these two issues from our recent studies. The first part deals with β-mannosylation and α-sialylation known as the two most difficult glycosylation reactions which were now made possible by means of an “intramolecular aglycon delivery” system and control by “auxiliary”, respectively. In the second part, the remarkably efficient “orthogonal glycosylation strategy” which was developed based on tactical analysis of oligosaccharide synthesis is described.

A series of iminocyclitols was prepared using a versatile synthetic strategy, and their inhibition of glycosidases was evaluated using capillary electrophoresis. The study has demonstrated that remarkable specificities in enzyme inhibition can be achieved with small modifications on the aglycon side chain and the ring nitrogen. Among the compounds synthesized, (2R,3R,4R,5R)-N-methyl-2-(acetamidomethyl)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidine was found to be very potent against β-N-acetylhexosaminidase P with the Ki value of 80 nM.

糖あるいは糖鎖は代謝、細胞間認識、感染といった様々な生体認識現象に一次的に関与しているばかりでなく、癌の転移に伴い発現する糖転位酵素もあり、タンパク質と糖の間の認識機構を調べ阻害剤等の研究を行うことは、将来的に新しい医薬へと繋がる可能性を秘めており重要である。ところが、現時点においては如何なる化合物がこうした生体反応を効率良く阻害するかを予測することは不可能に近い。このような理由から多岐に渡る化合物群の中から、目的に合うものを検索しようとするコンビナトリアルケミストリーの手法に基づく研究が有効である。また、糖が連続するキラルな炭素から成っていることを考えると、糖をキラルテンプレートに利用することも考えられる。本レビューは、盛んになりつつある糖関連ライブラリーに関する研究についての概説を試みるが、あくまでも“糖”が中心になっている研究に限定した。また、今後のライブラリー研究に展開が期待されるものについても割愛させていただいた。

This paper describes the synthesis of 1,1-linked galactosyl mannosides as sialyl Lewis X mimetics that contain a spiro-ring to position the carboxylate group in a well-defined orientation. It was found that compound 4 is more active as a P-selectin inhibitor (IC50 = 19 μM) than the parent disaccharide 2, which contains a flexible carboxyl group (IC50 = 193 μM). This result is consistent with that observed in the previous NMR study of sialyl Lewis X bound to P-selectin. The chemistry described here should be useful for the development of selective inhibitors of E-, P-, and L-selectins.

Oligosaccharides, commonly found on the cell surfaces, are deeply involved in a variety of important biological functions, yet demanding difficulties synthesizing such structures limit the investigation of their functions. Technologies to chemically synthesize these oligosaccharides have dramatically advanced during the last two decades mainly due to the introduction of good anomeric leaving groups. In addition, tactical analyses have been addressed to enhance the overall efficiency of oligosaccharide synthesis. Based on the advancement of solution-phase chemistry, solid-phase technologies are being investigated in connection with the current trend of combinatorial chemistry and high throughput screening. This review summarizes the necessary solution-phase methodologies, the status of solid-phase synthesis of oligosaccharides, and combinatorial synthesis of oligosaccharide libraries.

In an effort to develop new structures as inhibitors of both influenza virus proteins hemagglutinin and neuraminidase, a series of sialic acid derivatives, including those with one of the hydrogen atoms at the C-3 position replaced by either OH or F, were synthesized. The sialic acid derivative with a 3-eq-OH group was first synthesized by means of a new process and used as the key intermediate for further derivatization at the C-3 position. The stability of these compounds under acid- and sialidase-catalyzed hydrolysis conditions was studied, and the results showed that these compounds exhibit stronger resistance towards both conditions than their parent p-nitrophenyl α-sialoside. Further inhibition assay indicated that the 3-ax-OH or F derivatives 4, 5, and 24, the 4-epimer of 4, are effective specific inhibitors of the sialidases from Clostridium perfringens, among other bacterial sialidases tested. The 3-eq-OH derivative 3, however, showed little inhibition. The same tendency was observed for the inhibition of human influenza sialidases N1 and N2. Compounds 3−5 and sialic acid were then converted into the distealoylphosphatidylethanolamine conjugates. Of these liposome-like compounds, the ones from 4 and 5 showed potent and selective inhibitory activities against the hemagglutinin H3 subtype, but displayed resistance to the influenza virus neuraminidases N1 and N2.