title: Molecular recognition in naphthoquinone derivatives - G-quadruplex complexes by NMR.
abstract: BACKGROUND
  G-quadruplexes have become important drug-design targets for the treatment of various human disorders such as cancer, diabetes and cardiovascular diseases. Recently, G-quadruplex structures have been visualized in the DNA of human cells and appeared to be dynamically sensitive to the cell cycle and stabilized by small molecule ligands. A small library of isoxazolo naphthoquinones (1a-h), which exhibited a strong antiproliferative activity on different cancer cell lines, was studied as potential ligands of G-quadruplex DNA.
  
  
  METHODS
  The DNA binding properties of a series of the selected compounds have been analyzed by fluorescence assays. NMR/modeling studies were performed to describe the complexes between G-quadruplex DNA sequences and two selected compounds 1a and 1b.
  
  
  RESULTS
  1a and 1b in the presence of G-quadruplexes, d(T(2)AG(3)T)(4), d(TAG(3)T(2)A)(4) and d(T(2)G(3)T(2))(4), showed good ability of intercalation and the formation of complexes with 2:1 stoichiometry. 1a showed an important interaction with the sequence Pu22 belonging to the promoter of oncogenes c-myc.
  
  
  CONCLUSIONS
  The ligands directly interact with the external G-tetrads of the G-quadruplexes, without alterations in the structure of the G-quadruplex core. The role of the adenine moieties over the G-tetrads in the stabilization of the complexes was discussed.
  
  
  CONCLUSIONS
  The results obtained suggested that the strong antiproliferative activity of isoxazolo naphthoquinones is not due to the Hsp90 inhibition, but mainly to the interaction at the level of telomeres and/or at the level of gene promoter. These findings can be used as a basis for the rational drug design of new anticancer agents.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della scienza 3, 20126 Milan, Italy. Electronic address: b.riva10@campus.unimib.it.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Riva
authors.affiliation: Department of Chemical and Biological Engineering, Chalmers University of Technology SE-412 96 Göteborg, Sweden. Electronic address: rubenf@chalmers.se.
authors.forename: Ruben
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, Via Celoria 2, 20133 Milan, Italy.
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.affiliation: Scientia Advice, Desio, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, Via Celoria 2, 20133 Milan, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scaglioni
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, Via Celoria 2, 20133 Milan, Italy. Electronic address: stefania.mazzini@unimi.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mazzini
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005453:Fluorescence; D054856:G-Quadruplexes; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones
keywords: DNA-binding drugs; G-quadruplex; Isoxazolo naphthoquinone; Molecular modeling; NMR studies