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Synthesis and study of novel multifunctional cyclodextrin-deferasirox hybrids
journal contribution
posted on 2023-06-09, 18:00 authored by John SpencerJohn Spencer, Jose Miguel Gascon, Valentina Oliveri, Andrew McGownAndrew McGown, Ecem Kaya, yu-lin Chen, Carol Austin, Martin Walker, Frances Platt, Graziella VecchioMetal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann Pick C or for hypervitaminosis. We have conjugated deferasirox, via an amide coupling reaction, to both 6A-amino-6A-deoxy-ß-cyclodextrin and 3A-amino-3A-deoxy-2A(S),3A(R)-ß-cyclodextrin, at the upper and lower rim respectively creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of ß-cyclodextrin with deferasirox to significantly improve the biological properties and reduce the cytotoxicity of this drug.
Funding
NPC-C: Adding a Chemistry Element to Niemann-Pick C Research; G1484; NIEMANN-PICK RESEARCH FOUNDATION; NPRF SPENCER/01
History
Publication status
- Published
File Version
- Accepted version
Journal
ChemMedChemISSN
1860-7179Publisher
WileyExternal DOI
Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-06-06First Open Access (FOA) Date
2020-06-04First Compliant Deposit (FCD) Date
2019-06-05Usage metrics
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