Studies of the Mechanism of Action of Platinum(II) Complexes with Potent Cytotoxicity in Human Cancer Cells

Publikace: JOURNAL OF MEDICINAL CHEMISTRY 52, 5474-5484 Autoři: Krause-Heuer, AM., Grunert, R., Kuhne, S., Buczkowska, M., Wheate, NJ., Le Pevelen, DD., Boag, LR., Fisher, DM., Kasparkova, J., Malina, J., Bednarski, PJ., Brabec, V., Aldrich-Wright, JR. Rok: 2009

Abstrakt

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 all intercalating ligand (1,10-phenanthroline or a methylated derivative) and AL is an ancillary ligand (diaminocyclohexane, diplienylethylenediamine 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-fluoroplienyl)-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.