Urotensin II(4–11) Azasulfuryl Peptides: Synthesis and Biological Activity

Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4–11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp7 and Lys8 residues...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-05, Vol.59 (10), p.4740-4752
Main Authors: Merlino, Francesco, Yousif, Ali M, Billard, Étienne, Dufour-Gallant, Julien, Turcotte, Stéphane, Grieco, Paolo, Chatenet, David, Lubell, William D
Format: Article
Language:English
Subjects:
Animals
Aorta - drug effects
Aorta - metabolism
Cells, Cultured
CHO Cells
Cricetulus
Humans
Life Sciences
Male
Rats
Rats, Sprague-Dawley
Urotensins - chemical synthesis
Urotensins - chemistry
Urotensins - pharmacology
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Summary:Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4–11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp7 and Lys8 residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII(4–11) analogs 6–11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6–11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII(4–11) derivatives 7–9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00108