Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimer's disease?
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.
Narlawar
Rajeshwar
R
Clemens Schöpf Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, 64287 Darmstadt, Germany.
Pickhardt
Marcus
M
Leuchtenberger
Stefanie
S
Baumann
Karlheinz
K
Krause
Sabine
S
Dyrks
Thomas
T
Weggen
Sascha
S
Mandelkow
Eckhard
E
Schmidt
Boris
B
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
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D003474:Curcumin