Merlino, Francesco (2014) Design and Synthesis of New Urotensin-II Derivatives. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Lingua: English
Title: Design and Synthesis of New Urotensin-II Derivatives
Date: 31 March 2014
Number of Pages: 120
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Scuola di dottorato: Scienze farmaceutiche
Dottorato: Scienza del farmaco
Ciclo di dottorato: 26
Coordinatore del Corso di dottorato:
D'Auria, Maria
Date: 31 March 2014
Number of Pages: 120
Uncontrolled Keywords: Urotensin-II; peptidomimetic; SAR; medicinal chemistry; cardiovascular agents; amide isosters
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica
Date Deposited: 07 Apr 2014 09:24
Last Modified: 05 May 2017 01:00


This study was focused on the development of new Urotensin-II (U-II) derivatives, which could provide exhaustive structure-activity relationships (SAR) information about this important peptide-hormone whom role in physiological and pathological pathways is still unknown. Optimization of lead compounds P5U and urantide, so far recognized as the most potent agonist and antagonist, respectively, was aimed to stabilize specific conformation and to improve pharmacokinetic properties. Therefore, first series of peptides has been designed by replacement of native residues with uncoded amino acids in P5U and urantide sequences. In particular, point-modification upon positions of (L/D)-Trp7 and Tyr9 were evaluated since they belong to the cyclic portion of the peptide, also known as the core sequence of Urotensin-II analogues for being essential in the biological activity. However, the development of peptides as drugs in a therapeutic application is often hampered mainly due to their unfavorable pharmacokinetic properties. For this reason, N-methylation of peptide bonds in U-II(4-11) sequence was used as chemical tool to synthesize a series of derivatives. These compounds were biologically evaluated and subsequent conformational studies were performed on more interesting compounds elucidating the effects induced by this modification. Also, complementary synthetic strategy to address pharmacokinetic issues related to peptides as drug candidates consists in the development of peptidomimetics. N-aminosulfamides are peptidomimetics in which the CαH and the carbonyl of an amino acid residue are both respectively replaced by a nitrogen atom and a sulfonyl group. Aza-sulfuryl amino acids have been inserted into the cyclic portion of the U-II(4-11) sequence in replacement of the Trp7 and Lys8 amino acid residues. Thus, novel analogues have been designed and successfully synthesized giving the opportunity to explore potential effects generated by this modification.

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