Cyclodextrin 3‐Functionalized with 8‐Hydroxyquinoline as an Antioxidant Inhibitor of Metal‐Induced Amyloid Aggregation

Abstract

Cyclodextrins are used increasingly in pharmacotherapy. Experimental and clinical data suggest that cyclodextrins can be used not only as excipients for marketed drugs, but also as active pharmaceutical ingredients to treat neurological diseases including Niemann–Pick type C disease. Disruption of metal and cholesterol homeostasis, protein misfolding, and aggregation are recognized among the major pathological features in triggering neurodegenerative disorders, and therefore it is becoming more and more evident that the next generation of therapies should have multiple functions to combat the multifactorial nature of diseases. A novel class of compounds obtained by conjugating 8‐hydroxyquinoline with cyclodextrin has been proposed to combine antioxidant activity, chelating, antiaggregant, and inclusion ability into one compound designed for metal‐associated neurodegenerative diseases. Herein, the synthesis and characterization of the new compound 3A‐deoxy‐3A‐[(8‐hydroxyquinolyl)‐2‐methylamino]‐2A(S),3A(R)‐β‐cyclodextrin is reported. Moreover, the interaction of copper–Aβ and zinc–Aβ amyloid with this class of cyclodextrin conjugates was investigated for the first time. New information about the effects of different modified chelating cyclodextrins may be important for further development of drugs against neurodegenerative disorders.

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

“…The conjugation of HQs with sugars improves their properties as demonstrated by us . In particular, the conjugation of β‐CyD with HQ imparts synergistic effects on the inhibition of self‐induced and metal‐induced Aβ aggregation . CyDs can be functionalized with HQs at the secondary and primary rim, modifying or substituting one or more OH groups .…”

Cyclodextrins 3‐Functionalized with 8‐Hydroxyquinolines: Copper‐Binding Ability and Inhibition of Synuclein Aggregation

“…(4)w ere synthesized as reported elsewhere. [13,14] Thin-layer chromatography (TLC) was performed on silica gel plates (Merck 60-F254). Carbohydrate derivatives were detected on TLC by UV and/or anisaldehyde test.…”

“…In vitro antioxidant assays were performed by 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt (ABTS) radical cation decolorization assay by using 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) as reported elsewhere. [13,14] Spectrophotometrictitrations Both competition and direct UV/Vis titrations were performed in buffered aqueous solution (pH 7.4, MOPS 10 mm)a t2 58Cw ith an Agilent 8453 diode-array spectrophotometer.I nthe competition experiments, increasing amounts of as tandard EDTAs olution (5 Ä 6.5 10 À4 m)w ere added with ap recision burette (Hamilton) into the cell containing ak nown volume (usually 2mL) of either CuL (L = 1, 2,o r4)o rC u 2 L( L= 4)c omplex solution. These complexes were typically prepared by adding aC u 2 + solution (7 10 À4 Ä 1 10 À3 m)t oasolution of the proper ligand (1.5 Ä 5 10 À5 m)t ohave am etal/ligand ratio of 1:1o r2:1 in the cell.…”

“…(2), [13] [14] and 3 A , [13] (Figure 1). Comparedt ot he large number of 6-monofunctionalized CyDss tudied, very few 3-functionalized CyDs have been thoroughly investigated so far.T his inspired us to explore their potentiala sc opper(II) chelators and inhibitors of metal-induced aSyn aggregation.…”

Zinc Complexes of Cyclodextrin‐bearing 8‐Hydroxyquinoline Ligands: A Comparative Study

“…[7,8] In our previous studies, we demonstrated that glycoconjugation of HQ improvedo rp rovided new properties to the conjugates. [9][10][11][12] In particular,c yclodextrin (CyD) derivatives are able to scavenge free radicals and to inhibit metal-induced aggregation of Ab and aSyn. [13,14] This latter capacity seems to be strictly relatedt ot he metal-binding ability of these compounds.…”