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

Abstract

Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R¹ and R², and an aromatic group in R³. While contraction/elongation of the guanidine carrying side chains (R¹ and R²) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R³) resulted in an EC₅₀ of 61μM (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.

Keywords: CXCR4 antagonist; Peptidomimetic; Scaffold.