The tris(aminoethy1) and triarnino derivatives of pentaerythritol have been used as scaffolds or templates for the attachment of immunologically relevant carbohydrates such as ~-Galp(l+3)GalNAc (T) and GalNAc (Tn), through amide linkages with the respective a-glycolyl and a-N-acetyl-L-serinyl glycosides. These clustered glycosidic motifs are intended as haptens for use in the preparation of tumor specific carbohydrate antigens and vaccines. The importance of specific carbohydrate antigens in understanding the etiology of cell surface phenomena during the proliferation of various types of cancers has been amply documented (1). Indeed, tumor-associated antigens are expressed to varying degrees on the surface of cancer cells, and their presence can be quantitatively related to tumor progression (2). Such tumor-associated antigens are D-GalNAc (Tn) (3,4) and Thomsen-Friedenreich antigen D-Galp(l+3)GalNAc (T) (3, 5), which are present as terminal units in glycoproteins expressed on the cell surface (6). Their presence, either alone or as sialyl glycosides such as sialyl Tn (7), and their overexpression has been demonstrated to be linked with certain types of tumors (see, for example, ref. 8).In view of the immunological specificity of such tumorassociated antigens, we considered the incorporation of Tn and T glycosidic motifs in bi-and trianternary structures and their use as potential antigens. Administration of such antigens to patients in remission may produce enough circulating tumorspecific antibodies to protect them from recurring tumors. The notion of a "cancer vaccine" has been a subject of great interest over the years, and the prospects for its realization is a much sought after goal (9).The potential ofclustered antigens for cooperative binding to several protein receptors has been previously discussed, principally by Lee et al. In this paper, we report the synthesis of novel di-and trihaptenic clusters composed of Tn and T glycosides attached to linker arms derived from pentaerythritol(16). In the preceding paper (16) we described the synthesis of various podands prepared from pentaerythritol by suitable chemical modification. We have now selected two triamino derivatives 1 and 2 to form clusters containing two and three Tn and T carbohydrate residues that are glycosidically attached to serine and glycolic acid spacers 3 and 4 (Scheme 1). The length of the spacer between the cluster and the terminal carboxylic acid may have an influence on the efficacy of its coupling with proteins, and ultimately on its immunogenicity. Thus, we chose ally1 and 1-octenyl chains as sources for the terminal carboxylic acids.Synthesis of Galp(l+3)GalNAc disaccharides The synthesis of the disaccharide 7 was done by a classical Koenig-Knorr reaction with 2,3,4,6-tetra-0-acetyl-a-D-galactopyranosyl bromide 5 as a glycosyl donor and tert-butyldimethylsilyl 2-azido-2-deoxy-4,6-0-isopropylidene-a-Dgalacto-pyranoside 6 (17b) as acceptor (Scheme 2). Glycosidations with Ag,C03-AgC10, as promoter in dichloromethane afforded ...
Pentaerythritol(2,2-bis-hydroxymethyl-propane-1,3-diol) was converted into a series of mono-, di-, and trisubstituted derivatives, comprising ally1 ethers and amino-alkyl ethers, by systematic chemical manipulation of the hydroxy groups. The remaining hydroxymethyl group in the case of the trisubstituted analog was functionalized with ether groups bearing terminal o-carboxyl or o-alkene groups. These derivatives are versatile templates and scaffolds for single, double, or triple substitution with appropriate ligands forming amides and esters, and allowing the attachment of the w-alkene or o-carboxyl group to solid support for combinatorial chemistry.Key words: molecular diversity, scaffolds, templates and tris(2-aminoethy1)-pentaerythritol.RCsumC : Le pentaCrythritol(2,2-bis-hydroxymethyl-propane-1,3-diol) a CtC converti en une sCrie de dCrivCs mono-, di-et trisubstituis portant des groupes Cther allylique et Cther aminoalkyle par manipulation systkmatique des fonctions hydroxy. Le groupe hydroxymCthyle restant dans le cas des dCrivCs trisubstituks a CtC fonctionnalise par un des groupes ethers avec un groupe terminal carboxy ou alcinyle. Les derives sont utiles comme des sources de branchement des ligands pharmacologiquement actives par des liaisons amides ou ester. Des applications dans la chimie combinatorielle sur phase solide sont aussi envisageables.Mots elks : diversite moleculaire, tris(2-aminoethy1)-pentaerythritol.Recent interest in chemical diversity in conjunction with combinatorial methods of lead structure generation has instigated a search for readily available polyfunctional organic molecules that can be manipulated in a systematic manner (for recent reviews, see ref. 1). Such molecules can be utilized as templates or scaffolds onto which one can introduce variable functionality with spatially predetermined dispositions (2). For example, the incorporation of specific pharmacophores or related motifs at the extremities of such scaffolds can lead to binding at different receptor sites with potentially novel therapeutic applications (3). Alternatively, the attachment of the template or scaffold molecule to a polymer support through one of its arms, allows the voluntary elaboration of one or more remaining chains in a parallel or combinatorial mode for the discovery of biologically active sequences on growing chains. In the case of templates capable of replicating outwards from a core unit, it is possible to construct dendritic molecules (for selected examples, see ref. 4) with intriguing shapes and exciting physical properties.In connection with our interest in the general area of chemical and functional diversity (5), we wished to prepare organic templates capable of accommodating one, or more, bioactive molecules in order to release them in a sustained manner in a chemically or enzymatically induced process. Another objec- hanessia@ere.umontreal.ca tive was to prepare polyfunctional molecules that could allow us to generate clusters of immunologically relevant haptens on a given template...
Sodium salt of 0‐carboxymethyl derivatives of tamarind kernel powder (TKP), at different levels of substitution, was prepared in iso‐propanol medium. The derivatives were characterised by degree of substitution (DS), intrinsic viscosity and elution profile (GPC). Alkaline solutions, purified by alcohol precipitation showed higher intrinsic viscosity due to an alkali soluble fraction. Solution properties of the derivatives as a function of DS were found to be affected both by the substituent groups as well as by the alkali used for derivatization. Swelling power, solubility and tolerance to organic solvents of the derivatives increased with increasing carboxymethylation. The interaction properties of TKP with calcium chloride and sodium tetraborate were found to be reversed upon carboxymethylation.
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