title: Activation of trans geometry in bifunctional mononuclear platinum complexes by a non-bulky methylamine ligand.
abstract: In order to shed light on the mechanism that underlies activity of bifunctional mononuclear Pt(II) analogs of transplatin we examined in the present work a DNA binding mode of the analog of transplatin, namely trans-[Pt(CH3NH2)2Cl2], in which NH3 groups were replaced only by a small, non-bulky methylamine ligand. This choice was made because we were interested to reveal the role of the bulkiness of the amines used to substitute NH3 in transplatin to produce antitumor-active Pt(II) drug. The results indicate that trans-[Pt(CH3NH2)2Cl2] forms a markedly higher amount of more distorting intrastrand cross-links than transplatin which forms in DNA preferentially less distorting and persisting monofunctional adducts. Also importantly, the accumulation of trans-[Pt(CH3NH2)2Cl2] in tumor cells was considerably greater than that of transplatin and cisplatin. In addition, the results of the present work demonstrate that the replacement of ammine groups by the non-bulky methylamine ligand in the molecule of ineffective transplatin results in a radical enhancement of its activity in tumor cell lines including cisplatin-resistant tumor cells. Thus, activation of the trans geometry in bifunctional mononuclear Pt(II) complexes can be also accomplished by replacement of ammine groups in transplatin by non-bulky methylamine ligands so that it is not limited only to the replacement by relatively bulky and stereochemically more demanding amino ligands.
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Frybortova
authors.forename: Olga
authors.initials: O
authors.lastname: Novakova
authors.forename: Jana
authors.initials: J
authors.lastname: Stepankova
authors.forename: Vojtech
authors.initials: V
authors.lastname: Novohradsky
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D018736:DNA Adducts / Q000737:chemistry*; D005260:Female; D006801:Humans; D008024:Ligands; D008744:Methylamines / Q000737:chemistry*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D008024:Ligands; D008744:Methylamines; D009944:Organoplatinum Compounds; C034697:transplatin; D010984:Platinum; C027451:methylamine; D002945:Cisplatin
keywords: Activation of trans geometry; Cytotoxicity; DNA adducts; Platinum(II)-based agents