& Cyclodextrins Unusual Cyclodextrin Derivatives as a New Avenue to Modulate Self- and Metal-Induced Ab Aggregation Valentina Oliveri, [a, b] Francesco Bellia, [c] Adriana Pietropaolo, [d] and Graziella Vecchio* [a] Abstract: Mounting evidence suggests an important role of cyclodextrins in providing protection in neurodegenerative disorders. Metal dyshomeostasis is reported to be a patho- genic factor in neurodegeneration because it could be re- sponsible 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 exam- ple 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-b aggregation seems to be led by synergistic effects of both cyclodextrin and hydroxy- quinoline. Moreover, the derivatives are also able to complex metal ions and to inhibit metal-induced protein aggregation. Therefore, these compounds could have potential as thera- peutic agents in diseases related to protein aggregation and metal dyshomeostasis. Introduction Cyclodextrins (CyDs) are a well-known family of cyclic oligosac- charides consisting of (1,4)-linked a-d-glucopyranose units. [1] CyDs are torus-shaped molecules; the primary hydroxyl groups of the sugars are located at the narrow edge and the secon- dary hydroxyl groups at the wider edge of the cone. The cen- tral cavity of the torus provides a favorable hydrophobic envi- ronment and accounts for the wide deployment of CyDs in the pharmaceutical industry for solubilizing drugs by forming in- clusion complexes. A host of chemical manipulations have been undertaken to achieve desired improvements such as in- crease of solubility, masking taste, reduced toxicity, among others. [2] Sugammadex is an example of the chemical addition of selected functional groups to improve the solubility, entrap- ment, and binding security of a pharmacologically active guest. Indeed, it is a selective relaxant binding agent that is li- censed for the reversal of rocuronium- and vecuronium-in- duced neuromuscular block. [3] Furthermore, numerous studies have shown that CyDs are able to remove cellular cholesterol and alleviate its neuronal storage and for this reason the Food and Drug Administration (FDA) approved the administration of hydroxypropyl b-CyD in twin girls suffering from Niemann–Pick C disease (NPC). [4] Known as “childhood Alzheimer’s”, NPC is an autosomal reces- sive neurodegenerative disorder characterized by accumulation of unesterified cholesterol and other lipids in lysosomal stor- age organelles, [5] oxidative stress, [6, 7] and dyshomeostasis of metal ions. [8, 9] Moreover, the neuroprotection by CyD has been reported in vivo in the case of other neurodegenerative diseas- es. [10] In particular, b-CyD, consisting of seven glucose units, is able to interact with Ab and substantially decrease its neuro- toxic effects in vitro [11, 12] and in vivo. [13] Disruption of metal and cholesterol homeostasis are two major pathological features in neurodegenerative disorders such as Alzheimer’s disease (AD), [14–16] Parkinson’s disease (PD), [17] as well as NPC. [18] Nevertheless, native CyDs are not able to complex metal ions at physiological pH. [19] To improve the CyD metal-binding ability we functionalized b-CyD with 8- hydroxyquinoline (OHQ), [20–22] a well-known chelating moiety. The obtained compounds have demonstrated interesting fea- tures including the enhancement of solubility, reduced toxicity, and multifunctionality. OHQ was the scaffold of choice because it has emerged as a privileged structure for new drug candi- dates. [23] Among OHQ derivatives, clioquinol (CQ) and PBT2 are reported to have the highest interest in the treatment of neu- rodegenerative disorders, such as AD and Huntington’s disease (HD). [24] Despite its failure as a drug, [25] CQ proved that metal chelation has a good potential for the AD treatment and the positive outcomes from in vitro and patient studies have in- [a] Dr. V. Oliveri, Prof. G. Vecchio Dipartimento di Scienze Chimiche Università di Catania, Viale A. Doria 6, 95125, Catania (Italy) E-mail : gr.vecchio@unict.it [b] Dr. V. Oliveri Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici C.I.R.C.M.S.B, Unità di Ricerca di Catania 95125 Catania (Italy) [c] Dr. F. Bellia Istituto di Biostrutture e Bioimmagini, CNR Via P. Gaifami 18, 95126 Catania, Italy [d] Dr. A. Pietropaolo Dipartimento di Scienze della Salute Università di Catanzaro, Viale Europa, 88100 Catanzaro, Italy Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201502155. Chem. Eur. J. 2015, 21, 14047 – 14059 # 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 14047 Full Paper DOI: 10.1002/chem.201502155