Formation of lactones from sialylated MUC1 glycopeptides

The tumor-associated carbohydrate antigens T,, T, sialyl T, and sialyl T are expressed on mucins in several epithelial cancers. This has stimulated studies directed towards development of glycopeptide-based anticancer vaccines. Formation of intramolecular lactones involving sialic acid residues and suitably positioned hydroxyl groups in neighboring saccharide moieties is known to occur for glycolipids such as gangliosides. It has been suggested that these lactones are more immunogenic and tumor-specific than their native counterparts and that they might find use as cancer vaccines. We have now investigated if lactonization also occurs for the sialyl T-N and T antigens of mucins. It was found that the model compound sialyl T benzyl glycoside 6, and the glycopeptide Ala-Pro-Asp-Thr-Arg-Pro-Ala 7 from the tandem repeat of the mucin MUC1, in which Thr stands for the 2,3-sialyl-T antigen, lactonized during treatment with glacial acetic acid. Compound 6 gave the 1 '' -> 2' lactone as the major product and the corresponding 1 '' -> 4' lactone as the minor product. For glycopeptide 7 the 1 '' -> 4' lactone constitued the major product, whereas the 1 '' -> 2' lactone was the minor one. When lactonized 7 was dissolved in water the 1 '' -> 4' lactone underwent slow hydrolysis, whereas the 1 '' -> 2' remained stable even after a 30 days incubation. In contrast the corresponding 2,6-sialyl-T-N glycopeptide 8 did not lactonize in glacial acetic acid.