Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid

Anna Peters; Catriona Mccallion; Andrew Booth; Julie A Adams; Karen Rees-Unwin; Alain Pluen; John Burthem; Simon Webb

doi:10.1039/C8OB01439F

Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid

Anna Peters, Catriona Mccallion, Andrew Booth, Julie A Adams, Karen Rees-Unwin, Alain Pluen, John Burthem, Simon Webb

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Abstract

A bis(cyclam)-capped lipid, obtained through a short synthetic pathway, binds cell surface CXCR4 and prevents migration of chronic lymphocytic leukaemia cells.A bis(cyclam)-capped cholesterol lipid designed to bind C–X–C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C–X–C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 μM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.

Original language	English
Pages (from-to)	6479-6490
Number of pages	12
Journal	Organic and Biomolecular Chemistry
Volume	16
Issue number	35
Early online date	20 Aug 2018
DOIs	https://doi.org/10.1039/C8OB01439F
Publication status	Published - 21 Sept 2018

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title = "Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid",

abstract = "A bis(cyclam)-capped lipid, obtained through a short synthetic pathway, binds cell surface CXCR4 and prevents migration of chronic lymphocytic leukaemia cells.A bis(cyclam)-capped cholesterol lipid designed to bind C–X–C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C–X–C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 μM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.",

author = "Anna Peters and Catriona Mccallion and Andrew Booth and Adams, {Julie A} and Karen Rees-Unwin and Alain Pluen and John Burthem and Simon Webb",

note = "Funding Information: This work was supported by a University of Manchester EPSRC Doctoral Prize Award (grant number EP/N509565/1), an EPSRC NOWNANO DTC studentship (grant number EP/G03737X/1), funding from the Manchester Pharmacy School (University of Manchester, UK) and a Colloid Science PhD studentship from the School of Chemistry (University of Manchester, UK). We thank Mrs Rehana Sung for her guidance in developing HPLC protocols and the School of Chemistry{\textquoteright}s nuclear magnetic resonance (NMR) spectroscopy service. We also thank Dr Reynard Spiess and the Mass Spectrometry Service in the School of Chemistry (University of Manchester) for mass spectrometry support. Finally, we thank Dr Nigel Hodson (BioAFM Facility, University of Manchester) for his help in both preparing the samples and performing AFM imaging. Publisher Copyright: {\textcopyright} 2018 The Royal Society of Chemistry. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

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AU - Pluen, Alain

AU - Burthem, John

AU - Webb, Simon

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N2 - A bis(cyclam)-capped lipid, obtained through a short synthetic pathway, binds cell surface CXCR4 and prevents migration of chronic lymphocytic leukaemia cells.A bis(cyclam)-capped cholesterol lipid designed to bind C–X–C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C–X–C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 μM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.

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DO - 10.1039/C8OB01439F

M3 - Article

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JO - Organic and Biomolecular Chemistry

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IS - 35

ER -

Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid

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