Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R-1 and R-2, and an aromatic group in R-3. While contraction/elongation of the guanidine carrying side chains (R-1 and R-2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R-3) resulted in an EC50 of 61 mu M (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent. (C) 2016 Elsevier Ltd. All rights reserved.