title: Complexes of the antitumoral drugs Doxorubicin and Sabarubicin with telomeric G-quadruplex in basket conformation: ground and excited state properties.
abstract: We studied the binding of two anthracycline drugs, Doxorubicin and Sabarubicin, to a model telomeric sequence 5'-d[GGG(TTAGGG)(3)]-3' (21-mer), assuming the basket G-quadruplex (G4) conformation in Na(+)-rich aqueous solution. We used an approach that combines spectroscopic and microcalorimetric techniques to obtain information about ground and excited state properties of the most stable complexes. Both drugs bind to the 21-mer in basket conformation and complexes of 1:1 and 2:1 drug : 21-mer stoichiometry coexist in solution. Binding constants were determined from fluorescence and isothermal titration calorimetry experiments. For both drugs association is driven by enthalpy and disfavoured by entropy in the case of two sequential binding events to different sites. The drug fluorescence is completely quenched in the 1:1 complex, most likely by electron transfer from the guanine system to the anthraquinone moiety, while part of the emission survives in the 2:1 complex. Circular dichroism (CD) of the individual complexes is dominated by the G-quadruplex signal in the UV and by the anthracycline signal in the near-UV and Vis region. The experimental CD spectra combined with conformational calculations at MM level and quantum mechanical calculation of the rotational strength of the electronic transitions afforded information on the binding geometries.
authors.affiliation: Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, via Gobetti 101, I-40129, Bologna, Italy.
authors.forename: Ilse
authors.initials: I
authors.lastname: Manet
authors.forename: Francesco
authors.initials: F
authors.lastname: Manoli
authors.forename: Barbara
authors.initials: B
authors.lastname: Zambelli
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Andreano
authors.forename: Annalisa
authors.initials: A
authors.lastname: Masi
authors.forename: Luciano
authors.initials: L
authors.lastname: Cellai
authors.forename: Stefano
authors.initials: S
authors.lastname: Ottani
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marconi
authors.forename: Sandra
authors.initials: S
authors.lastname: Monti
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D001483:Base Sequence; D002942:Circular Dichroism; D004187:Disaccharides / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry*; D054856:G-Quadruplexes; D009690:Nucleic Acid Conformation; D011789:Quantum Theory; D012964:Sodium / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D016615:Telomere / Q000737:chemistry / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000903:Antibiotics, Antineoplastic; D004187:Disaccharides; D004317:Doxorubicin; D012964:Sodium; C107602:sabarubicin