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Chemistry. 2015 Nov 16;21(47):16887-94. doi: 10.1002/chem.201502475. Epub 2015 Oct 7.

Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors.

Author information

1
Institute for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476.
2
Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany).
3
Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Republic of Korea).
4
Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried (Germany).
5
WCU Biomodulation Major, Center for Food and Bioconvergence, Department of Agricultural Biotechnology, Seoul National University, Seoul (Republic of Korea).
6
Department of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching (Germany).
7
Center for Medical Biotechnology, University of Duisburg-Essen, 45117 Essen (Germany).
8
School of Biosciences, Cardiff University, Cardiff (Wales, UK).
9
Institute for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476. ltietze@gwdg.de.

Abstract

The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy- (2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4 μM and 12.2 μM, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50 =4.6 μM). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.

KEYWORDS:

JNK1; drug design; flavonoids; inhibitors; synthetic drugs

PMID:
26541354
DOI:
10.1002/chem.201502475
[Indexed for MEDLINE]

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