CXCR4 chemokine receptors are found on the surface of immune, and other, cells, and together with the specific natural ligand, stromal cell-derived factor-1α (SDF-1α, also known as CXCL12), have been revealed to play a role in a number of disease states. Within the last ten years the CXCR4 and CCR5 co-receptors have been revealed as the entry route for HIV into cells, generating interest in a new therapeutic approach to treatment via fusion inhibitor drugs rather than the current preference for reverse transcriptase and protease inhibitors. CXCR4 expression has also been reported in at least 23 different cancers. CXCL12 stimulation of tumor growth, angiogenesis, and metastasis of breast cancer cells has been described. Target organs for breast metastases such as liver, lung, and bone have high levels of CXCL12, triggering the specific migration of breast tumor cells that express the CXCR4 receptor. Due to the wide-ranging potential biomedical applications that might result, our aim is to develop new antagonists for the CXCR4 co-receptor. They are conformationally fixed macrocyclic compounds where the unrestrained equivalent is a known CXCR4 antagonist. The SWOSU-Hull collaboration has produced well over 50 metal complexes of bis-tetraazamacrocycle ligands for screening as CXCR4 antagonists. The bis-linked complexes are highly efficient antagonists, while single-macrocycle analogues are much less effective. Our objectives were to synthesize analogues of our most effective bis-tetraazamacrocycle metal complexes and to characterize their chemical and physical properties in preparation for determining their antagonism of CXCR4.

Modified tetraazamacrocycles as improved CXCR4 antagonists

ACS Spring 2022

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