genistein and Alzheimer-Disease

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butyrylcholinesterase; Carbamates; Cell Line; Cell Survival; Cholinesterase Inhibitors; Copper; Dose-Response Relationship, Drug; Drug Development; Flavanones; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

Topics: Acetylcholinesterase; Aluminum Chloride; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Development; Humans; Ligands; Molecular Structure; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Structure-Activity Relationship; Zebrafish

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Membrane Permeability; Cholinesterases; Diabetes Mellitus, Type 2; Drug Discovery; Glucosides; Glycoside Hydrolases; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Molecular Structure; Phosphorylation; Polyphenols; Proto-Oncogene Proteins c-fyn; tau Proteins

A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ₁₋₄₂ aggregation, Cu(2+)-induced Aβ₁₋₄₂ aggregation, and human AChE-induced Aβ₁₋₄₀ aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu(2+)-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Drug Design; Genistein; Inhibitory Concentration 50; Kinetics; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Peptide Fragments; Spectrometry, Mass, Electrospray Ionization

Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Caseins; Flavonoids; Humans; Methylation; Milk; Structure-Activity Relationship