title: Understanding the interaction of an antitumoral platinum(II) 7-azaindolate complex with proteins and DNA.
abstract: The reactivity of the [Pt(dmba)(aza-N1)(dmso)] complex 1, (a potential antitumoral drug with lower IC50 than cisplatin in several tumoral cell lines) with different proteins and oligonucleotides is investigated by means of mass spectrometry (ESI-TOF MS). The results obtained show a particular binding behaviour of this platinum(II) complex. The interaction of 1 with the assayed proteins apparently takes place by Pt-binding to the most accessible coordinating amino acids, presumably at the surface of the protein -this avoiding protein denaturation or degradation- with the subsequent release of one or two ligands of 1. The specific reactivity of 1 with distinct proteins allows to conclude that the substituted initial ligand (dmso or azaindolate) is indicative of the nature of the protein donor atom finally bound to the platinum(II) centre, i.e. N- or S-donor amino acid. Molecular modeling calculations suggest that the release of the azaindolate ligand is promoted by a proton transfer to the non-coordinating N present in the azaindolate ring, while the release of the dmso ligand is mainly favoured by the binding of a deprotonated Cys. The interaction of complex 1 with DNA takes always place through the release of the azaindolate ligand. Interestingly, the interaction of 1 with DNA only proceeds when the oligonucleotides are annealed forming a double strand. Complex 1 is also capable to displace ethidium bromide from DNA and it also weakly binds to DNA at the minor groove, as shown by Hoechst 33258 displacement experiments. Furthermore, complex 1 is also a good inhibitor of cathepsin B (an enzyme implicated in a number of cancer related events). Therefore, although compound 1 is definitely able to bind proteins that can hamper its arrival to the nuclear target, it should be taken into consideration as a putative anticancer drug due to its strong interaction with oligonucleotides and its effective inhibition of cat B.
authors.affiliation: Departament de Química, Facultat de Ciències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193, Barcelona, Spain.
authors.forename: Katia G
authors.initials: KG
authors.lastname: Samper
authors.forename: Venancio
authors.initials: V
authors.lastname: Rodríguez
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ortega-Carrasco
authors.forename: Sílvia
authors.initials: S
authors.lastname: Atrian
authors.forename: Jean Didier
authors.initials: JD
authors.lastname: Maréchal
authors.forename: Natalia
authors.initials: N
authors.lastname: Cutillas
authors.forename: Ana
authors.initials: A
authors.lastname: Zamora
authors.forename: Concepción
authors.initials: C
authors.lastname: de Haro
authors.forename: Mercè
authors.initials: M
authors.lastname: Capdevila
authors.forename: José
authors.initials: J
authors.lastname: Ruiz
authors.forename: Òscar
authors.initials: Ò
authors.lastname: Palacios
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D006690:Bisbenzimidazole / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects*; D004996:Ethidium / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011506:Proteins / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D008024:Ligands; D009944:Organoplatinum Compounds; D011506:Proteins; D004247:DNA; D002401:Cathepsin B; D004996:Ethidium; D006690:Bisbenzimidazole