| Avtor/Urednik | Knez, Damijan; Sosič, Izidor; Pišlar, Anja; Mitrović, Ana; Jukič, Marko; Kos, Janko; Gobec, Stanislav | |
| Naslov | Biological evaluation of 8-Hydroxyquinolines as multi-target directed ligands for treating Alzheimer's disease | |
| Tip | članek | |
| Vol. in št. | Letnik 16, št. 9 | |
| Leto izdaje | 2019 | |
| Obseg | str. str. 801-814 | |
| ISSN | 1567-2050 - Current Alzheimer research | |
| Jezik | eng | |
| Abstrakt | Background: Accumulating evidence suggests that multi-target directed ligands have a great potential for the treatment of complex diseases such as Alzheimer's disease (AD). Objectives: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. Method: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore on, chelation, antioxidative properties and the permeability of blood-brain barrier (BBB) were evaluated by spectroscopy- based assays and the inhibition of amyloid [beta] (A[beta]) aggregation was determined in immunoassay. Cell-based assays were performed to determine the cytotoxicity, neuroprotection against toxic A[beta] species, and the effects of compound 2 on apoptotic cascade. Results: Compounds 2-4 competitively inhibited cathepsin B [beta]-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited A[beta] aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 [micro]M. Compound 2 exerted neuroprotective effects towards A[beta] toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with A 1-42 . Conclusions: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD. | |
| Proste vsebinske oznake | 8-hydroxyquinoline PBT2 nitroxoline multi-target directed ligands (MTDLs) Alzheimer's disease cathepsin B inhibition metal chelation neuroprotective activity |