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

被引：145
作者：
Narlawar, Rajeshwar
Pickhardt, Marcus
Leuchtenberger, Stefanie
Baumann, Karlheinz
Krause, Sabine
Dyrks, Thomas
Weggen, Sascha
Mandelkow, Eckhard
Schmidt, Boris
机构：
[1] Clemens Schöpf Institute of Chemistry and Biochemistry, Darmstadt University of Technology, 64287 Darmstadt
[2] Max Planck Unit for Structural Molecular Biology, c/o DESY, 22607 Hamburg
[3] Emmy Noether Research Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz
[4] F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Preclinical Research CNS
[5] Bayer Schering Pharma AG, Molecular Imaging Research S109, 06, 614A, 13353 Berlin
来源：
CHEMMEDCHEM | 2008年 / 3卷 / 01期
关键词：
D O I：
10.1002/cmdc.200700218
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Curcumin binds to the amyloid[3 peptide (A beta) 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 A beta(42) aggregates. Accordingly, replacement of the 1,3-dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar A beta(42) aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.
引用
收藏
页码：165 / 172
页数：8
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