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

摘要

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. (C) 2014 Elsevier Ltd. All rights reserved.