Modulation of drug activation profiles through carboxylate ligand modification in cytotoxic trans-platinum planar amine compounds

Abstract

Transplatinum planaramine (TPA) compounds possessing carboxylate ligands in the trans position have been shown to be potential antitumor drugs in a variety of cell types, including cisplatin and oxaliplatin-resistant cell lines. In this work, we ask whether the nature and stability of the carboxylate ligand can be tuned in an attempt to manipulate the extent of serum protein binding; and consequently influence cytotoxicity, cellular drug accumulation and DNA adduct formation. Monitoring the interactions of selected TPAs with N-acetyl-methionine (NAM) by (1)H and (195)Pt NMR spectroscopy shows significant differences in the rate of sulfur binding. TPA-containing acetate ligands show a much lower sulfur binding rate than those possessing formate leaving groups. The same trend was seen when acetate and formate TPA compounds were incubated with human serum albumin and the reaction monitored for 24 h. To understand whether these results could be translated into a cellular medium, MTT cytotoxicity assays were conducted for each compound, before and after incubation with whole serum. Both the formate and acetate compounds, t-[Pt(4-pic)NH(3)(OFm)(2)] and t-[Pt(4-pic)NH(3)(OAc)(2)], showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum. The same trends were seen when monitoring the effects of protein binding on cellular uptake and DNA platination. The rate of protein binding/drug deactivation was shown to be directly related to the stability of the leaving group (OAc(-) > OFm(-) > Cl(-)). Thus, our results suggest that utilization of the 'carboxylate strategy' substantially enhances the cellular efficacy of TPA compounds over cisplatin by allowing for an optimal balance between cytotoxic and metabolic efficiency.

Platinum-based drugs and proteins: Reactivity and relevance to DNA adduct formation

“…Obviously, we expected to observe different protein platination according to the number of reactive amino acid residues and to their accessibility, which is dictated by the protein tridimensional architecture [33]. In addition the nature of the ligand and leaving groups largely affects the reactivity towards DNA as well as toward single aminoacids [19, 22]. For this reason we thought that the same is likely to occur on full length proteins…”

“…Among them t rans -platinum compounds containing at least one planar ammine (TPAs) are as cytotoxic as cisplatin but are not cross-resistant [18]. The effects of leaving groups and of the aromatic heterocyclic planar systems on efficiency, kinetics, and DNA platination mode have been investigated and may partly help to explain the unique cytotoxic profile of TPAs [19, 20]. In addition, different DNA-protein cross-linking efficiency can further contribute to driving distinct cellular responses between cisplatin and TPAs [21].…”

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

“…These compounds, having the general formula trans -[PtLL'Cl 2 ], are of interest because many of them display in vitro anticancer activity superior to that of cisplatin, despite their trans stereochemistry. 158–163 Additionally, they exhibit no cross-resistance with cisplatin. 158,159,161 Their preparation begins with the complex cis -[PtL 2 Cl 2 ], the synthesis of which has been described earlier.…”

In Vitro Anticancer Activity ofcis-Diammineplatinum(II) Complexes with β-Diketonate Leaving Group Ligands

“…23 Exchange of the original halide leaving groups of these trans platinum(II) compounds with carboxylates led to new complexes with improved aqueous solubility, hydrolytic stability, and cellular uptake. 24–28 …”