Unusual Cyclodextrin Derivatives as a New Avenue to Modulate Self‐ and Metal‐Induced Aβ Aggregation

Abstract

Mounting evidence suggests an important role of cyclodextrins in providing protection in neurodegenerative disorders. Metal dyshomeostasis is reported to be a pathogenic factor in neurodegeneration because it could be responsible for damage involving oxidative stress and protein aggregation. As such, metal ions represent an effective target. To improve the metal-binding ability of cyclodextrin, we synthesized three new 8-hydroxyquinoline-cyclodextrin conjugates with difunctionalized cyclodextrins. In particular, the 3-difunctionalized regioisomer represents the first example of cyclodextrin with two pendants at the secondary rim, resulting in a promising compound. The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self-induced amyloid-β aggregation seems to be led by synergistic effects of both cyclodextrin and hydroxyquinoline. Moreover, the derivatives are also able to complex metal ions and to inhibit metal-induced protein aggregation. Therefore, these compounds could have potential as therapeutic agents in diseases related to protein aggregation and metal dyshomeostasis.

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

“…As previously reported, native β‐CyD is not able to significantly affect Aβ aggregation at the tested concentrations, whereas HQ is not so efficient compared to CyD3IOX. For this reason, it is evident that both CyD and IOX moieties positively contribute to the antiaggregant action of CyD3IOX.…”

“…The 1 H NMR spectrum (Figure ) shows the presence of the quinoline protons in the aromatic region δ =8.78‐7.10 ppm and especially the downfield shift of H‐6 A and H‐6’A protons of the modified glucose unit, due to the formation of the amide bond between the C‐6 A and the quinoline moiety. The difference in the chemical shift of one H‐6 A proton ( δ =4.07 ppm) with respect to the other ( δ =3.41 ppm) is particularly evident, as generally observed in similar systems . The H‐5 A proton of the modified glucose unit is also shifted downfield at 3.95 ppm, whereas a shift to higher fields is observed for the H‐4 A proton (δ =3.42 ppm).…”

“…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 .…”

Porphyrin Cyclodextrin Conjugates Modulate Amyloid Beta Peptide Aggregation and Cytotoxicity

“…[5,6] Among these,p hthalocyanines are the most commonly investigated compounds, [7][8][9] whereas the effect of porphyrins on Ab aggregationa nd toxicity has been less explored. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation.…”

Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

“…Moreover, H‐6 protons (Hs‐6) of the CyDs are spread as a consequence of the presence of the aromatic moiety linked to the CyD rim. In particular, the H‐6A protons appear at δ =4.05 and 3.04 ppm because of the aromatic ring current effect as reported for other aromatic CyD derivatives …”