Cleavage of the Pt–S bond of thiolated terpyridine–platinum(ii) complexes by copper(ii) and zinc(ii) ions in phosphate buffer

Many efforts in the development of platinum complexes as anticancer drugs have been contemplated in order to reduce the cytotoxicity and to improve the platin drug-resistance.1 Since sulfur-containing compounds such as glutathione and metallothioneins are rich in cells, the formation of the S–Pt bond is generally believed to be one of the major mechanisms in the resistance to cis-platin drugs in biological processes.2 In contrast, recent NMR studies by Sadler and coworkers reveal that S-bound l-methionine on PtII acts as a reversible binding ligand and is capable of undergoing intermolecular replacement by 5A-GMP in phosphate buffer (pH 7.2).3 In fact, the concentration of glutathione (GSH) in intracellular cells is commonly high ( > 1 mm). Therefore, in the reaction with platin drugs, the formation of thiolate–platinum adducts is inevitable.4 The thiolate ion is capable of providing a stronger binding affinity owing to its better s-donating ability.5 Such a Pt–S bond is considered relatively inert, which may cause the inhibition of the anticancer activity of platin drugs. Thus, the great challenge is to break the Pt–S bond in the thiolate–platinum adducts. To approach this goal, thiolated derivatives of terpy– platinum(ii) complexes are used as a source to study the Pt–S bond owing to their characteristic electronic absorption and NMR spectra.6–8 Here, we report that transition metals such as CuII or ZnII are capable of inducing cleavage of the Pt–S bond of thiolated terpyridine platinum(ii) complexes, [Pt(terpy)(AET)]+ (AET = 2-aminoethanethiol) and [Pt(terpy)(BAT)]4+ [BAT = N,NA-bis(aminoethyl)aminoethanethiol], particularly in phosphate buffer as shown in Fig. 1. The introduction of a triamine moiety to the complex structure increases the dissociation rate and the selectivity of the Pt–S bond cleavage in thiolate–platinum complexes. To our knowledge, this is the first reported example of Pt–S bond cleavage among thiolate– platinum(ii) complexes in phosphate buffer. [Pt(terpy)(AET)]+ was prepared by published methods.11 The synthesis of a triamine derivative, [Pt(terpy)(BAT)]4+, was achieved by the coupling reaction of [Pt(terpy)Cl]+ with the modified multistep synthesis12–15 of triaminothiol, 1, in water as illustrated in Scheme 1. The NMR spectrum of [Pt(terpy)(BAT)]4+ in D2O showed a new downfield peak at d 8.82 and the UV–VIS spectrum displayed the absorbances at 486 nm (e = 698 dm3 mol21 cm21), 342 (12 959), 329 (12 397) and 311 (11 903) in phosphate buffer (pH 8.0), which agreed with the characteristic features for establishing the formation of thiolate– platinum bonds in the previous report.11 In addition, the integration ratio of protons of terpyridine and the triamine moiety in NMR spectra (D2O) was approximately 0.93, suggesting no S-bridged diplatinum complex was generated.14 In the presence of CuCl2·6H2O (42 mm), the solution of [Pt(terpy)(BAT)]4+ (40 mm) exhibited a decreasing UV–VIS absorption at 342 nm accompanied by an increasing absorption at 329 nm in phosphate buffer (10 mm, pH 8.0). An isosbestic point was observed at 337 nm in the spectrum, suggesting no intermediate had been generated in the reaction with metal ions. Also, no significant alteration was observed in the absence of CuII. The cleavage of the Pt–S bond of [Pt(terpy)(BAT)]4+ (40 mm) in the titration with CuII (10–84 mm) was found to require 1 equiv. of CuII to complete the reaction in 120 min. This dissociation of the Pt–S bond of [Pt(terpy)(BAT)]4+ was revealed to be a pH dependent process in the range pH 4.8–10.0. The reactivity of the Pt–S bond cleavage was reduced with a decreasing pH and ceased at pH < 6, implying that the participation of the amino group plays a vital role in the cleavage. In fact, when a hydroxylthiol derivative of [Pt(terpy)(SCH2CH2OH)], was used instead of an amino derivative, under the same conditions, no cleavage of the Pt–S bond was observed. The isolation of the cleavage product was performed in MeOH in order to simplify the product analysis. After the addition of CuCl2·6H2O, a red solution of [Pt(terpy)(BAT)]4+ turned into a blue-green suspension containing orange solid. This orange solid was isolated in a yield of 75–80% with electronic absorptions at 382, 332 and 320 nm in phosphate buffer (pH 8) and NMR peaks in D2O at d 7.8 (m), 7.5 (m) and 7.2 (t), suggesting it lacked the Pt–S bond linkage. Furthermore, FAB mass and isotope abundance simulation studies disclosed that the molecular ion at 464 contained a chloride ion, suggesting that [Pt(terpy)Cl]+ was one of the cleavage products.