title: Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimer's disease?
abstract: 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.
authors.affiliation: Clemens Schöpf Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, 64287 Darmstadt, Germany.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Narlawar
authors.forename: Marcus
authors.initials: M
authors.lastname: Pickhardt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Leuchtenberger
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.forename: Thomas
authors.initials: T
authors.lastname: Dyrks
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002645:Chickens; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D003474:Curcumin