Configurationally restricted bis-tetraazamacrocyclic complexes: chemokine receptor antagonists

McRobbie, Graeme Walter John

Abstract

The chemokine receptor CXCR4 is a trans-membrane protein which has been implicated in many physiological and pathological processes including cancer, rheumatoid arthritis and most significantly HIV replication. CXCR4 plays a vital role in embryonic development but is not essential at the post-development stage; therefore, it has been identified as a potential therapeutic target.

Bis-macrocyclic drugs (e.g. AMDS 100) bind to aspartate residues on the CXCR4 surface and inhibit HIV replication by blocking the interaction of gp!20/gp41 with the protein. The incorporation of transition metals (e.g. zinc(II) and copper(II)) into the macrocyclic cavity increases anti-viral potency. The addition of a bridging ethylene unit to the macrocyclic framework locks the complex into a single configuration, potentially optimising the interaction with the receptor.

A series of configurationally restricted macrocyclic compounds have been prepared utilising bis-aminal chemistry. Characterisation by X-ray crystallography and X-ray absorption spectroscopy has confirmed that the complexes possessing an ethylene bridge between adjacent nitrogen atoms are fixed in the trans-II configuration and that complexes containing an ethylene bridge between non-adjacent nitrogen atoms adopt the cis-V configuration. In addition, solution EXAFS has been used as a model to probe the binding of the complexes to aspartate residues on the receptor surface.

The zinc(II) trans-II and copper(II) cis-V complexes reported here are more potent against HIV replication than AMDS 100 (IC₅₀ values against IIIB ; 0.00208 µM, 0.00491 µM and 0.018 µM respectively), confirming the importance of coordination interactions for potent binding to CXCR4 and also validating the strategy of configurationally fixing the macrocyclic unit for optimising receptor binding. It is believed that both thermodynamic and kinetic properties are important for effective binding to CXCR4.

Citation

McRobbie, G. W. J. (2009). Configurationally restricted bis-tetraazamacrocyclic complexes: chemokine receptor antagonists. (Thesis). University of Hull. Retrieved from https://hull-repository.worktribe.com/output/4213191

• Thesis Type: Thesis
• Deposit Date: Oct 9, 2012
• Publicly Available Date: Feb 22, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4213191
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: Mar 1, 2009