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

被引：150

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

页码：165 / 172

页数：8

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