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

J Med Chem. 2016 May 26;59(10):4740-52. doi: 10.1021/acs.jmedchem.6b00108. Epub 2016 May 17.

Abstract

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 Trp(7) and Lys(8) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects*
  • Aorta / metabolism
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Humans
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Urotensins / chemical synthesis*
  • Urotensins / chemistry
  • Urotensins / pharmacology*

Substances

  • Urotensins
  • urotensin II

Grants and funding