Synthesis and study of novel multifunctional cyclodextrin‐deferasirox hybrids

Spencer, John, Gascon, Jose Miguel, Oliveri, Valentina, McGown, Andrew, Kaya, Ecem, Chen, yu-lin, Austin, Carol, Walker, Martin, Platt, Frances and Vecchio, Graziella (2019) Synthesis and study of novel multifunctional cyclodextrin‐deferasirox hybrids. ChemMedChem. ISSN 1860-7179

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Abstract

Metal 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‐β‐cyclodextrin and 3A‐amino‐3A‐deoxy‐2A(S),3A(R)‐β‐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 β‐cyclodextrin with deferasirox to significantly improve the biological properties and reduce the cytotoxicity of this drug.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RM Therapeutics. Pharmacology > RM0300 Drugs and their actions
Depositing User: John Spencer
Date Deposited: 06 Jun 2019 13:01
Last Modified: 01 Jul 2019 13:16
URI: http://sro.sussex.ac.uk/id/eprint/84122

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Project NameSussex Project NumberFunderFunder Ref
NPC-C: Adding a Chemistry Element to Niemann-Pick C ResearchG1484NIEMANN-PICK RESEARCH FOUNDATIONNPRF SPENCER/01