Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres

Org Biomol Chem. 2010 Feb 7;8(3):616-21. doi: 10.1039/b917236j. Epub 2009 Dec 4.

Abstract

A set of cyclic peptide analogues of a selective CXCR4 antagonist FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)] were synthesized and bioevaluated. Using (E)-alkene and (Z)-fluoroalkene dipeptide isosteres for Arg-Arg and Arg-Nal substructures, indispensable or the partial contribution of the two peptide bonds to the CXCR4 antagonism and anti-HIV activity was demonstrated. FC131 and the analogues were shown to selectively inhibit SDF-1 binding to CXCR4, whereas no inhibition of binding of SDF-1 to CXCR7 was observed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemistry*
  • Amino Acid Sequence
  • Cell Line
  • Dipeptides / chemistry*
  • HIV / drug effects
  • Halogenation
  • Humans
  • Inhibitory Concentration 50
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Static Electricity
  • Stereoisomerism

Substances

  • Alkenes
  • Dipeptides
  • Peptides, Cyclic
  • Receptors, CXCR4