Synthesis of glycosylated ß³-homo-threonine conjugates for mucin-like glycopeptide antigen analogues.

ABSTRACT

Glycopeptides from the mucin family decorated with tumour-associated carbohydrate antigens (TACA) have proven to be important target structures for the development of molecularly defined anti-cancer vaccines. The strategic incorporation of ß-amino acid building blocks into such mucin-type sequences offers the potential to create pseudo-glycopeptide antigens with improved bioavailability for tumour immunotherapy. Towards this end, T(N) and TF antigen conjugates O-glycosidically linked to Fmoc-ß³-homo-threonine were prepared in good yield via Arndt-Eistert homologation of the corresponding glycosyl α-amino acid derivative. By incorporation of T(N)-Fmoc-ß³hThr conjugate into the 20 amino acid tandem repeat sequence of MUC1 using sequential solid-phase glycopeptide synthesis, a first example of a mixed α/ß-hybrid glycopeptide building block was obtained. The latter is of interest for the development of novel glycoconjugate mimics and model structures for anti-cancer vaccines with increased biological half-life.