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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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 languageEnglish
Pages (from-to)6479-6490
Number of pages12
JournalOrganic and Biomolecular Chemistry
Issue number35
Early online date20 Aug 2018
Publication statusPublished - 21 Sept 2018


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