title: Nemorubicin and doxorubicin bind the G-quadruplex sequences of the human telomeres and of the c-MYC promoter element Pu22.
abstract: BACKGROUND
  Intra-molecular G-quadruplex structures are present in the guanine rich regions of human telomeres and were found to be prevalent in gene promoters. More recently, the targeting of c-MYC transcriptional control has been suggested, because the over expression of the c-MYC oncogene is one of the most common aberration found in a wide range of human tumors.
  
  
  METHODS
  The interaction of nemorubicin and doxorubicin with DNA G-quadruplex structures has been studied by NMR, ESI-MS and molecular modelling, in order to obtain further information about the complex and the multiple mechanisms of action of these drugs.
  
  
  CONCLUSIONS
  Nemorubicin intercalates between A3 and G4 of d(TTAGGGT)4 and form cap-complex at the G6pT7 site. The presence of the adenine in this sequence is important for the stabilization of the complex, as was shown by the interaction with d(TTGGGTT)4 and d(TTTGGGT)4, which form only a 1:1 complex. The interaction of doxorubicin with d(TTAGGGT)4 is similar, but the complex appears less stable. Nemorubicin also binds with high efficiency the c-MYC G-quadruplex sequence Pu22, to form a very well defined complex. Two nemorubicin molecules bind to the 3'-end and to the 5'-end, forming an additional plane of stacking over each external G-tetrad. The wild type c-MYCPu22 sequence forms with nemorubicin the same complex.
  
  
  CONCLUSIONS
  Nemorubicin and doxorubicin, not only intercalate into the duplex DNA, but also result in significant ligands for G-quadruplex DNA segments, stabilizing their structure; this may in part explain the multiple mechanisms of action of their antitumor activity.
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, Via Celoria 2, 20133 Milano, 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 Milano, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Mondelli
authors.affiliation: Scientia Advice of Roberto Artali, Desio, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.affiliation: Nerviano, Medical Sciences, Oncology-Chemical Core, Technologies Department, viale Pasteur, 10, 20014 Nerviano, Milano, Italy.
authors.forename: Federico Riccardi
authors.initials: FR
authors.lastname: Sirtori
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, Via Celoria 2, 20133 Milano, Italy. Electronic address: stefania.mazzini@unimi.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mazzini
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry*; D054856:G-Quadruplexes; D016259:Genes, myc; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D021241:Spectrometry, Mass, Electrospray Ionization; D016615:Telomere
chemical_list: D000970:Antineoplastic Agents; C000609287:nemorubicin; D004317:Doxorubicin
keywords: DNA-binding drugs; Daunomycins; G-quadruplex; Molecular modeling; NMR; c-MYC