Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors
| Autor: | Sohee Baek, Saman Zakpur, Marcelino Arciniega, Lutz F. Tietze, Judith Hierold, Ki Won Lee, Rene Rieger, Tae Gyu Lim, Robert Huber |
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| Rok vydání: | 2015 |
| Předmět: |
Ultraviolet Rays
Stereochemistry Quercetagetin Antineoplastic Agents Catalysis Biological Factors Inhibitory Concentration 50 chemistry.chemical_compound Humans Mitogen-Activated Protein Kinase 8 IC50 Biological evaluation chemistry.chemical_classification Chemistry Kinase Organic Chemistry General Chemistry Flavones 3. Good health Enzyme Design synthesis Chromones Docking (molecular) Drug Design Cancer cell Biologie |
| Zdroj: | Chemistry - A European Journal. 21:16887-16894 |
| ISSN: | 0947-6539 |
| DOI: | 10.1002/chem.201502475 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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