Synthesis of clustered D-GalNAc (Tn) and D-Galβ(1→3)GalNAc (T) antigenic motifs using a pentaerythritol scaffold

Abstract

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 ...

Cluster Mannosides as Inhibitors of Type 1 Fimbriae-Mediated Adhesion ofEscherichia coli: Pentaerythritol Derivatives as Scaffolds

“…Ϫ NMR spectra were measured with a Bruker AMX 400 (400 MHz for 1 H and 100.67 MHz for 13 C NMR) or a DRX 500 (500 MHz for 1 H and 125.84 MHz for 13 C NMR) spectrometer. Chemical shifts are in ppm, relative to internal TMS (δ ϭ 0.00 for 1 H and 13 C NMR) or solvent peaks, which were calibrated as follows: CDCl 3 (δ ϭ 7.26 for 1 H and δ ϭ 77.00 for 13 …”

“…Peptide linkages were chosen to assemble tumor-associated saccharides en route to haptens for anti-tumor vaccine development. [13] Scheme 1. Pentaerythritol-based cluster glycosides as depicted were designed to serve as high mannose-type glycan mimetics, in which C 3 spacers, highlighted by black dots, are thought to substitute monosaccharide units In addition, galabioside clusters were synthesised on the basis of pentaerythritol derivatives and proved to be excellent in vitro inhibitors of hemagglutination caused by Streptococcus suis.…”

Synthesis and Liquid Crystalline Properties of Mono‐, Di‐ and Tri‐O‐alkyl Pentaerythritol Derivatives Bearing Tri‐, Di‐ or Monogalactosyl Heads: The Effects of Curvature of Molecular Packing on Mesophase Formation

“…For example, Hanessian et al prepared clustered a-d-GalNAc-Ser (Tn) and b-d-Gal-(1!3)-a-d-GalNAc-Ser antigenic motifs, by condensation of the corresponding glycopeptides with alkyl tris(aminoethyl) pentaerythritol. [27] A similar pentaerythritol derivative was used to obtain clusters of a-d-Gal-(1!3)-b-d-Gal glycosides of quinic acid. [28] Recently, glycotope biosteres bearing b-dgalactose moieties have been synthesized by the Sonogashira reaction of tetra-O-iodobenzyl pentaerythritol and 2-propinyl galactosides.…”

“…Alternatively, compound 14 g was prepared in 40 % yield from 5 g and bromide 9 using Fields' conditions. [27,40] For purification and identification purposes, the per-O-acetyl galactosides 14 a,f-h were prepared from their benzoyl counterparts 13 a,f-h by Zemplen de-O-benzoylation and re-O-acetylation.…”

Synthesis of chemically and functionally diverse scaffolds from pentaerythritol

“…We have used the monofunctional tris(2-aminoethyl) derivatives 9 and 10 as tripodal primary amines for amide bond formation with appropriate glycosylamino acid derivatives (14). Such clustered glycopeptide derivatives are interesting haptens for immunological studies in conjunction with the preparation of artificial vaccines (15) against certain types of tumors.…”