Synthesis of New Ligands of Urokinase Receptor and New Urotensin-II Derivatives

Unit 1: The urokinase-type plasminogen activator receptor (uPAR) is involved in the regulation of cell migration. The uPAR is formed by three domains connected by short linker region. The Ser88-Arg-Ser- Arg-Tyr92 is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as result of its binding with formyl peptide receptor (FPRs). With aim to perform a SAR study on this sequence we have synthesized a large peptide library using phosphorylated amino acids, non-coded amino acids, D-amino acid scan and cyclic analogues. A new two potent inhibitors of cell migration, uPAR2 and uPAR18, have been identified represented, respectivetly, by the analogue with phosphorylated Ser90 and the analogue with cyclic conformation. Unit 2: Urotensin II (U-II), is a cyclic peptid has been described as the most potent vasoconstrictor documented. The vasocontriction effect of U-II is a result of the binding with its receptor UT receptor. The cyclic region of U-II, c[Cys-Phe-Trp-Lys-Tyr-Cys], plays an essential role in terms of affinity for UT receptor. We developed new two different libraries of U-II analogues carried structure modification on the peptide bond to explore new SARs on the cyclic region of U-II. Peptoids analogues represent the first library whose the side chain are appended to N-atom rather than the ?- Carbon. The second library represented by N-aminosulfamide analogues (azasulfurylpeptides), a class of peptidomimetics, in which the C?H and the carbonyl are respectively replaced by a nitrogen atom and a sulfonyl group.