Corrigendum to: Editorial: Anticancer Platinum Complexes - State of the Art and Future Prospects.

An Editorial was published in the journal "Anti-Cancer Agents in Medicinal Chemistry", Volume 7, No. 01, 2007, pp: 1-2 [1]. The guest editor is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original editorial can be found online at: https://www.eurekaselect.com/article/3355.

Corrigendum to: Searching for the Magic Bullet: Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue.

An article was published in the journal "Anti-Cancer Agents in Medicinal Chemistry", Volume 7, No. 01, 2007, pp: 55-73 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: https://www.eurekaselect.com/article/3359.

Corrigendum to: Update of the Preclinical Situation of Anticancer Platinum Complexes: Novel Design Strategies and Innovative Analytical Approaches.

An article was published in the journal "Current Medicinal Chemistry," Volume 12, No. 18, 2005, pp: 2075-2094 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: http://www.benthamscience.com/article/5874.

Wells-Dawson phosphotungstates as mushroom tyrosinase inhibitors: a speciation study.

In order to elucidate the active polyoxotungstate (POT) species that inhibit fungal polyphenol oxidase (AbPPO4) in sodium citrate buffer at pH 6.8, four Wells-Dawson phosphotungstates [α/ß-PV2WVI18O62]6- (intact form), [α2-PV2WVI17O61]10- (monolacunary), [PV2WVI15O56]12- (trilacunary) and [H2PV2WVI12O48]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 183W-NMR, 31P-NMR spectroscopy and mass spectrometry. The intact Wells-Dawson POT [α/ß-PV2WVI18O62]6- shows partial (~ 69%) disintegration into the monolacunary [α2-PV2WVI17O61]10- anion with moderate activity (Ki = 9.7 mM). The monolacunary [α2-PV2WVI17O61]10- retains its structural integrity and exhibits the strongest inhibition of AbPPO4 (Ki = 6.5 mM). The trilacunary POT [PV2WVI15O56]12- rearranges to the more stable monolacunary [α2-PV2WVI17O61]10- (~ 62%) accompanied by release of free phosphates and shows the weakest inhibition (Ki = 13.6 mM). The hexalacunary anion [H2PV2WVI12O48]12- undergoes time-dependent hydrolysis resulting in a mixture of [H2PV2WVI12O48]12-, [PV8WVI48O184]40-, [PV2WVI19O69(H2O)]14- and [α2-PV2WVI17O61]10- which together leads to comparable inhibitory activity (Ki = 7.5 mM) after 48 h. For the solutions of [α/ß-PV2WVI18O62]6-, [α2-PV2WVI17O61]10- and [PV2WVI15O56]12- the inhibitory activity is correlated to the degree of their rearrangement to [α2-PV2WVI17O61]10-. The rearrangement of hexalacunary [H2PV2WVI12O48]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 [α2-PV2WVI17O61]10-. The good inhibitory effect of the Wells-Dawson [α2-PV2WVI17O61]10- anion is explained by the low charge density of its protonated forms Hx[α2-PV2WVI17O61](10-x)- (x = 3 or 4) at pH 6.8.

Aluminum-Substituted Keggin Germanotungstate [HAl(H2O)GeW11O39]4-: Synthesis, Characterization, and Antibacterial Activity.

We report on the new monosubstituted aluminum Keggin-type germanotungstate (C4H12N)4[HAlGeW11O39(H2O)]·11H2O ([Al(H2O)GeW11]4-), which has been synthesized at room temperature via rearrangement of the dilacunary [γ-GeW10O36]8- polyoxometalate precursor. [Al(H2O)GeW11]4- has been characterized thoroughly both in the solid state by single-crystal and powder X-ray diffraction, IR spectroscopy, thermogravimetric analysis, and elemental analysis as well as in solution by cyclic voltammetry (CV) 183W, 27Al NMR and UV-vis spectroscopy. A study on the antibacterial properties of [Al(H2O)GeW11]4- and the known aluminum(III)-centered Keggin polyoxotungstates (Al-POTs) α-Na5[AlW12O40] (α-[AlW12O40]5-) and Na6[Al(AlOH2)W11O39] ([Al(AlOH2)W11O39]6-) revealed enhanced activity for all three Al-POTs against the Gram-negative bacterium Moraxella catarrhalis (minimum inhibitory concentration (MIC) up to 4 µg mL-1) and the Gram-positive Enterococcus faecalis (MIC up to 128 µg mL-1) compared to the inactive Al(NO3)3 salt (MIC > 256 µg mL-1). CV indicates the redox activity of the Al-POTs as a dominating factor for the observed antibacterial activity with increased tendency to reduction, resulting in increased antibacterial activity of the POT.

Keggin-type polyoxotungstates as mushroom tyrosinase inhibitors - A speciation study.

Mushroom tyrosinase abPPO4 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 [Xn+W12O40](8-n)- in order to elucidate charge-dependent activity correlations. Kinetic data were obtained from the dopachrome assay and 183W 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 [PW12O40]3- was completely hydrolyzed to its moderately active lacunary form Hx[PW11O39](7-x)- (Ki = 25.6 mM), [SiW12O40]4- showed the most pronounced inhibition effects with a Ki of 4.7 mM despite of partial hydrolysis to its ineffective lacunary form Hx[SiW11O39](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 [PW11O39{Ni(H2O)}]5- enzymatic inhibition was clearly restored (Ki = 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.

Biological activity of PtIV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis.

We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV 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(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) and cis,cis,trans-[Pt(NH3)2(CBDCA)(O2CCH2CH2CO2H)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. 195Pt 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 H2AX 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 pH2AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.

A fluorescent oxaliplatin derivative for investigation of oxaliplatin resistance using imaging techniques.

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.

Vanadium(V) Complexes with Substituted 1,5-bis(2-hydroxybenzaldehyde)carbohydrazones and Their Use As Catalyst Precursors in Oxidation of Cyclohexane.

Six dinuclear vanadium(V) complexes have been synthesized: NH4[(VO2)2((H)LH)] (NH4[1]), NH4[(VO2)2((t-Bu)LH)] (NH4[2]), NH4[(VO2)2((Cl)LH)] (NH4[3]), [(VO2)(VO)((H)LH)(CH3O)] (4), [(VO2)(VO)((t-Bu)LH)(C2H5O)] (5), and [(VO2)(VO)((Cl)LH)(CH3O)(CH3OH/H2O)] (6) (where (H)LH4 = 1,5-bis(2-hydroxybenzaldehyde)carbohydrazone, (t-Bu)LH4 = 1,5-bis(3,5-di-tert-butyl-2-hydroxybenzaldehyde)carbohydrazone, and (Cl)LH4 = 1,5-bis(3,5-dichloro-2-hydroxybenzaldehyde)carbohydrazone). The structures of NH4[1] and 4-6 have been determined by X-ray diffraction (XRD) analysis. In all complexes, the triply deprotonated ligand accommodates two V ions, using two different binding sites ONN and ONO separated by a diazine unit -N-N-. In two pockets of NH4[1], two identical VO2(+) entities are present, whereas, in those of 4-6, two different VO2(+) and VO(3+) are bound. The highest oxidation state of V ions was corroborated by X-ray data, indicating the presence of alkoxido ligand bound to VO(3+) in 4-6, charge density measurements on 4, magnetic susceptibility, NMR spectroscopy, spectroelectrochemistry, and density functional theory (DFT) calculations. All four complexes characterized by XRD form dimeric associates in the solid state, which, however, do not remain intact in solution. Compounds NH4[1], NH4[2], and 4-6 were applied as alternative selective homogeneous catalysts for the industrially significant oxidation of cyclohexane to cyclohexanol and cyclohexanone. The peroxidative (with tert-butyl hydroperoxide, TBHP) oxidation of cyclohexane was performed under solvent-free and additive-free conditions and under low-power microwave (MW) irradiation. Cyclohexanol and cyclohexanone were the only products obtained (high selectivity), after 1.5 h of MW irradiation. Theoretical calculations suggest a key mechanistic role played by the carbohydrazone ligand, which can undergo reduction, instead of the metal itself, to form an active reduced form of the catalyst.

Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application.

Platinum(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.

A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs.

A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models.

Bulky N(,N)-(di)alkylethane-1,2-diamineplatinum(II) compounds as precursors for generating unsymmetrically substituted platinum(IV) complexes.

Investigations of the influence of bulky groups in the equatorial ligand sphere of platinum(IV) compounds on the complexes' stability and reaction pattern were performed. Four dihydroxidoplatinum(IV) complexes were reacted with anhydrides, cinnamoyl chloride, and n-propyl isocyanate and yielded the symmetric dicarboxylated products or, if steric hindrance was observed, unsymmetrically substituted monocarboxylated analogues. With the aim of raising the steric demand, the following ligands were chosen: N-cyclohexylethane-1,2-diamine, N,N-dimethylethane-1,2-diamine, N,N-diethylethane-1,2-diamine, and N,N-diisopropylethane-1,2-diamine. All of the novel complexes were characterized by electrospray ionization mass spectrometry (ESI-MS), one- and two-dimensional NMR spectroscopy, elemental analysis, and reversed-phase HPLC; complexes B3, C3, C6, and D4 were also analyzed by X-ray diffraction. Additionally, the cytotoxicities of 10 compounds toward the cisplatin-sensitive cell line CH1 and the intrinsically cisplatin-resistant cell lines A549 and SW480 were investigated, and IC50 values down to the nanomolar range were found. To aid in the interpretation of structure-activity relationships, log k(w) values as a measure for the lipophilicity were determined for all of the new complexes, and the rates of reduction of C1, C3, and C4 relative to satraplatin were determined by means of NMR spectroscopy and ESI-MS.

Influence of extracellular pH on the cytotoxicity, cellular accumulation, and DNA interaction of novel pH-sensitive 2-aminoalcoholatoplatinum(II) complexes.

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-κ(2)N,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.

Theoretical investigations and density functional theory based quantitative structure-activity relationships model for novel cytotoxic platinum(IV) complexes.

Octahedral platinum(IV) complexes are promising candidates in the fight against cancer. In order to rationalize the further development of this class of compounds, detailed studies on their mechanisms of action, toxicity, and resistance must be provided and structure-activity relationships must be drawn. Herein, we report on theoretical and QSAR investigations of a series of 53 novel bis-, tris-, and tetrakis(carboxylato)platinum(IV) complexes, synthesized and tested for cytotoxicity in our laboratories. The hybrid DFT functional wb97x was used for optimization of the structure geometry and calculation of the descriptors. Reliable and robust QSAR models with good explanatory and predictive properties were obtained for both the cisplatin sensitive cell line CH1 and the intrinsically cisplatin resistant cell line SW480, with a set of four descriptors.

Unsymmetric mono- and dinuclear platinum(IV) complexes featuring an ethylene glycol moiety: synthesis, characterization, and biological activity.

Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log k(w)) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC(50) values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances.

Novel oximato-bridged platinum(II) di- and trimer(s): synthetic, structural, and in vitro anticancer activity studies.

Novel platinum complexes of trans geometry [PtCl(2){(Z)-R(H)C═NOH}(2)] [R = Me (1), Et (3)] and [PtCl(2){(E)-R(H)C═NOH}{(Z)-R(H)C═NOH}] [R = Me (2), Et (4)] as well as the classic trans-[PtCl(2)(R(2)C═NOH)(2)] [R = Me, Et] were reacted with an equivalent amount of silver acetate in acetone solution at ambient temperature, resulting in formation of unprecedented head-to-tail-oriented oximato-bridged dimers [PtCl{µ-(Z)-R(H)C═NO}{(Z)-R(H)C═NOH}](2) [R = Me (5), Et (7)], [PtCl{µ-(Z)-R(H)C═NO}{(E)-R(H)C═NOH}](2) [R = Me (6), Et (8)], and [PtCl(µ-R(2)C═NO)(R(2)C═NOH)](2) [R = Me (9), Et (10)], correspondingly. The dimeric species feature a unique six-membered diplatinacycle and represent the first example of oxime ligands coordinated to platinum via the oxygen atom. All complexes were characterized by elemental analyses, electrospray ionization mass spectrometry, IR and multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, as well as X-ray diffraction in the cases of dimers 6 and 9. Furthermore, the crystal and molecular structures of a trimeric oximato-bridged complex 11 comprising three platinum units connected in a chain way were established. The cytotoxicity of both dimers and the respective monomers was comparatively evaluated in three human cancer cell lines: cisplatin-sensitive CH1 cells as well as cisplatin-resistant SW480 and A549 cells, whereupon structure-activity relationships were drawn. Thus, it was found that dimerization results in a substantial (up to 7-fold) improvement of IC(50) values of (aldoxime)Pt(II) compounds, whereas for the analogous complexes featuring ketoxime ligands the reverse trend was observed. Remarkably, the novel dimers yielded no cross-resistance with cisplatin in SW480 cells, exhibiting up to 2-fold enhanced cytotoxicity in comparison with the CH1 cell line and thereby possessing a promising potential to overcome resistance toward platinum anticancer drugs. The latter point was also confirmed by investigating the potency of apoptosis induction in the case of one monomer as well as one dimer; the investigated complexes proved to be strong apoptotic agents which could induce cell death even in the cisplatin-resistant SW480 cell line.

Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues.

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.

A SAR study of novel antiproliferative ruthenium and osmium complexes with quinoxalinone ligands in human cancer cell lines.

A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC(50) values of 6-60 µM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 µM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate.

Cellular accumulation and DNA interaction studies of cytotoxic trans-platinum anticancer compounds.

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; r (b) 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.

Synthesis, characterization, and cytotoxic activity of novel potentially pH-sensitive nonclassical platinum(II) complexes featuring 1,3-dihydroxyacetone oxime ligands.

The reaction of 1,3-dihydroxyacetone oxime with diam(m)minediaquaplatinum(II) under basic conditions produced zwitterionic diam(m)mine(3-hydroxy-2-(oxidoimino)propan-1-olato-κ(2)N,O)platinum(II) complexes featuring the N,O-chelating ligand. Upon reaction with hydrochloric acid, it was possible to isolate either the singly protonated species still exhibiting the intact N,O-chelate or the open-chain chlorido complex. All complexes were characterized in detail with multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, ESI mass spectrometry, and in one case X-ray diffraction. Cytotoxicity was investigated in three human cancer cell lines (CH1, SW480, and A549). The obtained IC(50) values are in the medium or even low micromolar range, remarkable for platinum complexes having N(3)O or N(3)Cl coordination spheres. To study the solution behavior of the prepared complexes at physiologically relevant proton concentrations, time-dependent (1)H NMR measurements were performed for the ethane-1,2-diamine-containing series at pH values of 7.4, 6.0, and exemplarily 5.0. While the zwitterionic complex proved to be stable at both pH 7.4 and 6.0, the protonated species were deprotonated at pH 7.4, tending toward ring opening in slightly acidic environments, as characteristic for many solid tumors. Finally, the open-chain form stayed intact at pH 6.0, being completely converted into its chelated analogue at pH 7.4. A pH-dependent evaluation of antiproliferative effects of the two latter complexes at pH 7.4 and pH 6.0 revealed an activation under slightly acidic conditions, which might be of interest for further in vivo studies.