Selective synthesis of an elusive C-functional bis-cyclam and study of its inhibition of the CXCR4 chemokine receptor

Abstract

This article presents the controlled synthesis of a rare example of C,C′-linked bis-cyclam architecture in mild conditions through the “bis-aminal” route previously used for the advantageous synthesis of cyclam, N- and C-functional cyclams and N,N′-bis-cyclams. Two synthetic pathways were explored with the smart design of α,β-unsaturated ketones or alkyl halides bis-cyclizing agents. The first led to the isolation of a key intermediate for the future design of N-functionalized bis-cyclams, whereas the second allowed the preparation of the targeted C,C′-xylylene-bis-cyclam under mild conditions with decent yield. This compound was then studied as a CXCR4 receptor inhibitor, one of the main applications known for bis-macrocyclic compounds, in particular in the context of HIV (human immunodeficiency virus) infection. Although results demonstrated that its potency is lower (i.e. 137-fold higher IC₅₀) than the gold standard AMD3100 against HIV infection, clear evidence of CXCR4 inhibition is presented, confirming the potential of this novel architecture and related compounds in this research field.