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

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Baek,  Sohee
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

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Arciniega,  Marcelino
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

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Huber,  Robert
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0029-596E-D
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.