Synthesis and Study of Multifunctional Cyclodextrin-Deferasirox Hybrids

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 type C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6^A -amino-6^A -deoxy-β-cyclodextrin and 3^A -amino-3^A -deoxy-2^A (S),3^A (S)-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 to decrease the cytotoxicity of this drug.

Keywords: Niemann-Pick; antioxidant; deferasirox; iron complexes; protein aggregation.