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.
Professor John Greenman J.Greenman@hull.ac.uk
Professor of Tumour Immunology
Erik De CLercq
Timothy J. Hubin
Professor Steve Archibald S.J.Archibald@hull.ac.uk
Professor in Molecular Imaging Chemistry
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|
|Peer Reviewed||Peer Reviewed|
|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|
|Keywords||Chemokine receptor; Immune system; Antiviral; CXCR4; Medicinal inorganic chemistry|
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