Elucidating the reactivity of Pt(II) complexes with (O,S) bidentate ligands towards DNA model systems

• Published in: Journal of inorganic biochemistry 2016-07, Vol.160, p.198-209
• Main Authors: Mügge, Carolin, Musumeci, Domenica, Michelucci, Elena, Porru, Francesca, Marzo, Tiziano, Massai, Lara, Messori, Luigi, Weigand, Wolfgang, Montesarchio, Daniela
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Binding Sites; CD spectroscopy; Coordination Complexes - chemical synthesis; DNA interaction; ESI-MS spectrometry; G-Quadruplexes; Guanine - analogs & derivatives; Guanine - chemistry; Guanine binding; Ligands; Models, Chemical; Oligodeoxyribonucleotides - chemistry; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Platinum - chemistry; Pt(II)-based anticancer agents; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.02.013

In the search for novel platinum-based anticancer therapeutic agents, we have recently established a structural motif of (O,S) bidentate ligands bound to a Pt(II) metal center which is effective against various cancer cell lines. Aiming at further enhancing the cytotoxicity of metal-based drugs, the identification of potential biological targets and elucidation of the mode of action of selected lead compounds is of utmost importance. Here we report our studies on the DNA interaction of three representative Pt(II) complexes of the investigated series, using various model systems and analytical techniques. In detail, CD spectroscopy as well as ESI-MS and MS2 techniques were applied to gain an overall picture of the binding properties of this class of (O,S) bidentate Pt(II) compounds with defined oligonucleotide sequences in single strand, duplex or G-quadruplex form, as well as with the nucleobase 9-methylguanine. On the whole, it was demonstrated that the tested compounds interact with DNA and produce conformational changes of different extents depending on the sequence and structure of the examined oligonucleotide. Guanine was established as the preferential target within the DNA sequence, but in the absence or unavailability of guanines, alternative binding sites can be addressed. The implications of these results are thoroughly discussed. Three representative Pt(II) complexes with (O,S) bidentate ligands, active against various cancer cell lines, were investigated as DNA-binders using several model systems by means of CD, ESI-MS and MS/MS techniques. [Display omitted] •Bioactive Pt(II) complexes with (O,S) bidentate ligands have been investigated.•Their binding properties to model DNA systems were analysed using CD, ESI-MS and MS2.•Various DNA models were applied, including different oligonucleotide sequences.•Higher binding ability to single strand than to duplex or G-quadruplex was found.•Guanines were identified as the preferential binding sites on the DNA sequences.