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 CXCR4 antagonists in prior work.  Our objectives were to synthesize alternatively cross-bridged cyclen complexes and to characterize their chemical properties prior to determining if changing our typical ethyl-bridges to alternatively bridged macrocycles enhances the antagonism of CXCR4. Synthetic routes extending our cyclen-based ligand syntheses to use new cross-bridges were developed.  Copper(II), nickel(II), cobalt(II), and zinc(II) complexes of single macrocyle dibenzyl and unsubstituted alternatively bridged cyclens were synthesized.  Electrospray mass spectra, elemental analyses, and 1H and 13C NMR spectra were collected to characterize the ligands and complexes. The ligand synthesis of the new cross-bridged ligands is more synthetically challenging than our typical ethyl cross-bridged versions.  However, single-macrocycle ligands have been made.  Complexation with the desired metal ions proceeded as expected.  Characterization of the metal complexes is ongoing. 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 cyclen ligands and their transition metal complexes as CXCR4 antagonists

247th National Meeting (2014)

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