Research objectives and content
The project involves a general approach to the synthesis of
conformationally restricted mimetics of B- and Y-turns in biologically active peptides and proteins. The approach will be applied to the peptide hormones vasopressin and oxytocin which are used as drugs. Vasopressin is involved in regulation of urine production and blood pressure, whereas oxytocin causes milk ejection and uterine contractions in mammals. The synthetic routes to the mimetics are short and convergent, and allow facile preparation of mimetics with various side chains at all positions in the turn. The synthesis of the key building blocks in enantomerically pure form relies on the Sharpless epoxidation of allylic alcohols. The mimetics can be elongated at their termini by standard methodology for peptide synthesis and therefore allow facile incorporation into biologically active peptides and proteins.
The prepared analogues of vasopressin and oxytocin containing the mimetics will be evaluated for physiological activity, and their conformations will be determined by a combination of spectroscopic and computational techniques.
It is expected that the analogues will display increased stability on oral administration and that information on the biologically active conformation of the hormones will be obtained.
Training content (objective, benefit and expected impact)
I will get a further improvement of my experience in modern organic synthetic chemistry. Furthermore I will acquire detailled knowledge in the fields of modern peptide synthesis and structure determination by spectroscopic and computational techniques.
Links with industry / industrial relevance (22)
The pharmacological properties of the analogues will be evaluated in collaboration with FERRING Pharmaceuticals in Malmo.