title: A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin.
abstract: A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.
authors.affiliation: Department of Chemistry, University of Warwick, Warwick, CV4 7AL, Coventry (UK).
authors.forename: Evyenia
authors.initials: E
authors.lastname: Shaili
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).
authors.forename: Marta
authors.initials: M
authors.lastname: Fernández-Giménez
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).
authors.forename: Savina
authors.initials: S
authors.lastname: Rodríguez-Astor
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).
authors.forename: Albert
authors.initials: A
authors.lastname: Gandioso
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).
authors.forename: Lluís
authors.initials: L
authors.lastname: Sandín
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Vélez
authors.affiliation: Departament de Biologia, Universitat de Girona, Campus Montilivi, 17071, Girona (Spain).
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
authors.affiliation: Department of Chemistry, University of Warwick, Warwick, CV4 7AL, Coventry (UK).
authors.forename: Guy J
authors.initials: GJ
authors.lastname: Clarkson
authors.affiliation: Photobiology Unit, Department of Dermatology, Ninewells Hospital, Dundee, DD1 9SY (UK).
authors.forename: Julie A
authors.initials: JA
authors.lastname: Woods
authors.affiliation: Department of Chemistry, University of Warwick, Warwick, CV4 7AL, Coventry (UK). P.J.Sadler@warwick.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain). vmarchan@ub.edu.
authors.forename: Vicente
authors.initials: V
authors.lastname: Marchán
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D012313:RNA; D019791:Guanidine
keywords: DNA; antitumor agents; photochemistry; platinum; structure-activity relationships