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The biological activity of four cisplatin-like Pt-phosphane complexes, namely, cis-[PtCl2(L)2], L = PPh3, P(Ph)2( p-C6H4-COOH), P(Ph)2(-CH2CH2-COOH) and its succinimidyl ester derivative, has been tested on monolayer cultures of three tumour cell lines (namely, A2780 human ovarian carcinoma and its cisplatin-resistant form A2780Cp8, and human colon adenocarcinoma HCT116). These complexes can undergo intramolecular rearrangements by virtue of their functionalized phosphanes, thereby existing as fully opened (O) or fully closed (C) forms. Our results show that only the opened forms exhibit moderate activity, which, although inferior to the activity exhibited by the archetype metallo-drug cisplatin, is substantially retained in the A2780Cp8 cell line, yielding very low resistance factors. The trend is also maintained on the less cisplatin-sensitive HCT116 line. When the complexes assume the bis-chelated (C) form, the antiproliferative activity is deeply reduced. Two Pt-amine congeners, containing β-alanine and 3-methoxypropylamine, with C and O structures, respectively, were synthesized and their antiproliferative propensity was evaluated for comparison purposes, and a similar scenario was observed. [ABSTRACT FROM AUTHOR]

As reported in our previous papers, a series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and studied as anti-tuberculosis agents. Here, the capability of the shake-flask method was studied and the retention time (expressed as log K) of 20 compounds were determined by RP-HPLC analysis. We found that the prediction of log P by the RP-HPLC analysis can result in a high accuracy and can replace the shake-flask method avoiding the experimental problems presented by quinoxaline di-N-oxides. The studied compounds were subjected to the ALOGPS module with the aim of comparing experimental log Po/w values and predicted data. Moreover, a preliminary in silico screening of the QSAR relationship was made confirming the influence of reduction peak potential, lipophilicity, H-bond donor capacity and molecular dimension descriptors on anti-tuberculosis activity. [ABSTRACT FROM AUTHOR]

Enantiomeric complexes of formula [PtCl2L2] [L2 is ( R)-(+)-BINAP and ( S)-(−)-BINAP, where BINAP is 2,2′-bis(diphenylphosphane)-1,1′-binaphthyl, and ( R)-(+)-DABN and ( S)-(−)-DABN, where DABN is 1,1′-binaphthyl-2,2′-diamine], were tested for their cytotoxic activity against three cancer cell lines and for their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar experiments were carried out on prototypal complexes cisplatin and cis-[PtCl2(PPh3)2] for comparison. Platinum complexes containing phosphanes proved less cytotoxic to cancer cell lines and less likely to interact with the nucleobases of the G-quadruplex than those containing amines; in both cases the S-(−) isomer was more active than the R-(+) counterpart. More specifically, whereas all the platinum complexes were able to platinate the G-quadruplex structure from the human telomeric repeat, the extent and sites of platination depended on the nature of the ligands. Complexes containing (bulky) phosphanes interacted only with the adenines of the loops, whereas those containing the less sterically demanding amines interacted with adenines and some guanines of the G-quartet. [ABSTRACT FROM AUTHOR]

Abstract: Sulfonated aromatic pollutants such as 1,5-naphthalenedisulfonic acid (NDS or Armstrong’s acid) are persistent compounds and thus resist environmental breakdown and microbial treatment. This study investigated the photo-oxidative degradation of such a persistent polar pollutant in the absence and presence of H2O2. The degradation of aqueous NDS solutions by photolysis was found to be efficient only in the presence of H2O2. The combination of UV irradiation and H2O2 leads to progressive degradation of NDS, which is converted into new, more biodegradable and non-toxic species. [Copyright &y& Elsevier]

Sulfonated aromatic pollutants such as Armstrong’s acid, or 1,5-naphthalenedisulfonic acid (NDS), are recalcitrant to environmental breakdown and microbial treatment. This study investigated the effects of H2O2 concentration, pH, microwave (MW) power and irradiation time on the oxidative degradation of NDS in aqueous solutions. The formation of hydroxyl radicals as the active oxidant was confirmed by electron paramagnetic resonance spin trapping. A combination of both H2O2 and MW heating proved essential for NDS degradation. Degradation factors of f ⩾70% were obtained after about 20min of irradiation at [H2O2]:[NDS] ratios=10. Acidic conditions were found to be more favorable to the degradation of NDS, and the process follows pseudo-first-order kinetics. Attempts to scale-up the process using a conventional MW reactor provided less striking results. [Copyright &y& Elsevier]

Abstract: A study of the electrochemical behavior of a series of antimetastatic mono- and di-ruthenium complexes, namely [Na][trans-RuIIICl4(DMSO)(L)] and [Na]2[{trans-RuIIICl4(DMSO)}2(μ-L)], L=pyrazine (pyz), pyrimidine (pym), 4,4′-bipyridine (bipy), and 1,2-bis-(4-pyridyl)ethylene (etbipy), is reported. The results obtained show that in all dimeric Ru(III) complexes linked by heterocyclic non-chelating N-donor bridges, the two redox centers behave independently (with no remarkable electrochemical interaction), thus conferring no advantage in the likely hypothesis they act as pro-drugs (activation by reduction). Moreover, electrochemical evaluation of interaction between albumin and the title complexes confirms that this protein can act as the vehicle for drugs of this type in blood. [Copyright &y& Elsevier]

This article focuses on a study conducted to examine the use of high performance liquid chromatography-mass spectrometry to investigate the oxidative destruction pathway of aromatic sulfonate wastes. The so-called lagoons are open-air basins in which industrial wastes have been disposed a long time. Typically, lagoons contain aromatic sulfonates coming from sulfonation processes in the manufacture of dyes, surfactants, detergents, and pharmaceutics. The muddy wastes are characterized by high values of chemical oxygen demand and contain high concentrations of salts, typically sodium sulfate. Therefore, aromatic sulfonates must be destroyed to prevent environmental contamination. No data are available about a direct toxicity for human health and environment coming from aromatic sulfonates. A remediation strategy for waste destruction is based on electrochemical oxidation techniques that can be based on direct electrochemical oxidation or on mediated electrochemical oxidation. The oxidants are electrochemically regenerated to minimize the possible formation of secondary wastes.

Abstract: The electrochemical study on Pt(II) organometallic and organic ethynylated compounds bearing nitro substituents in the phenyl groups has been performed, demonstrating that the presence of severe chemical irreversibility accompanying the electron transfer, preclude an evaluation of the electronic communication between redox active centres. The X-ray structure of the complex trans-[Pt(CC6H4NO2)2(PPh3)2] is showed. [Copyright &y& Elsevier]

An electrochemical and biological study of interaction between the prototypical antimetastatic drug imidazolium trans-tetrachlorodimethylsulfoxideimidazoleruthenate (III) complex, [ImH][RuCl4(DMSO)(Im)] (DMSO = dimethylsulfoxide, Im = imidazole), nicknamed NAMI-A, and several biomolecules, namely DNA, bovine (BSA) and human (HSA) serum albumin, is reported. Electrochemistry offers great advantages over the existing devices based on optical techniques, since it provides rapid, simple, and low-cost information whether the interaction occurs or not. Moreover, we describe some biochemical assays to test the interaction of NAMI-A with ribonucleoprotein telomerase and protein Taq polymerase. All the data confirm the preferential interaction of NAMI-A with proteins with respect to nucleotides, especially when compared with the behaviour of the well-known alkylating drug cisplatin in the presence of the same targets. [Copyright &y& Elsevier]

Cisplatin is widely employed as a first-line chemotherapeutic agent for many solid tumors, including malignant pleural mesothelioma (MPM). However, its clinical use is limited by heavy side effects and acquired resistance, the latter being mainly related to enhanced DNA repair. Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPis) have been carried out, with the hope that such combinations might lead to improved therapeutic efficacy against tumors. Here, the synthesis and efficacy in reducing MPM cell viability of four cisplatin-based Pt(IV) prodrugs containing the PARPi 3-aminobenzamide (3-ABA) fragment are described. The most promising conjugate is more effective than cisplatin or cisplatin/3-ABA combination, administered in equimolar doses, in inhibiting PARP-1 activity and inducing apoptosis in BRCA1/2 wild type MPM cells, grown as monolayer or as multicellular spheroids. [ABSTRACT FROM AUTHOR]

Fungal infections pose a serious threat to human health. Polyoxometalates (POMs) are metal–oxygen clusters with potential application in the control of microbial infections. Herein, the Ag3PW12O40 composites have been synthesized and verified by Fourier transform infrared (FT-IR) spectrum, transmission electron microscopy (TEM), scanning electron microscope (SEM), elemental analysis, and X-ray diffraction (XRD). The antifungal activities of Ag3PW12O40 were screened in 19 Candida species strains through the determination of minimum inhibitory concentration (MIC) by the microdilution checkerboard technique. The minimum inhibitory concentration (MIC50) values of Ag3PW12O40 are 2~32 μg/mL to the Candida species. The MIC80 value of Ag3PW12O40 to resistant clinical isolates C. albicans HL963 is 8 μg/mL, which is lower than the positive control, fluconazole (FLC). The mechanism against C. albicans HL963 results show that Ag3PW12O40 can decrease the ergosterol content. The expressions of ERG1, ERG7, and ERG11, which impact on the synthesis of ergosterol, are all prominently upregulated by Ag3PW12O40. It indicates that Ag3PW12O40 is a candidate in the development of new antifungal agents. [ABSTRACT FROM AUTHOR]

Every year, more Cu(II) complexes are proven to be biologically active species, but very few are developed as drugs or entered in clinical trials. This is due to their poor water solubility and lipophilicity, low stability as well as in vivo inactivation. The possibility to improve their pharmacological and/or oral administration profile by incorporation into inorganic or organic matrix was studied. Most of them are either physically encapsulated or conjugated to the matrix via a moiety able to coordinate Cu(II). As a result, a large variety of species were developed as delivery carriers. The organic carriers include liposomes, synthetic or natural polymers or dendrimers, while the inorganic ones are based on carbon nanotubes, hydrotalcite and silica. Some hybrid organic-inorganic materials based on alginate-carbonate, gold-PEG and magnetic mesoporous silica-Schiff base were also developed for this purpose. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is a rare tumor associated with asbestos exposure. Mesothelioma carcinogenesis is related to enhanced reactive oxygen species (ROS) production and iron overload. Despite the recent advances in biomedical sciences, to date the only available treatments include surgery in a small fraction of patients and platinum-based chemotherapy in combination with pemetrexed. In this view, the purpose of this study was to evaluate the therapeutic potential of the newly synthetized platinum prodrug Pt(IV)Ac-POA compared to cisplatin (CDDP) on human biphasic mesothelioma cell line MSTO-211H using different complementary techniques, such as flow-cytometry, transmission electron microscopy (TEM), and immunocytochemistry. Healthy mesothelial cell lines Met-5A were also employed to assess the cytotoxicity of the above-mentioned compounds. Our in vitro results showed that Pt(IV)Ac-POA significantly interfere with iron metabolisms and more importantly is able to trigger cell death, through different pathways, including ferroptosis, necroptosis, and apoptosis, in neoplastic cells. On the other hand, CDDP triggers mainly apoptotic and necrotic cell death. In conclusion, Pt(IV)Ac-POA may represent a new promising pharmacological agent in the treatment of malignant mesothelioma. [ABSTRACT FROM AUTHOR]

The current standard oncotherapy for glioblastoma is limited by several adverse side effects, leading to a short-term patient survival rate paralleled by a worsening quality of life (QoL). Recently, Complementary and Integrative Medicine's (CIM) innovative approaches have shown positive impacts in terms of better response to treatment, side effect reduction, and QoL improvement. In particular, promising potential in cancer therapy has been found in compounds coming from phyto- and mycotherapy. The objective of this study was to demonstrate the beneficial effects of a new phyto-mycotherapy supplement, named Ganostile, in the human glioblastoma cell line U251, in combination with chemotherapeutic agents, i.e., Cisplatin and a new platinum-based prodrug. Choosing a supplement dosage that mimicked oral supplementation in humans (about 1 g/day), through in vitro assays, microscopy, and cytometric analysis, it has emerged that the cells, after 48hr continuous exposure to Ganostile in combination with the chemical compounds, showed a higher mortality and a lower proliferation rate than the samples subjected to the different treatments administered individually. In conclusion, our data support the use of Ganostile in integrative oncology protocols as a promising adjuvant able to amplify conventional and new drug effects and also reducing resistance mechanisms often observed in brain tumors. [ABSTRACT FROM AUTHOR]

Platinum (Pt)(II) square planar complexes are well-known anticancer drugs whose Mechanism of Action (MOA) are finely tuned by the polar, hydrophobic and aromatic features of the ligands. In the attempt to translate this tunability to the identification of potential neurodrugs, herein, four Pt(II) complexes were investigated in their ability to modulate the self-aggregation processes of two amyloidogenic models: Sup35p7–13 and NPM1264–277 peptides. In particular, phenanthriplatin revealed the most efficient agent in the modulation of amyloid aggregation: through several biophysical assays, as Thioflavin T (ThT), electrospray ionization mass spectrometry (ESI-MS) and ultraviolet-visible (UV-vis) absorption spectroscopy, this complex revealed able to markedly suppress aggregation and to disassemble small soluble aggregates. This effect was due to a direct coordination of phenanthriplatin to the amyloid, with the loss of several ligands and different stoichiometries, by the formation of π–π and π–cation interactions as indicated from molecular dynamic simulations. Presented data support a growing and recent approach concerning the repurposing of metallodrugs as potential novel neurotherapeutics. [ABSTRACT FROM AUTHOR]

The effects of ferrocene (Fc) and ferrocenium (Fc+) induced in triple negative human breast cancer MCF-7 cells were explored by immunofluorescence, flow cytometry, and transmission electron microscopy analysis. The different abilities of Fc and Fc+ to produce reactive oxygen species and induce oxidative stress were clearly observed by activating apoptosis and morphological changes after treatment, but also after tests performed on the model organism D. discoideum, particularly in the case of Fc+. The induction of ferroptosis, an iron-dependent form of regulated cell death driven by an overload of lipid peroxides in cellular membranes, occurred after 2 h of treatment with Fc+ but not Fc. However, the more stable Fc showed its effects by activating necroptosis after a longer-lasting treatment. The differences observed in terms of cell death mechanisms and timing may be due to rapid interconversion between the two oxidative forms of internalized iron species (from Fe2+ to Fe3+ and vice versa). Potential limitations include the fact that iron metabolism and mitophagy have not been investigated. However, the ability of both Fc and Fc+ to trigger different and interregulated types of cell death makes them suitable to potentially overcome the shortcomings of traditional apoptosis-mediated anticancer therapies. [ABSTRACT FROM AUTHOR]

The complex [PtCl2(cyclohexane-1R,2R-diamine)] has been combined in a Pt(IV) molecule with two different bioactive molecules (i.e., the histone deacetylase inhibitor 2-propylpentanoic acid or valproic acid, VPA, and the potential antimetastatic molecule 4-isopropenylcyclohexene-1-carboxylic acid or perillic acid, PA) in order to obtain a set of multiaction or multitarget antiproliferative agents. In addition to traditional thermal synthetic procedures, microwave-assisted heating was used to speed up their preparation. All Pt(IV) complexes showed antiproliferative activity on four human colon cancer cell lines (namely HCT116, HCT8, RKO and HT29) in the nanomolar range, considerably better than those of [PtCl2(cyclohexane-1R,2R-diamine)], VPA, PA, and the reference drug oxaliplatin. The synthesized complexes showed pro-apoptotic and pro-necrotic effects and the ability to induce cell cycle alterations. Moreover, the downregulation of histone deacetylase activity, leading to an increase in histone H3 and H4 levels, and the antimigratory activity, indicated by the reduction of the levels of matrix metalloproteinases MMP2 and MMP9, demonstrated the multiaction nature of the complexes, which showed biological properties similar to or better than those of VPA and PA, but at lower concentrations, probably due to the lipophilicity of the combo molecule that increases the intracellular concentration of the single components (i.e., [PtCl2(cyclohexane-1R,2R-diamine)], VPA and PA). [ABSTRACT FROM AUTHOR]

The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naïve experiments indicates an energy-dependent, carrier-mediated transport: the organic cation transporters (OCTs) are the likely proteins involved. [ABSTRACT FROM AUTHOR]

In this work, 37 enological tannins of different classes were studied to investigate whether linear sweep voltammetry (LSV) could be a method to determine the family of a sample and its antioxidant capacity. A "wholistic" approach was used, combining LSV data with nuclear magnetic resonance (NMR), polyphenol quantification (Folin-Ciocalteu method and gravimetric analysis), antiradical activity (DPPH assay), and reducing capacity (FRAP assay). Voltammetric data were processed with statistical techniques and the results show the clustering of tannins in three different classes: ellagitannins, gallotannins, and condensed tannins. These findings were confirmed by NMR data treated with the same procedure. Finally, ellagitannins showed a high reducing capacity and gallotannins showed a high antiradical capacity. Importantly, LSV indices were shown to be significantly correlated with DPPH and FRAP parameters. Therefore, the hypothesis of LSV as a potentially useful technique to choose the most suitable tannin for a determined antioxidant purpose was successfully proved. • Linear sweep voltammetry classifies tannins in the belonging chemical classes. • Gallotannins are characterized by high antiradical capacity. • Ellagitannins are characterized by high reducing capacity. • LSV can be a tool to choose a suitable tannin for a specific antioxidant purpose. [ABSTRACT FROM AUTHOR]

Octahedral Pt(IV) prodrugs are an effective way to combine cisplatin-like moieties and a second drug to obtain selective and stimuli responsive bifunctional antiproliferative compounds. Recently, two bifunctional Pt(IV) complexes have shown interesting in vitro and in vivo effects in glioblastoma, the most aggressive primary brain tumor. An interesting observation indicates that 4,5-dihydroxy-9,10-dioxo-9,10- dihydroanthracene-2-carboxylic acid (rhein) can inhibit in vivo glioma tumor progression. Furthermore, a prodrug in which cisplatin was combined with two molecules of rhein showed a potency higher than that of cisplatin toward cisplatin-resistant lung carcinoma cells. However, the high lipophilicity of this type of complex affects their solubility and bioavailability. To overcome these limits, in the present work, three Pt (IV) derivatives were obtained by differently linking one molecule of rhein and one acetato ligand at the axial position to a cisplatin core. The complexes proved to be similar to or more potent than the parent cisplatin and rhein, and the reference drug temozolomide on two human glioblastoma cell lines (U87-MG and T98G). They retained their activity under hypoxia and caused a significant reduction in the motility of both cell lines, which can be related to their ability to inhibit MMP2 and MMP9 matrix metalloproteinases. Finally, physicochemical and computational studies indicated that these Pt(IV) derivatives are more prone than rhein to cross the blood--brain barrier. [ABSTRACT FROM AUTHOR]

The Pt(IV) complexes based on (SP-4-2)-dichlorido(cyclohexane-1,4-diamine)platinum(II) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid (POA) were investigated. Since POA contains a chiral carbon, all the possible Pt(IV) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt(IV) complexes containing the cyclohexane-1R,2R-diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC50), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied. Overall, the two series of Pt(IV) complexes showed similar cell penetration properties, being significantly better than that of the Pt(II) reference compounds. Finally, a representative compound of the whole set of complexes (i.e., that based on cyclohexane-1R,2R-diamine and racemic POA) was tested in vivo on mice bearing Lewis lung carcinoma, showing good tumor growth inhibition with negligible body weight loss. [ABSTRACT FROM AUTHOR]

Gliomas are the most frequent primary tumours of the nervous system, characterised by high degree of malignancy, widespread invasion and high-rate proliferation. Cisplatin and analogue are currently employed in clinical trials as active chemotherapeutic agents for the systemic treatment of this type of malignancy. Despite therapy benefits, clinical use of these agents is hampered by severe side effects including neurotoxicity. Therefore, the aim of the present study was to analyse the effect of a new compound of platinum(IV) conjugate, named Pt(IV)Ac-POA, which can generate a synergistic antineoplastic action when released along with cisplatin, after a specific reduction reaction within tumour cells. To assess the effects of the novel compound on rat C6 glioma cells, cell cycle and cell death activation analyses were carried out using flow cytometry. Morphological changes and activation of different cell death pathways were evaluated by both transmission electron microscopy and immunofluorescence microscopy. Protein expression was investigated by western blotting analysis. The novel compound Pt(IV)Ac-POA, bearing as axial ligand (2-propynyl)octanoic acid (POA), which is a histone deacetylase inhibitor (HDACi), acts as a prodrug in tumour cells, inducing cell death through different pathways at a concentration lower than those tested for other platinum analogues. The current results showed that Pt(IV)Ac-POA could represent a promising improvement of Pt-based chemotherapy against gliomas, either inducing a chemosensitisation and reducing chemoresistance. [ABSTRACT FROM AUTHOR]

Abstract Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T. cruzi strains of the parasite and their cytotoxicity on Vero cells to calculate the selectivity index (SI). Compound 2 , 1-ferrocenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one, stood out as the most promising derivative showing a half maximal inhibitory concentration (IC 50) value around 5 μM in both amastigote and trypomastigote forms of T. cruzi and SI values higher than 13, being the best value on the trypomastigote forms of the Arequipa strain (SI = 41.7). Moreover, 2 decreased the number of infected cells and was not genotoxic. Furthermore, its possible mechanism of action was studied through the alteration of the metabolites excreted by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase (SOD). Finally, docking studies were executed to analyze the binding mode of the studied compounds to Fe-SOD enzyme. Graphical abstract Image 1 Highlights • Novel ferrocenyl Mannich base derivatives were synthesized and characterized. • The activity and selectivity of the compounds against Chagas disease were evaluated. • The mechanism of action involves the inhibition of iron superoxide dismutase. [ABSTRACT FROM AUTHOR]

The formation of quadruple-stranded DNA induced by planar metal complexes has particular interest in the development of novel anticancer drugs. This is especially relevant for the inhibition of telomerase, which plays an essential role in cancer cell immortalization and is overexpressed in ca. 85–90% of cancer cells. Moreover, G-quadruplexes also exist in other locations in the human genome, namely oncogene promoter regions, and it has been hypothesized that they play a regulatory role in gene transcription. Herein we report a series of new anthracene-containing terpyridine ligands and the corresponding Cu(II) and Pt(II) complexes, with different linkers between the anthracenyl moiety and the terpyridine chelating unit. The interaction of these ligands and metal complexes with different topologies of DNA was studied by several biophysical techniques. The Pt(II) and Cu(II) complexes tested showed affinity for quadruplex-forming sequences with a good selectivity over duplex DNA. Importantly, the free ligands do not have significant affinity for any of the DNA sequences used, which shows that the presence of the metal is essential for high affinity (and selectivity). This effect is more evident in the case of the Pt(II) complexes. Moreover, the presence of a longer linker between the chelating terpyridine unit and the anthracene moiety enhances the interaction with G-quadruplex-forming sequences. We further evaluated the ability of the Cu(II) complexes to interact with, and stabilize G-quadruplex containing regions in oncogene promoters via a polymerase stop assay. These studies indicated that the metal complexes are able to induce G-quadruplex formation and stop polymerase activity. [ABSTRACT FROM AUTHOR]

The octanol/water partition coefficient, logP, is one of the most important physico-chemical parameters for the development of new metal-based anticancer drugs with improved pharmacokinetic properties. This study addresses an issue with the absence of publicly available models to predict logP of Pt(IV) complexes. Following data collection and subsequent development of models based on 187 complexes from literature, we validate new and previously published models on a new set of 11 Pt(II) and 35 Pt(IV) complexes, which were kept blind during the model development step. The error of the consensus model, 0.65 for Pt(IV) and 0.37 for Pt(II) complexes, indicates its good accuracy of predictions. The lower accuracy for Pt(IV) complexes was attributed to experimental difficulties with logP measurements for some poorly-soluble compounds. This model was developed using general-purpose descriptors such as extended functional groups, molecular fragments and E-state indices. Surprisingly, models based on quantum-chemistry calculations provided lower prediction accuracy. We also found that all the developed models strongly overestimate logP values for the three complexes measured in the presence of DMSO. Considering that DMSO is frequently used as a solvent to store chemicals, its effect should not be overlooked when logP measurements by means of the shake flask method are performed. The final models are freely available at http://ochem.eu/article/76903 . [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and mortal primary brain tumor in human. After standard therapies, that include surgical resection followed by radiotherapy and chemotherapy, it is difficult to completely remove the tumor and the development of relapses and resistance is almost inevitable. The chemotherapy now available also show important side effects, to overcame those limitation, new platinum-based drugs are being synthetized, Pt(IV)Ac-POA, (OC-6–44)-acetate-diamine-chloride(2-(2-propynyl)octanoato)platinum(IV), a prodrug having an Histone-3-DeAcetylase-Inhibitor as axial ligands, is one of them. Moreover, new compounds of plant origin are increasingly seen as potential sources of benefits in oncological treatments. The aim of the study is to investigate the possible contribution of micotherapy in the fight against GBM, its role in the metabolism of reactive oxygen species (ROS) and its synergic effect with a new platinum-based compound, Pt(IV)Ac-POA, on human glioblastoma U251 cells. Through cytofluorimetric and immunofluorescence analysis, the ability of the micotherapy in study to regulate the cell cycle was assessed, and its importance in controlling the cellular redox state was also revealed, opening to the possibility of a new therapy in which micotherapy can support the activity of new chemotherapy while reducing its side effects controlling inflammatory conditions in the microenvironment. Additionally, the combined therapy appeared able to induce regulated form of necrosis, such as ferroptosis, and to hinder the establishment of resistance mechanisms. [Display omitted] • Micotherapy determines a block in the cell cycle. • Micotherapy may offer support in the stemming of tumor cell migration. • Micotherapy can lead to mitochondrial disfunction and altered redox balance. • Decreasing of ACO2 and GPX4 with combined therapy indicate sensitivity to ferroptosis. • Micotherapy effect can be synergic to the one of chemotherapy. [ABSTRACT FROM AUTHOR]

The microwave-assisted synthesis of Pt(II) complexes containing several pyridines (i.e., pyridine L1 , 2-picoline L2 , 3-picoline L3 , 4-picoline L4 , 2,2′-bipyridine L5 ) is reported. For L1 – L5 , the reaction was successful in about 50% yield with all the ligands except L2 . The same method applied to 4,4′-bis(2-morpholinoethoxy)-2,2′-bipyridine ( L6 , a ligand showing interesting antiproliferative properties because of a high DNA affinity), was unsatisfactory. The corresponding complex cis -[PtCl 2 ( L6 )] was obtained only heating at reflux a mixture of [PtCl 2 (1,5-cyclooctadiene)] and L6 in acetonitrile for 24 h. Antiproliferative activity of [PtCl 2 ( L6 )] on four cancer cell lines (ovarian A2780 and its cisplatin-resistant variant A2780cisR, prostate PC3 and breast cancer MDA-MB-231) was compared with that of its ligand and the model complex [PtCl 2 ( L5 )]. These studies showed that [PtCl 2 ( L6 )] has just marginal activity towards the tested cells if compared with cisplatin. [ABSTRACT FROM AUTHOR]

Abstract: The bifunctional Pt(IV) conjugate cis,cis,trans-diamminedichloridobis(valproato)platinum(IV), based on the cisplatin square-plane with two axial valproato (2-propylpentanoate, VPA) ligands, has been re-synthesized with a modified procedure and its biological activity was compared with that of its isomer cis,cis,trans-diamminedichloridobis(n-octanoato)platinum(IV). Both complexes showed a striking cytotoxic effect (in the micro or sub-micromolar range) on various human carcinoma cell lines (namely ovarian, colon, breast and lung cancer), and, in particular, on cells derived from malignant pleural mesothelioma. This remarkable activity is due to the action of the cisplatin metabolite only, generated by the intracellular Pt(IV)→Pt(II) reduction, which concentration is greatly increased by the enhanced cellular accumulation of the original, highly lipophilic Pt(IV)-bis(carboxylato) complexes. The two axial VPA ligands are released in a too low concentration to act as histone deacetylase inhibitor (HDACI), as VPA works in the millimolar range, so that no synergism can be claimed. Moreover, n-octanoic acid is substantially deprived of any HDACI propensity. [Copyright &y& Elsevier]

[Display omitted] • Two Pt(IV) complexes were formulated with Intralipid to evaluate delivery to cancer cells. • Intralipid formulations show an increase in cell accumulation vs. free complexes. • Free complexes were more cytotoxic than their Intralipid formulations. • The presence of Intralipid was not totally detrimental of the potency. • A possible use in vivo of the Pt(IV)-Intralipid formulations should not be excluded. The two Pt(IV) complexes (OC -6–33)-(cyclohexane-1 R ,2 R -diamine)dichloridodiheptanoatoplatinum(IV) (1) and (OC -6–33)-(cyclohexane-1 R ,2 R -diamine)dichloridodioctanoatoplatinum(IV) (2) were formulated with Intralipid® (IL) as a proof-of-concept to evaluate the delivery of lipophilic metal compounds to cancer cells. Negatively charged nanoemulsions ranging from 287 to 312 nm were obtained. The IL formulations show an increase in cancer cell accumulation (A2780 ovarian cancer cells) by a factor 6–7 with respect to the free complexes. In spite of the expected antiproliferative properties, in the cytotoxicity experiments free complexes showed values of the half-maximal inhibitory concentration (IC 50) from 2 to 6 times lower with respect to the IL formulations. However, the presence of IL was not totally detrimental of the potency, that is still in the nanomolar range, and, hence, a possible use in vivo , should not be excluded a priori. [ABSTRACT FROM AUTHOR]

The chemical and biological features of two newly synthesized [PtCl(L)(2-aminonaphthalene)] complexes (L is NH or 2-aminonaphthalene) were compared with those of two already reported enantiomeric complexes of formula [PtCl(DABN)] [DABN is ( R)-1,1′-binaphthyl-2,2′-diamine or ( S)-1,1′-binaphthyl-2,2′-diamine]. Solution behavior, lipophilicity, cytotoxicity with regard to one colorectal (HCT116) and two ovarian (A2780 and A2780Cp8) human carcinoma cell lines, and in vitro DNA- and G-quadruplex-binding properties were evaluated. In particular, the cytotoxicity of [PtCl(NH)(2-aminonaphthalene)] was better than that of cisplatin for all cell lines, and rather resembled that of oxaliplatin. The solution behavior of the whole series of complexes and the absence of an evident relationship between lipophilicity and cytotoxicity seem to suggest that all these experimental parameters are probably smoothed out during the 3-day cytotoxicity experiments and do not strongly affect the half-maximal inhibitory concentrations. The results of electrophoretic studies indicate that different kinds of interaction with DNA can be involved in the mode of action of these complexes, with intercalation in double-stranded DNA and stacking on G-quadruplex DNA being strongly implicated in particular for [PtCl(NH)(2-aminonaphthalene)]. [ABSTRACT FROM AUTHOR]

Abstract: Mesothelioma is a rare form of cancer that affects the membranous lining of the chest (pleura) and, less commonly, the lining of the abdomen and heart. The disease carries a poor prognosis and is typically associated with exposure to asbestos, a mineral that has been widely used due to its fire resistance and insulating properties. The standard non-surgical treatment for malignant pleural mesothelioma (MPM) is polychemotherapy combining cisplatin/carboplatin and a second agent with a different mechanism of action. This review outlines the use of clinically approved platinum-drugs and the design of metal-drug candidates for the treatment of MPM. [Copyright &y& Elsevier]