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CXCR4 antagonists: a new generation of configurationally restricted bis-azamacrocyclic compounds

Khan, Abid; Nicholson, Gary; McRobbie, Graeme; Greenman, John; Pannecouque, Christophe; Daelemans, Dirk; Schols, Dominique; De CLercq, Erik; Hubin, Timothy J.; Archibald, Stephen J.

Authors

Abid Khan

Gary Nicholson

Graeme McRobbie

Christophe Pannecouque

Dirk Daelemans

Dominique Schols

Erik De CLercq

Timothy J. Hubin



Abstract

AMD3100 is a bis-azamacrocyclic compound that has been demonstrated to be a highly effective antagonist of the CXCR4 chemokine receptor. The two azamacrocyclic rings have been shown to interact with aspartate residues on the receptor via hydrogen bonding and electrostatic interactions. However, it is proposed that AMD3100 may bind metal ions in vivo and the active form may be a metal containing drug compound. This presents an issue as the metal complexes of AMD3100 exist in a configurational equilibrium some of which are better at binding to the receptor than others. The aim of this research is to design, synthesise and characterise new azamacrocyclic metal complexes with fixed configurations to provide optimised interactions with the CXCR4 receptor, increasing the potency and residence times of the new drugs relative to AMD3100. Informed design of a metal containing drug requires a comprehensive knowledge of coordination chemistry principles and must incorporate high kinetic stability of the complex to prevent exchange of the metal ion. New compounds containing zinc(II) and copper(II) were produced, which showed improved binding properties and increased anti-HIV potency. In vitro MT-4 anti-HIV infection assay, average EC50 HIV-1 (IIIB): SJA-GCV49(Zn) 2.5nM, SJA5(Cu) 4.3nM, SJA-GCV18(Cu)26nM. X-ray crystallographic and spectroscopic data of compounds mimicking the drug binding interactions with CXCR4 allow structure activity relationships to be elucidated with regard to the coordination chemistry of the metal centres.

Journal Article Type Article
Publication Date 2009-05
Journal ANTIVIRAL RESEARCH
Print ISSN 0166-3542
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 82
Issue 2
Pages A59-A60
APA6 Citation Khan, A., Nicholson, G., McRobbie, G., Greenman, J., Pannecouque, C., Daelemans, D., …Archibald, S. J. (2009). CXCR4 antagonists: a new generation of configurationally restricted bis-azamacrocyclic compounds. Antiviral research, 82(2), A59-A60. doi:10.1016/j.antiviral.2009.02.141
DOI https://doi.org/10.1016/j.antiviral.2009.02.141
Keywords Chemokine receptor; Immune system; Antiviral; CXCR4; Medicinal inorganic chemistry
Publisher URL https://www.sciencedirect.com/science/article/pii/S0166354209001685?via%3Dihub
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