Anticancer and DNA Binding Activities of Platinum (IV) Complexes; Importance of Leaving Group Departure Rate

Abstract

The two six-coordinate Pt(IV) complexes, containing bidentate nitrogen donor/methyl ligands with general formula [Pt(X)2Me2((t)bu2bpy)], where (t)bu2bpy = 4,4'-ditert-butyl-2,2'-bipyridine and X = Cl (C1) or Br (C2), serving as the leaving groups were synthesized for evaluation of their anticancer activities and DNA binding properties. To examine anticancer activities of the synthetic complexes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ethidium bromide/acridine orange (EB/AO) staining method were performed. The binding properties of these complexes to DNA and purine nucleotides were examined, using different spectroscopic techniques. These complexes demonstrated significant anticancer activities against three cancer cell lines Jurkat, K562, and MCF-7. On the basis of the results of EB/AO staining, C1 and C2 were also capable to induce apoptosis in cancer cells. These complexes comprise halide leaving groups, displaying different departure rates; accordingly, they demonstrated slightly dissimilar anticancer activity and significantly different DNA/purine nucleotide binding properties. The results of DNA interaction studies of these complexes suggest a mixed-binding mode, comprising partial intercalation and groove binding. Overall, the results presented herein indicate that the newly synthesized Pt(IV) complexes are promising class of the potential anticancer agents which can be considered as molecular templates in designing novel platinum anticancer drugs. This study also highlights the importance of leaving group in anticancer activity and DNA binding properties of Pt(IV) complexes.

Recent Advances in Platinum (IV) Complex‐Based Delivery Systems to Improve Platinum (II) Anticancer Therapy

“…77,78 In addition, the axial ligands was regarded as one of the most important parameters in determining the pharmacological properties of Pt (IV) complexes, such as reduction potential, lipophilicity, charge, stability, selectivity, and targeting, [78][79][80][81] whereas the cytotoxicity of Pt (IV) complexes depended on the equatorial ligands, sometimes on the leaving groups. 75,[82][83][84] For instance, tertraplatin with chloride as axial ligands showed high reduction potentials (Ep = -90 ± 20 mV vs. Ag/AgCl), leading to a rapid reduction in blood within seconds. By contrast iproplatin had r HAN ET AL.…”

Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents

“…In addition, the presence of two extra ligands in the axial positions relative to typical Pt(II) complexes offers the possibility of tuning various pharmacokinetic parameters, such as the hydrophilicity/lipophilicity ratio, reduction potential, and cancer microenvironment targeting. Although Pt(IV) complexes can interact with DNA in their oxidized forms, adduct formation is relatively slow (30,31). Thus, Pt(IV) complexes are generally considered to be prodrugs that must undergo reduction to produce the corresponding active Pt(II) form (32).…”

Cyclometallated platinum(IV) compounds as promising antitumour agents

“…A series of organometallic platinum(IV) compounds of general formulae I and II depicted in figure 5 display activity on leukaemia L1210 and on cisplatin resistant L1210/DDP cell lines although, according to the reduction potentials obtained by cyclic voltammetry, the polyfluorophenyl ligands greatly stabilise the platinum(IV) oxidationstate and these compounds are difficult to be reduced[85]. Other examples of organoplatinum(IV) complexes studied as anticancer agents are compounds of general formula [PtMe2X2( t Bubpy)] (X = Cl or Br) (structure III in figure 5) that were prepared by oxidative addition of X2 to the corresponding platinum(II) and display higher cytotoxic activity than cisplatin against Jurkat, K562 and MCF-7 cancer cell lines[86].…”