Chemokine receptors, together with their specific natural ligands, play a role in a number of disease states. We seek 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 have evaluated 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 redesign 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. Cu, Ni, Co, and Zn, complexes were synthesized. Electrospray mass spectra, elemental analysis, and X-ray crystallography were used to initially characterize the complexes. The 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. Screening of the metal complex CXCR4 and CCR5 antagonism by calcium ion signalling experiments is ongoing.

Bis- and pendant armed tetraazamacrocycle transition metal complex dual CXCR4/CCR5 antagonists

251st National Meeting (2016)

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