Chemical synthesis will provide homogeneous and robust molecules that mimic the O-glycopeptide architecture of O-mucins, which are associated with tumor cells of mucosal membranes. Particular attention is given to developing versatile and expedient methods to prepare these glycopeptide mimics. The prepared materials will be used to better define ? the structural parameters by which these molecules interact and function, and to develop potential therapeutics or diagnostics for cancer. The glyco-domains displayed on the cell surface act as key immunological recognition features directly or indirectly involved in antibody-antigen interactions. Many tumor cells have truncated glycosylation patterns that are antigenic, giving rise to their study as biomarkers for disease and to their potential for raising a neutralizing antibody response for vaccine development. The O-mucins maintain a common core saccharide, O-GalNAc 1-linked to Ser/Thr, known as Tn antigen. The proposed research is divided into four aims.
Aim 1 entails the development of expedient synthetic routes to the C-linked mimics of Tn antigen, specifically - Ser, Thr, Ala, Hse variations. Syntheses entail metathesis reactions between sugar-derived 1-heptenes and alkenyl substituted glycine derivatives. The inclusion of aim 2 will test the versatility of the synthetic method from aim 1 toward compounds with inhibitory activities for glyco-processing enzymes. Employing a common synthetic intermediate, the efficient preparation of iminosugars and glycosyl phosphate mimics will be ascertained. The products from aim 1 will be incorporated into glycopeptide sequences in aim 3. First, a model nonapeptide will be prepared for exploration of fundamental conformational influences. Next, C-glycopeptide synthesis will target three biomedically significant peptides: a tandem repeat of MUC4 (expressed in human pancreatic tumor cells), a tandem repeat of MUC1 (over-expressed with truncated glycoforms in numerous tumor cells), and the antiproliferative factor (APF) glycopeptide that inhibits epithelial cell growth in the bladder.
Aim 4, conducted in collaboration with Dr. J. J. Barchi at the ? National Cancer Institute (NCI)-Frederick, will examine the effects of glycopeptide conformational changes potentiated by C-versus O-linkages, and by variation of carbon chain length. These modifications will have implications for receptor binding and will impact biological activity. Immunological and other biomedical attributes of the C-linked mucins and APF will be investigated by Barchi and supporting labs at NCI-Frederick. Chemical synthesis will provide homogeneous and robust molecules that mimic the glycopeptide architecture associated with tumor cells of mucosal membranes. Particular attention is given to developing versatile and expedient methods to prepare these glycopeptide mimics. The prepared materials will be used to better define the structural parameters by which these molecules interact and function, and to develop potential therapeutics or diagnostics for cancer. ? ? ?
| Nolen, Ernest G; Li, Leyan; Waynant, Kristopher V (2013) Synthesis of ?-C-GlcNAc Ser from ?-C-Glc Ser. J Org Chem 78:6798-801 |
