title: Studies of the mechanism of action of platinum(II) complexes with potent cytotoxicity in human cancer cells.
abstract: We have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(I(L))(A(L))](2+), where I(L) is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and A(L) is an ancillary ligand (diaminocyclohexane, diphenylethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1-9) and the racemic compounds (10-12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10-12) was significantly lower compared to the complexes containing diaminocyclohexane (1-7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.
authors: School of Biomedical and Health Sciences, University of Western Sydney, Penrith South DC, NSW, Australia.
authors: Anwen M
authors: AM
authors: Krause-Heuer
authors: Renate
authors: R
authors: Grünert
authors: Sybill
authors: S
authors: Kühne
authors: Magdalena
authors: M
authors: Buczkowska
authors: Nial J
authors: NJ
authors: Wheate
authors: Delphine D
authors: DD
authors: Le Pevelen
authors: Leanne R
authors: LR
authors: Boag
authors: Dianne M
authors: DM
authors: Fisher
authors: Jana
authors: J
authors: Kasparkova
authors: Jaroslav
authors: J
authors: Malina
authors: Patrick J
authors: PJ
authors: Bednarski
authors: Viktor
authors: V
authors: Brabec
authors: Janice R
authors: JR
authors: Aldrich-Wright
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001692:Biological Transport; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004278:DNA, Superhelical / Q000737:chemistry / Q000235:genetics; D003850:Deoxyribonuclease I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D008024:Ligands; D009942:Organometallic Compounds; D010984:Platinum; D003850:Deoxyribonuclease I; D053148:Caspase 3; D002945:Cisplatin