CXCR4 chemokine receptors, together with their specific natural ligand, CXCL12, play a role in a number of disease states. We have developed efficient ethyl-bridged cyclam CXCR4 antagonists in prior work. Our objectives were to synthesize alternatively cross-bridged bis-tetraazamacrocycle metal complexes and to characterize their chemical properties prior to determining if changing our typical ethyl-bridged to alternatively bridged macrocycles enhances the antagonism of CXCR4. Synthetic routes extending our bis-linked ligand syntheses to use alternatively-bridged macrocycles were developed. Copper(II), nickel(II), cobalt(II), and zinc(II) complexes of single macrocyle model ligands were synthesized, before attempting complexation with the bis-linked targets. Electrospray mass spectra, UV-Visible spectra, cyclic voltammograms, and 1H and 13C NMR spectra were collected to characterize the complexes. The ligand syntheses of the new cross-bridged ligands is more synthetically challenging than our typical ethyl cross-bridged versions. 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. Bis-linked alternatively-bridged 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 even more efficient CXCR4 antagonists of this class.

New cross-bridged cyclam ligands and their transition metal complexes as CXCR4 antagonists

247th National Meeting (2014)

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