Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size
Isaline Renard1,2, Thomas D'huys3, Benjamin P Burke1
1Centre for Biomedicine and Positron Emission Tomography Research Centre, The University of Hull, Cottingham Road, Hull HU6 7RX, UK.
Pharmaceutics
|August 29, 2024
Summary
Chemokine receptor CXCR4 antagonists were developed using metal ions and rigid macrocycles. These compounds show high affinity and selectivity, offering potential for therapeutic applications in diseases like cancer and HIV.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Pharmacology
Background:
- Chemokine receptor CXCR4 plays a critical role in immune cell trafficking, HIV infection, inflammation, and cancer.
- Developing CXCR4 antagonists is crucial for therapeutic interventions in various diseases.
Purpose of the Study:
- To design and synthesize novel, high-affinity, rigidified CXCR4 antagonists incorporating metal ions.
- To investigate the influence of macrocyclic ring size and metal ion type (Cu(II), Zn(II)) on antagonist properties.
- To rationalize binding interactions and selectivity through structural and computational studies.
Main Methods:
- Synthesis of cross- and side-bridged tetraazamacrocyclic complexes.
- In vitro biological assays to determine receptor affinity, selectivity, and antagonist activity.
- X-ray crystallography and Density Functional Theory (DFT) computations for structural analysis.
Main Results:
- All developed zinc(II) complexes exhibited high-affinity CXCR4 antagonism.
- The bis-cross-bridged cyclen zinc(II) complex demonstrated significantly enhanced CXCR4 selectivity.
- Copper(II) complex properties were highly dependent on metal ion geometry.
- Structural data and DFT studies elucidated interactions with aspartate residues and rationalized affinities.
Conclusions:
- Rigidified macrocyclic complexes with metal ions are effective CXCR4 antagonists.
- Optimizing ring size and metal coordination enhances receptor selectivity and affinity.
- These findings support the development of novel therapeutics targeting CXCR4 for various diseases.
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