Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

Abstract: A zinc(II) containing configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been synthesized and shown to adopt only one configuration in solution. The single crystal X-ray structure reveals favorable binding to acetate via a bidentate chelation that can be related to the proposed interaction with aspartate on the receptor protein surface. The zinc(II) complex is highly active against HIV infection in vitro. AMD3100 (the octa HCl salt of 1-1′-[1,4-phenylenebis-(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane)), Figure 1c, is a drug that interacts with a cell surface protein (CXCR4) via hydrogen bonding interactions or more effectively as the metal complex via coordinate bonds with aspartate residues.1 On metal complex formation, the tetra-aza macrocyclic rings in AMD3100 show multiple configurations in solution.2 Configurationally fixed analogues would have the advantage of presenting onl