Synthesis and Identification of New 4-Arylidene Curcumin Analogues as Potential Anticancer Agents Targeting Nuclear Factor-κB Signaling Pathway.
ABSTRACT A series of curcumin analogues including new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogues can effectively decrease the growth of a panel of lung cancer cells at submicromolar and low micromolar concentrations. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogues exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogues also reduced the tumorigenic potential of cancer cells in a clonogenic assay.
- SourceAvailable from: Grzegorz Grynkiewicz
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ABSTRACT: Curcumin (diferuloylmethane) is a polyphenol natural product of the plant Curcuma longa, and has a diversity of antitumor activities. However, the clinical application of curcumin remains limited due to its poor pharmacokinetic characteristics. It is therefore critical to develop structural analogues of curcumin with increasing anticancer activity. T63, a new 4-arylidene curcumin analogue, was synthesized in our previous studies and exhibited higher in vitro and in vivo anti-tumor activities compared to curcumin. However, the precise molecular mechanism of its anti-tumor effects has not been well elucidated. Using a two-dimensional gel electrophoresis (2-DE)-based proteomic approach, we identified 66 differentially expressed proteins. Similarly to curcumin, T63 showed a diverse range of molecular targets. We proposed that induction of ROS generation and mitochondrial dysfunction, inhibition of proteasome, HSP90, and 14-3-3 proteins play important roles in T63-induced cell cycle arrest and apoptosis. These data indicate that the novel curcumin analogue T63 is a potent anti-tumor agent, which can induce cell cycle arrest and apoptosis, and also provided valuable resources for further study of the anti-tumor effects and molecular mechanisms of T63.Molecular BioSystems 03/2014; · 3.35 Impact Factor
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ABSTRACT: Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is an attractive target for cancer therapy. Despite a number of effective EGFR inhibitors are constantly expanding and different methods are being employed to obtain novel compounds, yet the search for newer EGFR inhibitors is still a major scientific challenge. In the present study, a molecular docking and molecular dynamics investigation has been carried with an ensemble of EGFR-TK structures against a synthetically feasible library of curcumin analogues to discover potent EGFR inhibitors. To resolve protein flexibility issue we have utilized 5 EGFR wild type crystal structures during docking as this gives improved possibility of identifying an active compound as compared to using a single crystal structure. We then identified five curcumin analogues representing different scaffolds that can serve as lead molecules. Finally, the 5ns molecular dynamics simulation shows that knoevenagel condensate of curcumin specifically C29 and C30 can be used as starting blocks for developing effective leads capable of inhibiting EGFR.Gene 01/2014; · 2.20 Impact Factor