Chemokine receptors, together with their specific natural ligands, play a role in a number of disease states. We propose to systematically synthesize and evaluate potential CXCR4/CCR5 dual antagonists based on our published potent transition metal complex CXCR4 antagonists and the only known dual CXCR4/CCR5 antagonist (whose potency is not desirably high against either receptor). Upon synthesis and chemical characterization, and with the help of collaborators, we will evaluate the antagonism of both CXCR4 and CCR5 in cell lines previously developed for such studies—with the results of these screens feeding back into the iterative re-design of additional dual antagonist complexes. Synthetic routes were developed extending side- and cross-bridged ligand syntheses to include dichloropyridine moieties to impart CCR5 activity on tetraazamacrocycles. Cu2+, Ni2+, Co2+, and Zn2+, complexes were synthesized. Electrospray mass spectra, UV-Visible spectra, cyclic voltammograms, and 1H and 13C NMR spectra were collected to characterize the complexes.The ligand synthesis of the dichloropyridine containing ligands is more synthetically challenging than our typical ethyl cross-bridged ligands. However, single-macrocycle and bis-macrocycle ligands have been made. Complexation with the desired metal ions proceeded as expected. Characterization of the metal complexes is ongoing. While CXCR4/CCR5 dual antagonist tetraazamacrocycles are challenging to produce, once synthesized, metal ion complexation proceeds smoothly following known procedures. The resulting complexes will inform our understanding of the requirements for producing efficient CXCR4/CCR5 dual receptor antagonists.

Transition metal complex dual CXCR4/CCR5 antagonists

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.