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.

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

“…A generally positive correlation between K app and n was observed, which intuitively indicates that the complexes with higher DNA binding affinity were able to displace a higher number of EtBr molecules. The complexes incorporating dpq (1, 2, 5, 6) demonstrated much higher binding affinities than those incorporating phen (9,10,13,14). This is thought to be due to the larger aromatic surface of the dpq I L , as it contains a higher density of π-electrons that can stack with the basepairs in the binding site.…”

“…13 Despite the high activity of these complexes, there is much that is unknown regarding their mechanism of action. 13 A prominent example is that no clear correlation has been found between the DNA binding affinity and the cytotoxicity of these complexes.…”

“…13 Despite the high activity of these complexes, there is much that is unknown regarding their mechanism of action. 13 A prominent example is that no clear correlation has been found between the DNA binding affinity and the cytotoxicity of these complexes. 11,14,15 In this study, we have attempted to find such a correlation through both the synthesis of several platinum(II) anticancer complexes and the study of their DNA binding via fluorescent intercalator displacement assays (FIDs).…”

Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)]

“…[19] The results were expressed in terms of ng platinum/1 million cells. Solutions of double-helical calf thymus DNA were incubated with 4, 5 or cisplatin at the r i value 0.1 in 10mM NaClO 4 at 37 ºC (r i is defined as the molar ratio of free platinum complex to nucleotides at the onset of incubation with DNA).…”

DNA-based aptamer fails as a simultaneous cancer targeting agent and drug delivery vehicle for a phenanthroline-based platinum(II) complex

“…The highly aromatic phenanthroline-based complex is able to intercalate into double stranded DNA, although its mechanism of action is not thought to be related to its DNA binding [21].…”