title: Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells.
abstract: BACKGROUND
  Inhibition of the COP9 signalosome (CSN) associated kinases CK2 and PKD by curcumin causes stabilization of the tumor suppressor p53. It has been shown that curcumin induces tumor cell death and apoptosis. Curcumin and emodin block the CSN-directed c-Jun signaling pathway, which results in diminished c-Jun steady state levels in HeLa cells. The aim of this work was to search for new CSN kinase inhibitors analogue to curcumin and emodin by means of an in silico screening method.
  
  
  METHODS
  Here we present a novel method to identify efficient inhibitors of CSN-associated kinases. Using curcumin and emodin as lead structures an in silico screening with our in-house database containing more than 10(6) structures was carried out. Thirty-five compounds were identified and further evaluated by the Lipinski's rule-of-five. Two groups of compounds can be clearly discriminated according to their structures: the curcumin-group and the emodin-group. The compounds were evaluated in in vitro kinase assays and in cell culture experiments.
  
  
  RESULTS
  The data revealed 3 compounds of the curcumin-group (e.g. piceatannol) and 4 of the emodin-group (e.g. anthrachinone) as potent inhibitors of CSN-associated kinases. Identified agents increased p53 levels and induced apoptosis in tumor cells as determined by annexin V-FITC binding, DNA fragmentation and caspase activity assays.
  
  
  CONCLUSIONS
  Our data demonstrate that the new in silico screening method is highly efficient for identifying potential anti-tumor drugs.
authors.affiliation: Institute of Biochemistry, Charité, Universitätsmedizin Berlin, Monbijoustr, 2, 10117 Berlin, Germany. melanie.fullbeck@charite.de
authors.forename: Melanie
authors.initials: M
authors.lastname: Füllbeck
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.forename: Renate
authors.initials: R
authors.lastname: Dumdey
authors.forename: Cornelius
authors.initials: C
authors.lastname: Frommel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dubiel
authors.forename: Robert
authors.initials: R
authors.lastname: Preissner
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000075686:COP9 Signalosome Complex; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003474:Curcumin / Q000494:pharmacology*; D053938:DNA Fragmentation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004642:Emodin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008956:Models, Chemical; D015233:Models, Statistical; D046912:Multiprotein Complexes / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011419:Propidium / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D012984:Software; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; D016755:Proto-Oncogene Proteins c-jun; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D011419:Propidium; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; C022616:thiazolyl blue; D003474:Curcumin; D004642:Emodin