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Bioorg Med Chem. 2014 Sep 1;22(17):4759-69. doi: 10.1016/j.bmc.2014.07.004. Epub 2014 Jul 14.

Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4).

Author information

1
Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway.
2
Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
3
Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
4
Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway. Electronic address: jon.vabeno@uit.no.
5
Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway. Electronic address: Bengt-Erik.Haug@farm.uib.no.

Abstract

Structure-activity relationship studies of the cyclopentapeptide CXCR4 antagonists (cyclo(-l-/d-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-d-Tyr(5)-)) suggest that the l-/d-Arg(1)-Arg(2)-2-Nal(3) tripeptide sequence contained within these cyclopentapeptides serves as a recognition motif for peptidic CXCR4 antagonists. Starting by dissecting the cyclopentapeptide structure and reintroducing cyclic constraints in a stepwise manner, we here report a novel class of scaffold-based tripeptidomimetic CXCR4 antagonists based on the d-Arg-Arg-2-Nal motif. Biological testing of the prototype compounds showed that they represent new peptidomimetic hits; importantly, the modular nature of the scaffold provides an interesting starting point for future ligand optimization.

KEYWORDS:

CXCR4 antagonist; Cyclopentapeptide; Peptidomimetic; Scaffold

PMID:
25082513
DOI:
10.1016/j.bmc.2014.07.004
[Indexed for MEDLINE]

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