| Autor: |
He, Feng, Chou, C. James, Scheiner, Matthias, Poeta, Eleonora, Yuan Chen, Natalia, Gunesch, Sandra, Hoffmann, Matthias, Sotriffer, Christoph, Monti, Barbara, Maurice, Tangui, Decker, Michael |
| Zdroj: |
Journal of Medicinal Chemistry; April 2021, Vol. 64 Issue: 7 p3794-3812, 19p |
| Abstrakt: |
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10bas a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25−35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties. |
| Databáze: |
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