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

Hierold, J., Baek, S., Rieger, R., Lim, T.-G., Zakpur, S., Arciniega, M., et al. (2015). Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors. CHEMISTRY-A EUROPEAN JOURNAL, 21(47), 16887-16894. doi:10.1002/chem.201502475.

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 Creators:
Hierold, Judith1, Author
Baek, Sohee2, Author              
Rieger, Rene1, Author
Lim, Tae-Gyu1, Author
Zakpur, Saman1, Author
Arciniega, Marcelino2, Author              
Lee, Ki Won1, Author
Huber, Robert2, Author              
Tietze, Lutz F.1, Author
Affiliations:
1external, ou_persistent22              
2Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: HACAT HUMAN KERATINOCYTES; MATRIX METALLOPROTEINASE-1; TRANSCRIPTION FACTORS; MAPK PATHWAYS; CANCER CELLS; KINASE; ACTIVATION; INTEGRATION; EXPRESSION; FLAVONESdrug design; flavonoids; inhibitors; JNK1; synthetic drugs;
 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 mu M and 12.2 mu M, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50=4.6 mu M). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000366501600023
DOI: 10.1002/chem.201502475
 Degree: -

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Title: CHEMISTRY-A EUROPEAN JOURNAL
Source Genre: Journal
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Publ. Info: POSTFACH 101161, 69451 WEINHEIM, GERMANY : WILEY-V C H VERLAG GMBH
Pages: - Volume / Issue: 21 (47) Sequence Number: - Start / End Page: 16887 - 16894 Identifier: ISSN: 0947-6539