It is worthwhile noting that multivalency is a powerful design approach to increase the binding strength of synthetic carbohydrate ligands with protein receptors.1-3) Some carbohydrate chemists have developed methods to make glycoclusters for that reason, [4][5][6][7][8] however, these clusters are symmetrical structures and there are few asymmetrical ones. Asymmetrical clusters are expected not only to enhance binding affinity but also may resolve steric conformation of protein receptors. Therefore, we have devised three types of new glycocluster (Fig. 1). In our previous paper, 9) we synthesized the glycocluster using diverse 'glycocluster units' that make it possible to modulate optionally the length of the side chain by insertion of w-amino acid as spacer between the main chain and the carbohydrate moiety (Fig. 1B). The glycocluster units are composed of b-alanine derivative as a clusterchain unit, sugar unit and w-amino acids as a spacer. They provide diversity using different w-amino acids between the cluster-chain unit and sugar unit. This method is advantageous for the synthesis of diverse glycoclusters to combine several diverse glycocluster units.It is also important to consider not only side chain length but also the distance between the side chain branched points to give diversity to the glycoclusters. The steric distribution of carbohydrate residues on glycoconjugates will affect their interaction with lectins. Therefore, two kinds of w-amino acids (b-alanine and 6-aminocapronic acid) as spacers of different length were attached to the cluster-chain unit, and diverse glycocluster units were synthesized. The glycoclusters were elongated by coupling these units (Fig. 1C).In this paper we report the synthesis of glycocluster 1 which makes it possible to modulate optionally the distance between the side chain branch points (Fig. 2). Furthermore, we undertook to build a glycodendron derivative 2 using cluster-chain unit 16 as a dendron core.Synthesis of Glycocluster First, glycocluster units 12 and 13 were prepared as follows. Removal of the trichloroethyl group from cluster-chain unit 3, which was prepared according to the previous paper, 9) by Zn-AcOH provided acid-free cluster-chain unit 4 (93%). Coupling of compound 4 with each w-amino acid (b-alanine and 6-aminocapronic acid) trichloroethyl ester as a spacer in the presence of diethyl phosphorocyanidate (DEPC) in dry DMF -5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Received March 25, 2005; accepted May 20, 2005 The synthesis of an asymmetric glycocluster 1 has been achieved using two glycocluster units 12 and 13, prepared by coupling the cluster chain unit 4 with each w w-amino acid (b b-alanine and 6-aminocapronic acid) trichloroethyl ester, and peptidic C-terminal block glycocluster 16, prepared by coupling the bifunctional linker 14 with sugar unit 9. This method facilitated the synthesis of the cluster optionally modulated the distance between the side-chain branched points by using various w w-amino acids. We also synthesized glycode...
The roots of Bupleurum falcatum L. (Japanese name Saiko) have been used in Chinese and Japanese herbal medicines for the treatment of chronic hepatitis, nephrosis syndrome, and autoimmune diseases. Yamada et al. 1) and Sun et al.2) reported that a potent antiulcer pectic polysaccharide (Bupleuran 2IIc) was isolated from the hot-water extract of the roots. Bupleuran 2IIc consists of a galacturonan region, a "ramified" region (PG-1) composed of a rhamnogalacturonan core with neutral sugar side chains, and a rhamnogalacturonan II-like region 3) ; the ramified region has been considered important for the expression of immunopharmacologic activity (Fig. 1). We reported in our previous paper 4) that the synthetic model compound shows specific activity. On the other hand, a polyclonal antibody (antibupleuran 2IIc/PG-1-IgG) against the ramified region of bupleuran 2IIc (antibupleuran 2IIc/PG-1-IgG) was prepared, and the antigenic epitopes were characterized to be 6-linked galactosyl chains with either GlcA or 4-O-Me-GlcA as a nonreducing terminal.5) Bupleuran 2IIc has mitogenic activity in the murine spleen and Peyer's patch cells, and the mitogenic activity was reduced in the presence of the antipolysaccharide antibody (antibupleuran 2IIc/PG-1-IgG). The mitogenic activity of bupleuran 2IIc was reduced with the addition ofwhich are a part of the epitopes of antibupleuran 2IIc/PG-1-IgG.6) The proposed structure of the antigenic epitopes in PG-1 has been a target for the synthetic studies in our laboratory. Despite the specificity of the binding, it is known that polysaccharide chains generally interact with their protein receptors as a natural cluster. This explains why the binding affinity of a synthetic model compound to the active site is low in various cases.7) Construction of a glycocluster aimed at their bioactive augmentation is an important problem in glycoscience. 9) However, it did not led to a marked augmentation (data not shown). Meanwhile, we developed new peptidic glycoclusters and a glycodendron, which consist of a b-alanine derivative and Minamiooya, Machida, Tokyo 194-8511, Japan: and c Oriental Medicine Research Center, Kitasato Institute; 5-9-1 Shiroganedai, Minato-ku, Tokyo 108-8642, Japan. Received October 12, 2005; accepted December 28, 2005 Stereocontrolled syntheses of model compounds related to a major antigenic epitope against antibupleurum 2IIc/PG-1-IgG from antiulcer pectic polysaccharide are described. A trisaccharide derivative (13) was prepared as a precursor and a novel and simple approach for the rational design of a glycocluster and glycodendrimer was developed, through the syntheses of the fluorescence-labeled glycocluster (2) and glycodendrimer (3).
Chinese hamster ovary cells show endogenous high-affinity Na(+)-dependent glutamate transport activity. This transport activity is kinetically similar to a glutamate transporter family strategically expressed in the central nervous system and is pharmacologically unlike glutamate transporter-1 or excitatory amino acid carrier 1. The cDNA of a glutamate/aspartate transporter (GLAST)-like transporter was obtained and analyzed. The deduced amino acid sequence showed high similarity to human, mouse, and rat GLAST. We concluded that a GLAST-like glutamate transporter exists in Chinese hamster ovary cells that might confer the endogenous high-affinity Na(+)-dependent glutamate transport activity evident in these cells.
We synthesized 1) a trivalent analogue, N,NЈ,NЉ-tri-{5-[4-Omethyl-b -D-glucopyranosyluronic acid-(1→6)-b -D-galactopyranosyloxy]pentylcarbonylaminoethyl}-1,3,5-benzenetriamide (A) of b-D-GlcA4Me-(1→6)-b-D-Gal, which is related to a major antigenic epitope against antibupleurum 2IIc/PG-1-IgG from antiulcer pectic polysaccharide of Bupleurum falcatum L. (Japanese name Saiko), 2,3) and showed potent mitogenic activity and then previously showed 4) the AFM (atomic force microscopy) image of A in the ganglioside G M3 (GM3)/L-a-dipalmitoylphosphatidylcholine (DPPC) monolayer, where selective distribution of A in the GM3 region was found. Furthermore, we developed new peptidic glycoclusters and glycodentron, 5,6) and the fluorescence-labeledhave been synthesized for biological assay. Recently, we synthesized new glycocluster derivatives carrying double alkyl chains instead of fluorescent dansyl group. The distributions of the new derivatives, monomer type (1) and its clustering compound (2) in the GM3/DPPC monolayer have been examined using AFM, and the results have been promptly reported (Letters).8) (The details of synthesis have not been presented in the report 8) because of the limiting space.)Gangliosides are localized at the surface of mammalian membranes and participate in cellular interaction, differentiation and transformation.9-12) Ganglioside compositions are different among organs and/or tumors.13) Ganglioside G M1 (GM1) and ganglioside G D1a (GD1a) are present in caveolae membrane, whereas ganglioside G T1b (GT1b) is not present in caveolae.14) Membrane properties of GM1, GD1a and GT1b have been studied. [15][16][17] Studying drug distribution in biological membranes is interesting in how it relates to their pharmacological potency and is important to develop a convenient method for drug screening.In this study, the distributions of 1 and 2 in GM1/DPPC, GD1a/DPPC and GT1b/DPPC monolayers were observed using AFM. We report herein the results along with the syntheses of 1 and 2 (Fig. 1). Results and DiscussionSyntheses of Model Compounds Preparation of the designed trisaccharide monomer and tetramer derivative 1 and 2 were straightforward (Chart 1). Monomer amine derivative 3 and tetramer-cluster amine 6 were prepared according to the previous paper.6) 2-(Tetradecyl)hexadecanoic acid (4), was chosen as a fatty-alkyl residue. Coupling of amine derivatives 3 and 6 with 4 in the presence of diethyl phosphorocyanidate (DEPC) in dry DMF gave 5 (60%) and 7 (50%), respectively. Subsequent removal of all acyl groups and esters with sodium methoxide afforded the target compounds 1 and 2 in excellent yield.Distributions of 1 and 2 in the GM1/DPPC Monolayer First, the AFM image of the GM1/DPPC (4 : 6) monolayer at 37°C and 35 mN/m without 1 and 2 is shown in Fig. 2a. In Fig. 2a, the ratio of dark area to bright area is not 0.4, although the molar ratio of GM1 to DPPC is 0.4. This result Japan: and b Kyushu University of Health and Welfare; 1714-1 Yoshino-cho, Nobeoka, Miyazaki 882-8508, Japan. Received April 13, ...
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