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Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size.
Renard, Isaline; D'huys, Thomas; Burke, Benjamin P; Ajoleza, Trisha; Cain, Amy N; Funwie, Neil L; Khan, Abid; Maples, Danny L; Maples, Randall D; Matz, Dallas L; McRobbie, Graeme; Ullom, Robert; Prior, Timothy J; Linder, Douglas P; Van Loy, Tom; Hubin, Timothy J; Schols, Dominique; Archibald, Stephen J.
Afiliación
  • Renard I; Centre for Biomedicine and Positron Emission Tomography Research Centre, The University of Hull, Cottingham Road, Hull HU6 7RX, UK.
  • D'huys T; School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, UK.
  • Burke BP; Division of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
  • Ajoleza T; Centre for Biomedicine and Positron Emission Tomography Research Centre, The University of Hull, Cottingham Road, Hull HU6 7RX, UK.
  • Cain AN; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Funwie NL; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Khan A; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Maples DL; Centre for Biomedicine and Positron Emission Tomography Research Centre, The University of Hull, Cottingham Road, Hull HU6 7RX, UK.
  • Maples RD; Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
  • Matz DL; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • McRobbie G; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Ullom R; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Prior TJ; Centre for Biomedicine and Positron Emission Tomography Research Centre, The University of Hull, Cottingham Road, Hull HU6 7RX, UK.
  • Linder DP; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Van Loy T; Chemistry, Faculty of Science and Engineering, The University of Hull, Cottingham Road, Hull HU6 7RX, UK.
  • Hubin TJ; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
  • Schols D; Division of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
  • Archibald SJ; Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA.
Pharmaceutics ; 16(8)2024 Jul 28.
Article en En | MEDLINE | ID: mdl-39204345
ABSTRACT
Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Pharmaceutics Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Pharmaceutics Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Suiza