Synthesis, physicochemical properties and antioxidant activity of deferiprone-cyclodextrin conjugates and their iron(<scp>iii</scp>) complexes

Puglisi, Antonino; Spencer, John; Oliveri, Valentina; Vecchio, Graziella; Kong, Xiaole; Clarke, James; Milton, John

doi:10.1039/c1dt11677k

Cited by 22 publications

(33 citation statements)

References 38 publications

(33 reference statements)

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“…This behavior has been generally reported for functionalized CyDs and is due to the interaction of the functionalizing moiety with CyD. The addition of ADM did not significantly influenced CD signals at variance of CyD systems in which the pendant is included . The data further confirm the lid‐type geometry of IOX moiety as encapsulation of small molecules (ADM) into the cavity is not expected to affect this type of conformation.…”

Section: Resultssupporting

confidence: 82%

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

2017

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Alzheimer′s disease represents a daunting challenge for healthcare because it affects millions of people worldwide. The abnormal assembly of amyloid‐beta peptides into amyloid aggregates is a pathological hallmark of Alzheimer's disease. Properly functionalized cyclodextrins modulate amyloidogenesis. Here, we report the synthesis and characterization of a 6‐monofunctionalized cyclodextrin‐bearing a quinoline derivative (IOX1). Moreover, we tested the ability of the new compound and its 3‐monofunctionalized isomer to inhibit self‐induced Aβ aggregation in order to understand if the two isomers differently modulate aggregation process. The results further establish the potential of cyclodextrin conjugates as modulators of Aβ aggregation.

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Section: Resultssupporting

confidence: 82%

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

2017

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“…Compound 3 also has a moderate affinity for Cu 2+ as demonstrated by the value of 18.8 for log β (CuL), and 23.9 for log β 2 (CuL 2 ) reported elsewhere . As observed for iron, we anticipate the conjugation with CyD does not significantly modify the copper‐binding ability of the chelators . Moreover, we confirmed through UV/Vis and CD spectroscopy that both derivatives maintain the ability of 3 to complex copper ions.…”

Section: Resultssupporting

confidence: 84%

“…In the case of 2 , the hydroxy groups may be less available to react with the radical cation, probably due to the higher rigidity of the system relative to the analogous 6‐functionalized derivative. Similar behavior has also been reported for related cyclodextrin–deferiprone conjugates . However, the ability of 2 to scavenge free radicals is much higher than that of Trolox.…”

Section: Resultssupporting

confidence: 82%

“…NMR and CD data suggest the self‐inclusion of the a ring of the CyD derivatives, and this behavior could decrease the protonation constant of this phenol group relative to that of 3 . A decrease in the values of the protonation stability constants has been reported for other CyD derivatives and has been attributed to the hydrophobic effects of the CyD cavity …”

Section: Resultsmentioning

confidence: 54%

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Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

et al. 2019

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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 6A‐amino‐6A‐deoxy‐β‐cyclodextrin and 3A‐amino‐3A‐deoxy‐2A(S),3A(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.

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“…Polymorphic forms exhibit differences with respect to bioavailability, solubility and the stability of the crystalline forms (Yu et al, 2003), and influence the pharmacokinetics and pharmacodynamics of a drug administered into the body (Singhal & Curatolo, 2004). The Cambridge Structural Database (CSD; Groom et al, 2016) was searched for deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), (I) (see Scheme), and it was found that there are more metal complexes of deferiprone (Ahmed et al, 2000;Drouza et al, 2004;Puglisi et al, 2012;Wang et al, 2018). It exists in five polymorphic forms (, , , and "), of which the from is the thermodynamically more stable and commercially marketed, whereas the and forms exhibit better bioavailability (Censi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Two novel polymorphic forms of iron-chelating agent deferiprone

et al. 2020

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Thalassemia is a genetic blood disorder requiring life-long blood transfusions. This process often results in iron overload and can be treated by an ironchelating agent, like deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), C 7 H 9 NO 2 , in an oral formulation. The first crystal structure of deferiprone, (Ia), was reported in 1988 [Nelson et al. (1988). Can. J. Chem. 66, 123-131]. In the present study, two novel polymorphic forms, (Ib) and (Ic), of deferiprone were identified concomitantly with polymorph (Ia) during the crystallization experiments. Polymorph (Ia) was redetermined at low temperature for comparison of the structural features and lattice energy values with polymorphs (Ib) and (Ic). Polymorph (Ia) crystallized in the orthorhombic space group Pbca, whereas both polymorphs (Ib) and (Ic) crystallized in the monoclinic space group P2 1 /c. The asymmetric units of (Ia) and (Ib) contain one deferiprone molecule, while polymorph (Ic) has three crystallographically independent molecules (A, B and C). All three polymorphs have similar hydrogen-bonding features, such as an R 2 2 (10) dimer formed by O-HÁ Á ÁO hydrogen bonds, an R 4 3 (20) tetramer formed by C-HÁ Á ÁO hydrogen bonds andinteractions, but the polymorphs differ in their molecular arrangements in the solid state and are classified as packing polymorphs. O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds lead to the formation of two-dimensional hydrogen-bonded parallel sheets which are interlinked bystacking interactions. In the three-dimensional crystal packing, the deferiprone molecules were aggregated as corrugated sheets in polymorphs (Ia) and (Ic), whereas in polymorph (Ib), they were aggregated as a square-grid network. The characteristic crystalline peaks of polymorphs (Ia), (Ib) and (Ic) were established through powder X-ray diffraction analysis. The Rietveld analysis was also performed to estimate the contribution of the polymorphs to the bulk material.

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Synthesis, physicochemical properties and antioxidant activity of deferiprone-cyclodextrin conjugates and their iron(iii) complexes

Cited by 22 publications

References 38 publications

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

Two novel polymorphic forms of iron-chelating agent deferiprone

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