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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Biological Factors
  • Chromones / chemistry*
  • Chromones / metabolism
  • Chromones / pharmacology*
  • Drug Design
  • Flavones
  • Humans
  • Inhibitory Concentration 50
  • Mitogen-Activated Protein Kinase 8 / chemistry*
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Ultraviolet Rays


  • Antineoplastic Agents
  • Biological Factors
  • Chromones
  • Flavones
  • Mitogen-Activated Protein Kinase 8
  • quercetagetin