Synthesis and Detection of BODIPY-, Biotin-, and 19 F- Labeled Single-Entity Dendritic Heparan Sulfate Mimetics.

Autor: Spijkers-Shaw S; The Ferrier Research Institute, Victoria University of Wellington, Gracefield Research Centre, Lower Hutt, New Zealand.; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, United States., Devlin R; The Ferrier Research Institute, Victoria University of Wellington, Gracefield Research Centre, Lower Hutt, New Zealand., Shields NJ; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, 2006, Australia., Feng X; MR Solutions Ltd., Guildford, Surrey, GU3 1LR, UK.; Sydney Imaging, Core Research Facility, The University of Sydney, NSW, 2006, Australia., Peck T; School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington, 6140, New Zealand., Lenihan-Geels G; School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington, 6140, New Zealand., Davis C; School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington, 6140, New Zealand., Young SL; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, 2006, Australia.; Faculty of Science, University of Canterbury, Christchurch, New Zealand., La Flamme AC; School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington, 6140, New Zealand.; Centre for Biodiscovery, Victoria University of Wellington, Kelburn Parade, Wellington, New Zealand., Zubkova OV; The Ferrier Research Institute, Victoria University of Wellington, Gracefield Research Centre, Lower Hutt, New Zealand.; Centre for Biodiscovery, Victoria University of Wellington, Kelburn Parade, Wellington, New Zealand.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Mar 22; Vol. 63 (13), pp. e202316791. Date of Electronic Publication: 2024 Feb 20.
DOI: 10.1002/anie.202316791
Abstrakt: Heparin and heparan sulfate (HS) are naturally occurring mammalian glycosaminoglycans, and their synthetic and semi-synthetic mimetics have attracted significant interest as potential therapeutics. However, understanding the mechanism of action by which HS, heparin, and HS mimetics have a biological effect is difficult due to their highly charged nature, broad protein interactomes, and variable structures. To address this, a library of novel single-entity dendritic mimetics conjugated to BODIPY, Fluorine-19 ( 19 F), and biotin was synthesized for imaging and localization studies. The novel dendritic scaffold allowed for the conjugation of labeling moieties without reducing the number of sulfated capping groups, thereby better mimicking the multivalent nature of HS-protein interactions. The 19 F labeled mimetics were assessed in phantom studies and were detected at concentrations as low as 5 mM. Flow cytometric studies using a fluorescently labeled mimetic showed that the compound associated with immune cells from tumors more readily than splenic counterparts and was directed to endosomal-lysosomal compartments within immune cells and cancer cells. Furthermore, the fluorescently labeled mimetic entered the central nervous system and was detectable in brain-infiltrating immune cells 24 hours after treatment. Here, we report the enabling methodology for rapidly preparing various labeled HS mimetics and molecular probes with diverse potential therapeutic applications.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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