Design,Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors |
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| Authors: | Dr. Judith Hierold Dr. Sohee Baek Rene Rieger Dr. Tae‐Gyu Lim Saman Zakpur Dr. Marcelino Arciniega Prof. Ki Won Lee Prof. Robert Huber Prof. Lutz F. Tietze |
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| Affiliation: | 1. Institute for Organic and Biomolecular Chemistry, Georg‐August‐University G?ttingen, Tammannstrasse 2, 37077 G?ttingen (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, Lichtenbergstra?e 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) |
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| 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. |
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| Keywords: | drug design flavonoids inhibitors JNK1 synthetic drugs |
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