Synthesis of Dimeric Lewis A and Lewis B–Lewis A Tumor-Associated Carbohydrate Antigen Oligosaccharide Fragments

• Published in: Journal of organic chemistry 2023-05, Vol.88 (9), p.5554-5562
• Main Authors: Davidson, Jeffrey, Gauthier-Signore, Charles, Auzanneau, France-Isabelle
• Format: Article
• Language: English
• Subjects: Antigens, Tumor-Associated, Carbohydrate - chemistry; Glycosides; Glycosylation; Oligosaccharides - chemistry; Trisaccharides
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.3c00082

Despite the interesting potential of tumor-associated carbohydrate antigens (TACAs) dimLea and LebLea to develop anticancer immunotherapies, little research has been conducted on these antigens. In our quest to discover fragments of these TACAs that could be targeted for the development of anticancer therapeutics, we report the synthesis of eight tri- to pentasaccharide fragments of these oligosaccharides. Unforeseen synthetic challenges are reported such as the incompatibility of a bromoalkyl glycoside in the reduction conditions needed to reduce a trichloroacetamide, the mismatched reactivities in a 2 + 1 synthetic strategy, and the surprising greater reactivity of a C-4 GlcNAc hydroxyl group versus that of the galactosyl OH-3 in the selective glycosylation of a trisaccharide diol. The desired final compounds were eventually obtained following a stepwise approach as nonyl or 9-aminononyl glycosides after one-step deprotection reactions in dissolving metal conditions. The 9-aminononyl glycosides will be conjugated to carrier proteins and the nonyl pentasaccharide glycoside will be used as a soluble inhibitor in binding experiments. In contrast, the nonyl tetrasaccharide glycosides are poorly soluble in water and their use in biochemical experiments will be limited.