trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors

Seraj O. Alzahrani; Graeme McRobbie; Abid Khan; Thomas D'huys; Tom Van Loy; Ashlie N. Walker; Isaline Renard; Timothy J. Hubin; Dominique Schols; Benjamin P. Burke; Stephen J. Archibald

doi:10.1039/D3DT01729J

trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors

Seraj O. Alzahrani,^a Graeme McRobbie,^a Abid Khan,^ab Thomas D'huys,^c Tom Van Loy,^c Ashlie N. Walker,^e Isaline Renard,

^ad Timothy J. Hubin,

^e Dominique Schols,^c Benjamin P. Burke^a and Stephen J. Archibald

*^ad

Author affiliations

* Corresponding authors

^a Centre for Biomedicine and Positron Emission Tomography Research Centre, Hull York Medical School and University of Hull, Cottingham Road, Hull, UK
E-mail: [email protected]

^b The University of Manchester, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester, UK

^c KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium

^d School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor Lambeth Wing, St Thomas’ Hospital, London, UK

^e Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, USA

Abstract

The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.

Dalton Transactions

trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors

Abstract

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trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors

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