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RESEARCH PRODUCT

Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimer's disease?

Eckhard MandelkowSascha WeggenStefanie LeuchtenbergerKarlheinz BaumannSabine KrauseMarcus PickhardtThomas DyrksBoris SchmidtRajeshwar Narlawar

subject

CurcuminMagnetic Resonance SpectroscopyAmyloid betaStereochemistryTau proteinPeptidetau ProteinsBiochemistrychemistry.chemical_compoundInhibitory Concentration 50Radioligand AssayAlzheimer Diseasemental disordersDrug DiscoveryAmyloid precursor proteinFluorescence Resonance Energy TransferMoietyAnimalsHumansGeneral Pharmacology Toxicology and PharmaceuticsEnzyme InhibitorsCells CulturedCell ProliferationPharmacologychemistry.chemical_classificationAmyloid beta-PeptidesbiologyOrganic ChemistryP3 peptideIsoxazolesBiochemistrychemistrybiology.proteinCurcuminMolecular MedicinePyrazolesAmyloid Precursor Protein SecretasesAmyloid precursor protein secretaseChickens

description

Curcumin binds to the amyloid beta peptide (Abeta) and inhibits or modulates amyloid precursor protein (APP) metabolism. Therefore, curcumin-derived isoxazoles and pyrazoles were synthesized to minimize the metal chelation properties of curcumin. The decreased rotational freedom and absence of stereoisomers was predicted to enhance affinity toward Abeta(42) aggregates. Accordingly, replacement of the 1,3-dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar Abeta(42) aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.

yearjournalcountryeditionlanguage
2007-10-19ChemMedChem
10.1002/cmdc.200700218https://pubmed.ncbi.nlm.nih.gov/17943713