Curcumin‐Derived Pyrazoles and Isoxazoles: Swiss Army Knives or Blunt Tools for Alzheimer's Disease?

ChemMedChem - Tập 3 Số 1 - Trang 165-172 - 2008
Rajeshwar Narlawar1, Marcus Pickhardt2, Stefanie Leuchtenberger3, Karlheinz Baumann4, Sabine Krause5, Thomas Dyrks5, Sascha Weggen3, Eckhard Mandelkow�2, Boris Schmidt1
1Clemens Schöpf Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, 64287 Darmstadt, Germany, Fax: (+49) 6151-163278
2Max Planck Unit for Structural Molecular Biology c/o DESY, Notkestrasse 85, 22607 Hamburg, Germany
3Emmy Noether Research Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
4F. Hoffmann–La Roche Ltd., Pharmaceuticals Division, Preclinical Research CNS, Building 70/345, 4070 Basel, Switzerland
5Bayer Schering Pharma AG, Molecular Imaging Research, S109, 06, 614A, Müllerstrasse 178, 13353 Berlin, Germany

Tóm tắt

Abstract

Curcumin binds to the amyloid β peptide (Aβ) 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 Aβ42 aggregates. Accordingly, replacement of the 1,3‐dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar Aβ42 aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.

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ChemMedChem

Tập 3 Số 1

165-172

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