Inhibition of amyloid fibril formation and cytotoxicity by a chemical analog of Curcumin as a stable inhibitor.
Clinical application of curcumin for Alzheimer's disease treatment is severely limited with regard to its poor bioavailability, high rate of metabolism, and instability under neutral condition. In the current study, we designed three compounds in which the diketone moiety of curcumin was replaced by cyclohexanone. In these compounds, the linker length of the molecules was optimal; and substitution of dioxolane for hydroxyl groups on compound 3 should prevent metabolic inactivation. The inhibitory effect of the compounds was investigated against hen egg white lysozyme (HEWL) fibrillation using AFM (atomic force microscope), ThT (thioflavin T) and MTT assay. We found that all three compounds were able to inhibit HEWL aggregation in a dose-dependent manner and inhibit the cytotoxic activity of aggregated HEWL. Docking results demonstrated that the compounds could bind into lysozyme and occupy the whole active site groove. In conclusion, we present chemical analogs of curcumin with various modifications in the spacer and the phenolic rings as improved inhibitors of amyloid aggregation.
Biology Department, Payam Noor University, 19395-4697 Tehran, Islamic Republic of Iran. Electronic address: hramshini@yahoo.com.
Hassan
H
Ramshini
Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Islamic Republic of Iran.
Mohammad
M
mohammad-zadeh
Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
Azadeh
A
Ebrahim-Habibi
D000682:Amyloid / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003474:Curcumin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009113:Muramidase / Q000737:chemistry; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet
D000682:Amyloid; D009113:Muramidase; D003474:Curcumin
Amyloid disaggregation; Curcumin analog; Cytotoxicity; Docking; Drug discovery