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

Organic & Biomolecular Chemistry
Anna D PetersSimon J Webb

Abstract

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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Citations

Jul 12, 2019·Blood Advances·Catriona McCallionJohn Burthem
Jan 2, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hélio M T AlbuquerqueArtur M S Silva

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Methods Mentioned

BETA
NMR
acylation
dynamic
Dynamic light scattering
atomic force microscopy
column chromatography
AFM
FCS
antibody competition
flow cytometry

Software Mentioned

Flowing
Agilent MassHunter Workstation software
BD
Image [UNK]
GraphPad Prism

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