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In order to elucidate the active polyoxotungstate (POT) species that inhibit fungal polyphenol oxidase ( Ab PPO4) in sodium citrate buffer at pH 6.8, four Wells–Dawson phosphotungstates [ α / β -P V 2 W VI 18 O 62 ] 6− (intact form), [ α 2 -P V 2 W VI 17 O 61 ] 10− (monolacunary), [P V 2 W VI 15 O 56 ] 12− (trilacunary) and [H 2 P V 2 W VI 12 O 48 ] 12− (hexalacunary) were investigated. The speciation of the POT solutions under the dopachrome assay (50 mM Na-citrate buffer, pH 6.8; L -3,4−dihydroxyphenylalanine as a substrate) conditions were determined by 183 W-NMR, 31 P-NMR spectroscopy and mass spectrometry. The intact Wells–Dawson POT [ α / β -P V 2 W VI 18 O 62 ] 6− shows partial (~ 69%) disintegration into the monolacunary [ α 2 -P V 2 W VI 17 O 61 ] 10− anion with moderate activity ( K i  = 9.7 mM). The monolacunary [ α 2 -P V 2 W VI 17 O 61 ] 10− retains its structural integrity and exhibits the strongest inhibition of Ab PPO4 ( K i = 6.5 mM). The trilacunary POT [P V 2 W VI 15 O 56 ] 12− rearranges to the more stable monolacunary [ α 2 -P V 2 W VI 17 O 61 ] 10− (~ 62%) accompanied by release of free phosphates and shows the weakest inhibition ( K i = 13.6 mM). The hexalacunary anion [H 2 P V 2 W VI 12 O 48 ] 12− undergoes time-dependent hydrolysis resulting in a mixture of [H 2 P V 2 W VI 12 O 48 ] 12− , [P V 8 W VI 48 O 184 ] 40− , [P V 2 W VI 19 O 69 (H 2 O)] 14− and [ α 2 -P V 2 W VI 17 O 61 ] 10− which together leads to comparable inhibitory activity ( K i = 7.5 mM) after 48 h. For the solutions of [ α / β -P V 2 W VI 18 O 62 ] 6− , [ α 2 -P V 2 W VI 17 O 61 ] 10− and [P V 2 W VI 15 O 56 ] 12− the inhibitory activity is correlated to the degree of their rearrangement to [ α 2 -P V 2 W VI 17 O 61 ] 10− . The rearrangement of hexalacunary [H 2 P V 2 W VI 12 O 48 ] 12− into at least four POTs with a negligible amount of monolacunary anion interferes with the correlation of activity to the degree of their rearrangement to [ α 2 -P V 2 W VI 17 O 61 ] 10− . The good inhibitory effect of the Wells–Dawson [ α 2 -P V 2 W VI 17 O 61 ] 10− anion is explained by the low charge density of its protonated forms H x [ α 2 -P V 2 W VI 17 O 61 ] (10− x )− ( x  = 3 or 4) at pH 6.8.

AbstractPlatinum(IV) complexes are promising candidates as prodrugs for oral application in anticancer chemotherapy. However, only a few Pt(IV) compounds entered (pre)clinical trials, e.g. satraplatin, while most of the others were only tested in vitro. Aim of the study was investigation of the in vivo pharmacological behavior as well as the anticancer activity of two novel platinum(IV) complexes vs. satraplatin. The drugs were selected due to significantly different in vitro cytotoxicity while sharing some physicochemical properties (e.g. lipophilicity). Initial experiments indicated that the highly in vitro cytotoxic compound 1 ((OC-6-33)-dichloridobis((4-ethoxy)-4-oxobutanoato)-bis(ethylamine)platinum(IV)) was also characterized by high drug absorption and tissue platinum levels after oral application. Interestingly, analysis of serum samples using SEC-ICP-MS revealed that the administered drugs have completely been metabolized and/or bound to proteins in serum within 2 h after treatment. With regard to the activity in vivo, the outcomes were rather unexpected: although potent anticancer effect of 1 was observed in cell culture, the effects in vivo were rather minor. Nevertheless, 1 was superior to 2 ((OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)-bis((4-cyclopentylamino)-4-oxobutanoato)platinum(IV)) after i.p. administration, which was, at least to some extent, in accordance to the cell culture experiments. After oral gavage, both compounds exhibited comparable activity. This is remarkable considering the distinctly lower activity of 2 in cell culture as well as the low platinum levels detected both in serum and tissues after oral application. Consequently, our data indicate that the prediction of in vivo anticancer activity by cell culture experiments is not trivial, especially for orally applied drugs.Graphical Abstract

Research in the field of bioinorganic chemistry has been stimulated by the worldwide success of the anticancer drug cisplatin. 40 years after the first report about its biological activity, carboplatin and oxaliplatin are in routine clinical use today, whereas nedaplatin, lobaplatin, and heptaplatin (SKI2053R) are only approved in Japan, China, and South Korea, respectively. Up to now, about 35 platinum complexes entered clinical trials in order to circumvent the side-effects and the problem of tumor resistance to cisplatin. Additionally, improvement of tumor selectivity as well as the need for a broader spectrum of indications are the motivations for tremendous efforts in the development of novel anticancer platinum-based drugs. New synthetic strategies and innovative analytical approaches provide a basis for a deeper understanding of the pharmacological profile of cisplatin and analogues (biodistribution, clearance, detoxification, sideeffects, tumor specificity, cellular uptake, acquired or intrinsic resistance, platinum-DNA adduct removal by the cellular machinery) and give rise to a rational design of promising anticancer platinum coordination compounds. This article reviews the recent development of preclinical platinum complexes with interesting in vitro and in vivo tumor inhibiting properties. It focuses also on innovative synthetic strategies leading to novel classes of platinum complexes. A small part of the review is dedicated to new analytical approaches which have been supplied to or emerged in this field of research.

Oxaliplatin is the backbone of chemotherapy for advanced colorectal cancer and undergoes clinical trials for treatment of other tumour entities. However, acquired resistance is a major hurdle. Confocal microscopy is a useful tool to get an insight into the mechanisms of resistance but it requires fluorescent compounds. This work describes the synthesis of the novel oxaliplatin derivative (CFDA-oxPt) featuring 5(6)-carboxyfluorescein diacetate and evaluation of its applicability for the investigation of oxaliplatin resistance using imaging techniques. CFDA-oxPt was somewhat less cytotoxic than oxaliplatin in sensitive colorectal cancer cells, with EC50 values of 26 and 5.8 µM, respectively. Nevertheless, the potency of the novel complex was significantly decreased to the EC50 of 711.2 µM in oxaliplatin-resistant cells, as was the case for oxaliplatin (EC50 = 81 µM). After incubation, both nuclear and cytosolic localisation was observed. Over time CFDA-oxPt concentrated near the cell membrane and in the vesicular structures, in contrast to the platinum-free label, which was rapidly excreted. These findings suggest that CFDA-oxPt can be used to study oxaliplatin resistance and open the route to new fluorophore-tethered oxaliplatin derivatives.

Forty years after the discovery of the anticancer effects of cisplatin, scientists are still pursuing the development of platinum complexes with improved properties regarding side effects and resistance, which are two main problems in cisplatin treatment. Among these compounds, trans-configured platinum complexes with oxime ligands emerged as a new class with features distinct from those of established anticancer agents, including different DNA binding behavior, increased cellular accumulation, and a different pattern of protein interaction. We report herein on the reactivity with biomolecules of three novel pairs of cis- and trans-configured acetone oxime platinum(II) complexes and one pair of 3-pentanone oxime platinum(II) complexes. Cellular accumulation experiments and in vitro DNA platination studies were performed and platinum contents were determined by inductively coupled plasma mass spectrometry. The trans-configured complexes were accumulated in SW480 cells in up to 100 times higher amounts than cisplatin and up to 50 times higher amounts than their cis-configured counterparts; rb values (number of platinum atoms per nucleotide) were more than tenfold increased in cells treated with trans complexes compared with cells treated with cisplatin. The interaction of the complexes with DNA was studied in cell-free experiments with plasmid DNA (pUC19), in capillary zone electrophoresis with the DNA model 2-deoxyguanosine 5′-monophosphate, and in in vitro experiments showing the degree of DNA damage in the comet assay. Whereas incubation with cis compounds did not induce degradation of DNA, the trans complexes led to pronounced strand cleavage.

Extracellular acidity is a frequent pathophysiological condition of solid tumors offering possibilities for improving the tumor selectivity of molecular therapy. This might be accomplished by prodrugs with low systemic toxicity, attaining their full antitumor potency only under acidic conditions, such as bis(2-aminoalcoholato-κ²N,O)platinum(II) complexes that are activated by protonation of alcoholato oxygen, resulting in cleavage of platinum–oxygen bonds. In this work, we examined whether the pH dependency of such compounds is reflected in differential biological activity in vitro. In particular, the pH dependence of cytotoxicity, cellular accumulation, DNA platination, GMP binding, effects on DNA secondary structure, cell cycle alterations, and induction of apoptosis was investigated. Enhanced cytotoxicity of five of these complexes in non-small-cell lung cancer (A549) and colon carcinoma (HT-29) cells at pH 6.0 in comparison with pH 7.4 was confirmed: 50 % growth inhibition concentrations ranged from 42 to 214 μM in A549 cells and from 35 to 87 μM in HT-29 cells at pH 7.4 and decreased at pH 6.0 to 11–50 and 7.3–25 μM, respectively. The effects induced by all five pH-sensitive compounds involve increased 5′-GMP binding, cellular accumulation, and DNA platination as well as stronger effects on DNA secondary structure at pH 6.0 than at pH 7.4. As exemplified by treatment of A549 cells with a 2-amino-4-methyl-1-pentanolato complex, induction of apoptosis is enhanced at pH 6.5. These results confirm the increased reactivity and in vitro activity of these compounds under slightly acidic conditions, encouraging further evaluation of ring-closed aminoalcoholatoplatinum(II) derivatives in solid tumors in vivo.

Ascorbic acid has been previously discussed to have antitumor potential through its interaction with transition metal ions such as iron and copper. Furthermore, ascorbic acid may act as a reducing agent for Ru(III) compounds such as indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019), an investigational anticancer drug which is supposed to be activated by reduction, prior to binding to cellular target proteins. Therefore, we investigated the influence of ascorbic acid on the activity of this antitumor metal complex in cell culture studies. We show that co-incubation of equicytotoxic, constant amounts of KP1019 with high concentrations of ascorbic acid (50–700 μM) increases cytotoxicity of the ruthenium anticancer drug in the human colon carcinoma cell line SW480, human cervical carcinoma KB-3-1 cells, and the multidrug-resistant subline KBC-1, whereas addition of low concentrations (2.7–50 μM) has a strong chemoprotective effect in the human colon carcinoma cell line SW480, but not in multidrug-resistant KBC-1 cells. Although cellular uptake of KP1019 is not altered, ascorbic acid induce stronger interaction of the ruthenium compound with DNA both in SW480 cells and under cell-free conditions with plasmid DNA. Even if DNA interactions probably play a subordinate role in vivo given the extensive protein binding of the compound, our data exemplify that ascorbic acid enhances the reactivity of KP1019 with biomolecules. Moreover, we demonstrate that the levels of KP1019-generated reactive oxygen species are markedly decreased by co-incubation with ascorbic acid. Conclusively, our results indicate that application of high doses of ascorbic acid might increase the anticancer effects of KP1019.

The purpose of this study was to systematically investigate the relationships between reactivity, cellular accumulation, and cytotoxicity of a panel of oxaliplatin analogues with different leaving groups in human carcinoma cells. The reactivity of the complexes towards the nucleotides 2′-deoxyguanosine 5′-monophosphate and 2′-deoxyadenosine 5′-monophosphate was studied using capillary electrophoresis. Cellular accumulation and cytotoxicity were measured in an oxaliplatin-sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cell line pair (HCT-8/HCT-8ox). Platinum concentrations were determined by flameless atomic absorption spectrometry. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess cytotoxicity. Early cellular platinum accumulation was predominantly affected by lipophilicity. A relationship between reactivity and cellular accumulation was observed for three of four platinum complexes investigated, whereas the most lipophilic oxaliplatin analogue was an exception. Increased reactivity and reduced lipophilicity were associated with high cytotoxic activity. Resistance was influenced by lipophilicity but not by reactivity. The observed relationships may help in the design of analogues with high antitumoral activity in oxaliplatin-sensitive as well as oxaliplatin-resistant cells.

We have recently demonstrated that riboflavin ( Rf ) functions as unconventional bioorthogonal photocatalyst for the activation of Pt IV prodrugs. In this study, we show how the combination of light and Rf with two Pt IV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf -mediated activation of the cisplatin and carboplatin prodrugs cis , cis , trans -[Pt(NH 3 ) 2 (Cl) 2 (O 2 CCH 2 CH 2 CO 2 H) 2 ] ( 1 ) and cis , cis , trans -[Pt(NH 3 ) 2 (CBDCA)(O 2 CCH 2 CH 2 CO 2 H) 2 ] ( 2 , where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. 195 Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf - 1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf -mediated photochemical activation. Phosphorylation of H 2 AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH 2 AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.

Mushroom tyrosinase ab PPO4 is a commercially relevant polyphenol oxidase and has been being targeted for numerous inhibition studies including polyoxometalates (POMs). In the present work, its diphenolase activity was inhibited at pH 6.8 by a series of structurally related polyoxotungstates (POTs) of the α-Keggin archetype, exhibiting the general formula [X n+ W 12 O 40 ] (8−n)− in order to elucidate charge-dependent activity correlations. Kinetic data were obtained from the dopachrome assay and 183 W NMR was applied to obtain crucial insights into the actual Keggin POT speciation in solution, facilitating a straightforward assignment of inhibition effects to the identified POT species. While [PW 12 O 40 ] 3− was completely hydrolyzed to its moderately active lacunary form H x [PW 11 O 39 ] (7−x)− ( K i  = 25.6 mM), [SiW 12 O 40 ] 4− showed the most pronounced inhibition effects with a K i of 4.7 mM despite of partial hydrolysis to its ineffective lacunary form H x [SiW 11 O 39 ] (8−x)− . More negative Keggin cluster charges of 5− and 6− generally resulted in preclusion of inhibitory efficacy as well as hydrolysis, but with the Ni-substituted cluster [PW 11 O 39 {Ni(H 2 O)}] 5− enzymatic inhibition was clearly restored ( K i  = 9.7 mM). The inhibitory capacity of the structurally intact Keggin POTs was found to be inversely correlated to their net charge. The here applied speciation strategy is of utmost importance for any biological POM application to identify the actually active POM species.