Clioquinol and other hydroxyquinoline derivatives inhibit Aβ(1–42) oligomer assembly

Abstract

Soluble oligomeric amyloid-β (Aβ) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of Aβ oligomer formation with a single-site biotinylated Aβ(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC 50 's < 10 μM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block Aβ oligomer formation up to a concentration of 100 μM. Analogs of clioquinol have shown activity in reducing Aβ levels and improving behavioral deficits in mouse models of Aβ pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing Aβ oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials.

Label-free methods for probing the interaction of clioquinol with amyloid-β

“…The peptides were also diluted to 40 mM using PBS, and then subjected to 24 h incubation at 37 C with shaking at 800 rpm in order to produce the fibril seeds.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Indeed, clioquinol has shown efficacy in patients with AD and models in of disease. Clioquinol inhibits Aβ oligomer formation and protects against cell loss in an Aβ-injection model [211][212][213]. Nine weeks of oral clioquinol treatment in an AD mice lowered plaque burden and improved cognitive performance [196,214].…”

Design, Synthesis and Photochemical Reactivation of Caged Prodrugs of 8-Hydroxyquinoline-Based Enzyme Inhibitors

“…15) Recently, however, this situation seems to be changing somewhat, as mentioned above. As a typical example, 16) 5,7-dichloro-8-hydroxyquinoline (chloroxine, Chart 1), a topical antimicrobial agent, has been reported to be an inhibitor of biofilm formation of Candida albicans 17) and human platelet type 12-lipoxygenase. 18) It was reported that so-called "caged" drugs, particularly those containing photocleavable protecting groups, play important roles in the control of bioactivities.…”