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Thiosemicarbazones (TSCNs) constitute a broad family of compounds (R1R2C=N-NH-C(S)- NR3R4), particularly attractive because many of them display some biological activity against a wide range of microorganisms and cancer cells. Their activity can be related to their electronic and structural properties, which offer a rich set of donor atoms for metal coordination and a high electronic delocalization providing different binding modes for biomolecules. Heterocycles such as pyrrole, imidazole and triazole are present in biological molecules such as Vitamine B12 and amino acids and could potentially target multiple biological processes. Considering this, we have explored the chemistry and biological properties of thiosemicarbazones series and their complexes bearing heterocycles such as pyrrole, imidazole, thiazole and triazole. We focus at the chemistry and cytotoxicity of those derivatives to find out the structure activity relationships, and particularly we analyzed those examples with the TSCN units in which the mechanism of action information has been profoundly studied and pathways determined, to promote future studies for heterocycle derivatives.

Three thiosemicarbazone derivatives, namely 4-(dimethylamino)benzaldehyde 4,4-dimethylthiosemicarbazone (HL1), 4-(dimethylamino)benzaldehyde thiosemicarbazone (HL2), and 4-(dimethylamino)benzaldehy...

The synthesis and characterization of three new platinum complexes, with 3,5-diacetyl-1,2,4-triazole bis(4-N-isopropylthiosemicarbazone) as a ligand, are reported. The specific conditions under which solvent coordination takes place are reported and the X-ray structure of the complex with one solvent molecule of dimethyl sulfoxide is resolved. Analysis of the reactivity of these platinum compounds aids in finding the best solution profile for biological investigations. Then, the interactions of the complexes with biological models, such as calf-thymus DNA, are studied by using UV spectroscopy and tracking the changes in electrophoretic mobility produced in the supercoiled plasmid DNA model. Initial screening of these potential antitumoral compounds indicates possible selective antitumoral action.

Novel bisphosphonate platinum complexes: [Pt(isopropylamine) 2 (BP)]NO 3 (BP = pamidronate and alendronate) have been synthesized and characterized. Their monomeric structure contains a bisphosphonate acting as chelate ligand through its oxygen atom donors, conferring the compound's cationic structure with a good solubility in water. The study of the compounds in solution showed high stability up to 24 h. The cytotoxicity in cancer cell lines has been assessed. We also present preliminary studies on the evaluation of the affinity towards biological targets such as DNA (both calf thymus DNA and supercoiled plasmid DNA) and hydroxyapatite where the complexes showed a low DNA interaction, but a clear affinity for hydroxyapatite comparing to their precursors.

In this article, we report on the development of new metal-based anticancer agents with imaging, chemotherapeutic and photosensitizing properties. Hence, a new heterobimetallic complex (Pt-LQ-Re) was prepared by connecting a non-conventional trans-chlorido Pt(ii) complex to a photoactive Re tricarbonyl unit (LQ-Re), which can be replaced by 99mTc to allow for in vivo imaging. We describe the photophysical and biological properties of the new complexes, in the dark and upon light irradiation (DNA interaction, cellular localization and uptake, and cytotoxicity). Furthermore, planar scintigraphic images of mice injected with Pt-LQ-Tc clearly showed that the radioactive compound is taken up by the excretory system organs, namely liver and kidneys, without significant retention in other tissues. All in all, the strategy of conjugating a chemotherapeutic compound with a PDT photosensitizer endows the resulting complexes with an intrinsic cytotoxic activity in the dark, driven by the non-classical platinum core, and a selective activity upon light irradiation. Most importantly, the possibility of integrating a SPECT imaging radiometal (99mTc) in the structure of these new heterobimetallic complexes might allow for in vivo non-invasive visualization of their tumoral accumulation, a crucial issue to predict therapeutic outcomes.

[Background] Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed., [Methods] We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres., [Results] Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer., [Conclusions] The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer., The authors thank the donors and the biobank of the Hospital Universitario Virgen del Rocío-Instituto de Biomedicina de Sevilla (Sevilla, Spain) (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for the human specimens used in this study. SM-G was supported by a Sara Borrell grant from ISCIII (Codigo CD16/00230) and BFA is funded by the Spanish Ministry of Education (FPU12/01380). AC lab was supported by grants from the Spanish Ministry of Economy and Competitivity, Plan Estatal de I + D + I 2013–2016, ISCIII (Fis: PI15/00045), the Ministry of Science, Innovation and Universities (RTI2018–097455-B-I00) and CIBER de Cáncer (CD16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union), the AECC Foundation and Foundation Eugenio Rodriguez Pascual. Especial thanks to Consejeria de Salud of the Junta de Andalucia (PI-0397-2017) for supporting this work.

We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.

We report a combined experimental-theoretical study on the 31P NMR chemical shift for a number of trans-platinum(ii) complexes. Validity and reliability of the 31P NMR chemical shift calculations are examined by comparing with the experimental data. A successful computational protocol for the accurate prediction of the 31P NMR chemical shifts was established for trans-[PtCl2(dma)PPh3] (dma = dimethylamine) complexes. The reliability of the computed values is shown to be critically dependent on the level of relativistic effects (two-component vs. four component), choice of density functionals, dynamical averaging, and solvation effects. Snapshots obtained from ab initio molecular dynamics simulations were used to identify those solvent molecules which show the largest interactions with the platinum complex, through inspection by using the non-covalent interaction program. We observe satisfactory accuracy from the full four-component matrix Dirac-Kohn-Sham method (mDKS) based on the Dirac-Coulomb Hamiltonian, in conjunction with the KT2 density functional, and dynamical averaging with explicit solvent molecules.

We have selected a series of aliphatic amine platinum compounds bearing chloride and/or iodide as the leaving groups. The complexes’ cytotoxicity and interaction with DNA indicated differences in the reactivity. Now, we are reporting on the analysis of their molecular mechanism of action on gastric cancer cells. Our data reveals differences between them. Chlorido drugs showed similar behavior to cisplatin; they both required p53 to induce apoptosis but only cis-ipa showed DNA damage requirement for apoptosis induction. On the contrary, cis and trans iodido induced cell death independent of p53 activity, and they induced cell death through Bid activation, so their toxicity could be enhanced in a combined treatment with novel Bcl-2 protein family inhibitors. We also report the structural features of the DNA adduct for one of the complexes by X-ray diffraction. These findings represent a step forward in the search for new platinum-derived agents more specific and effective in the treatment of cancer., Authors A.G.Q., M.C., and A.A.-V. received funding from MINECO CTQ2015-68779-R. I.S.P. received funding from P17-01401 (supported by FEDER funds) from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, SpainNPL is a fellow of the Programa de Doctorado Biociencias Moleculares UAM, Madrid, Spain. NPL was supported by a fellowship Programa de Formación de Profesorado Universitario REF: FPU15/04669.

We report a combined experimental-theoretical study on the 31P NMR chemical shift for a number of trans-platinum(ii) complexes. Validity and reliability of the 31P NMR chemical shift calculations are examined by comparing with the experimental data. A successful computational protocol for the accurate prediction of the 31P NMR chemical shifts was established for trans-[PtCl2(dma)PPh3] (dma = dimethylamine) complexes. The reliability of the computed values is shown to be critically dependent on the level of relativistic effects (two-component vs. four component), choice of density functionals, dynamical averaging, and solvation effects. Snapshots obtained from ab initio molecular dynamics simulations were used to identify those solvent molecules which show the largest interactions with the platinum complex, through inspection by using the non-covalent interaction program. We observe satisfactory accuracy from the full four-component matrix Dirac-Kohn-Sham method (mDKS) based on the Dirac-Coulomb Hamiltonian, in conjunction with the KT2 density functional, and dynamical averaging with explicit solvent molecules.

One mononuclear and another dinuclear Pd(II) complexes bearing a α-N-heterocyclic thiosemicarbazone ligand have been synthesized, fully characterized and studied as biological agents. In both complexes, the palladium center is coordinated to 3,5-diacetyl-1,2,4-triazol bis(N4,N4-dimethylthiosemicarbazone) via three sites (N, N and S). Their binding ability to DNA has been evaluated using spectroscopic and biophysical techniques. Molecular docking and molecular dynamics calculations supports the existence of a minor groove binding mode between the studied compounds and DNA.

Three platinum complexes with cis and trans configuration cis-[Pt(TCEP)2Cl2], cis-[Pt(tmTCEP)2Cl2] and trans-[Pt(TCEP)2Cl2], where TCEP is tris(2-carboxyethyl)phosphine, have been synthesized and fully characterized by usual techniques including single-crystal X-ray diffraction for trans-[Pt(TCEP)2Cl2] and cis-[Pt(tmTCEP)2Cl2]. Here, we also report on an esterification process of TCEP, which takes place in the presence of alcohols, leading to a platinum complex coordinated to an ester tmTCEP (2-methoxycarbonylethyl phosphine) ligand. The stability in solution of the three compounds and their interaction with biological models such as DNA (pBR322 and calf thymus DNA) and proteins (lysozyme and RNase) have also been studied., This work was supported by Spanish MINECO: CTQ2015-68779R and CTQ2015-70371-REDT.

Two Pd(II) and Pt(II) complexes with two pyrrol-2-carbaldehyde N-p-chlorophenylthiosemicarbazone ligands are designed and characterized showing mononuclear structures. An important pharmacological property for both compounds is the high selectivity for tumor cells and a lack of activity in healthy cells. The Pd(II) compound shows a higher antitumor activity and selectivity than the Pt(II) compound. Both complexes present a variety of biological interactions: with DNA models (pBR322 and CT DNA), proteins (lysozyme and RNase) and other biological targets like proteosome. Our results show that the Pd(II) complex is a more interesting candidate for potential anticancer therapies than the Pt(II) complex, and we provide new insight into the design and synthesis of palladium compounds as potential antitumor agents., Puede accederse a los datos primarios de este trabajo haciendo clic en "Documentos relacionados"., Facultad de Ciencias Exactas, Centro de Química Inorgánica

The tetranuclear Pt complex (PtL)4 (where L2- is the anion derived from para-isopropyl thiosemicarbazone) was first described in A.G. Quiroga et al., J. Med. Chem. 41, 1998, 1399-1408. (PtL)4 manifests antiproliferative properties toward various cancer cell lines being a promising anticancer drug candidate. Yet, details of its reactivity with biomolecules have not been elucidated. To this end, we investigated the reactions of (PtL)4 with a few model proteins, i.e. bovine pancreatic ribonuclease (RNase A), cytochrome c (Cyt c) and hen egg white lysozyme (Lysozyme), through electrospray ionization mass spectrometry and other biophysical methods. A rich reactivity of (PtL)4 with the above-mentioned model proteins is observed, leading to the formation of numerous metallodrug-protein adducts. The tetranuclear complex breaks down and various fragments bind proteins up to high metal/protein ratios; this typically results into very complicated mass spectral patterns. However, some of the main mass peaks could be assigned in the case of the Lysozyme adduct. In addition, crystallographic data were obtained for the (PtL)4/Lysozyme and (PtL)4/RNase A adducts pointing at His side chains as the primary binding sites for monometallic Pt fragments. Notably, a few selected features of the interactions observed in the (PtL)4/protein adducts were reproduced by reacting (PtL)4 with a small molecule, i.e. N-methylimidazole. In conclusion, the present study confirms the prodrug nature of the tetraplatinum complex, clarifies one possible pathway for its activation through cluster disassembly and allows initial identification of adducts formed with a representative protein.

Pt(IV) complexes are known as prodrugs that can potentially overcome cisplatin limitations by slowing down its reactivity and, once reduced, act as the corresponding Pt(II) drugs. We report a new approach toward trans Pt(IV) complexes, conceived to afford nonconventional active trans Pt(II) complexes with dual-targeting properties. The reduction of the complexes has been studied in the presence of ascorbic acid and glutathione, showing that different species are formed in the process. The interaction with DNA after reduction has been also studied and correlated to the formation of Pt(II) species. The cytotoxicity profile of the Pt(IV) complexes corroborated the rationale behind this approach.

In order to target platinum complexes to cancer cells, trans-Pt(II) or trans-Pt(IV) complexes were bioconjugated to the cyclic peptide cRGDfK (cRGD), with affinity for αvβ3 integrin receptors, through their 4-picolinic acid spectator ligands. To tackle this goal, the Pt(II) and Pt(IV) precursors were activated at their carboxylic acid function and futher reacted with the cRGDfK peptide, to afford the bioconjugates Pt(II)-cRGD and Pt(IV)-cRGD, respectively. Pt(II)-cRGD was studied by 195Pt-NMR that confirmed the presence of the Pt(II) center. In contrast, the characterization of Pt(IV)-cRGD was not possible due to the tendency of this complex to undergo reduction to Pt(II) in solution. Thus, only the Pt(II)-cRGD complex was used for further biological studies, and it exhibited some cytotoxic activity against the HUVEC cell line, with the highest levels of αvβ3 expression. However, no improved effects were observed with respect to the Pt(II)-pic precursor. Studies by ICP-MS showed enhanced intracellular accumulation for Pt(II)-cRGD with respect to Pt(II)-pic in cancer cells. Overall, these results show that while Pt(II) bioconjugation enhances compound's uptake, it did not translate into an increase in cytotoxicity.

In this article, we report on the development of new metal-based anticancer agents with imaging, chemotherapeutic and photosensitizing properties. Hence, a new heterobimetallic complex (Pt-LQ-Re) was prepared by connecting a non-conventional trans-chlorido Pt(ii) complex to a photoactive Re tricarbonyl unit (LQ-Re), which can be replaced by

A novel series of platinum(II) complexes bearing aliphatic amines and ligands with DNA-targeting properties was synthesized to achieve more potent and selective metallodrugs. We developed six new platinum-based drugs, which contain methylamine, 1a-c, and isopropylamine, 2a-c, both in the trans position to a selected targeting ligand: naphthalimide. The activity of the complexes has been evaluated in order to confirm the improvements from our proposed approach, and the complexes demonstrate better cytotoxic activity on cancer cell lines when compared with the ligands and, importantly, with cisplatin. Further studies were performed to assess their subcellular localization and binding mode to DNA.

trans-Platinum complexes have been the landmark in unconventional drugs prompting the development of innovative structures that might exhibit chemical and biological profiles different to cisplatin. Iodido complexes signaled a new turning point in the platinum drug design field when their cytotoxicity was reevaluated and reported. In this new study, we have synthesized and evaluated diodidoplatinum complexes trans-[PtI2(amine)(pyridine)] bearing aliphatic amines (isopropylamine and methylamine) and pyridines in trans configuration. X-ray diffraction data support the structural characterization. Their cytotoxicity has been evaluated in tumor cell lines such as SAOS-2, A375, T-47D, and HCT116. Moreover, we report their solution behavior and reactivity with biological models. Ultraviolet-a (UVA) irradiation induces an increase in their reactivity towards model nucleobase 5&prime, GMP in early stages, and promotes the release of the pyridine ligand (spectator ligand) at longer reaction times. Density Functional calculations have been performed and the results are compared with our previous studies with other iodido derivatives.

The dibromido analogue of cisplatin, cis-PtBr2(NH3)2 (cisPtBr2 hereafter), has been prepared and characterised. Its solution behaviour in standard phosphate buffer, at pH 7.4, was investigated spectrophotometrically and found to reproduce quite closely that of cisplatin; indeed, progressive sequential release of the two halide ligands typically occurs as in the case of cisplatin, with a roughly similar kinetics. Afterward, patterns of reactivity toward model proteins and standard ctDNA were explored and the nature of the resulting interactions elucidated. The antiproliferative properties were then evaluated in four representative cancer cell lines, namely A549 (human lung cancer), HCT116 (human colon cancer), IGROV-1 (human ovarian cancer) and FLG 29.1 (human acute myeloid leukaemia). Cytotoxic properties in line with those of cisplatin were highlighted. From these studies an overall chemical and biological profile emerges for cisPtBr2 closely matching that of cisplatin; the few slight, but meaningful differences that were underscored might be advantageously exploited for clinical application.

Woodecement composites are interesting materials for structural and isolation purposes. Dimensional stability, economic factors and resistance to environmental degradation are features that can be exploited for housing components. The main inconvenient affecting its manufacture is the incompatibility between wood and cement, caused by setting inhibitory substances present in woods. Wood treatments are multivariable processes required for the appropriate cement setting reaction on wood surfaces. Treatment conditions affect the mechanical properties of the resulting composites. This work evaluates the simultaneous influence of the variables ruling three widely used wood treatments e water extraction, degradation by alkaline hydrolysis and retention of inhibitory substances e on the mechanical properties of wood fibers and of resulting woodecement composites. Populus Euroamericana wood fibers and Portland cement were selected as case materials. The alkaline hydrolysis was found as the most effective treatment for the suppression of inhibitory substances and the highest decrease on mechanical properties of resulting composites. Empirical relationships describing the dependence of the compressive modulus of elasticity and compression strength of woodecement composites with the wood treatment variables are presented. Fil: Quiroga, A.. Universidad Tecnológica Nacional. Facultad Regional Santa Fe; Argentina Fil: Marzocchi, V.. Universidad Nacional del Litoral. Facultad de Ingenieria Quimica. Instituto de Tecnologia Celulosica; Argentina Fil: Rintoul, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); Argentina

We have reported the synthesis and characterization of two new trans platinum complexes in the phosphane series, where the phosphane ligand is triphenylphosphine [P(Ph)3] and the group in the trans configuration is represented by chiral aliphatic amines, (racemic in complex 1 and S–NH2CH2CH(CH3)CH2CH3 in complex 2). The anti-proliferative activity detected in tumor cells treated with the two new complexes is more pronounced when the aliphatic amine is racemic compared to the S-enantiomer. Moreover, for both compounds, the activity is fast after cell exposure and, unlike that of cisplatin, virtually independent of the duration of cell challenge.

We show that UVA irradiation (365 nm) of the Pt-IV complex trans,trans,trans-[(PtCl2)-Cl-IV(OH)(2)(dimethylamine) (isopropylamine)] (1), induces reduction to Pt-II photoproducts. For the mixed amine Pt-II complex, trans[(PtCl2)-Cl-II(isopropylamine)(methylamine)] (2), irradiation at 365 nm increases the rate and extent of hydrolysis, triggering the formation of diaqua species. Additionally, irradiation increases the extent of reaction of complex 2 with guanosine-5'-monophosphate and affords mainly the bis-adduct, while reactions with adenosine-5'-monophosphate and cytidine-5'-monophosphate give rise only to mono-nucleotide adducts. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 1 and 2, and their photophysical and photochemical properties. UVA-irradiation can contribute to enhanced cytotoxic effects of diamine platinum drugs with trans geometry.

The reactivity of three cytotoxic trans-Pt(II) complexes bearing aliphatic amine ligands, with transferrin and single-stranded oligonucleotides as DNA models, was investigated by ESI-MS and the results obtained are discussed in comparison with cisplatin. Tandem MS studies provided additional information on the preferential Pt binding sites. To determine whether trans-Pt(II) complexes can migrate from a peptide to an oligonucleotide, transfer experiments were also performed using ESI-MS, and competitive binding of the trans-Pt(II) complexes toward a model peptide and different oligonucleotides was also investigated. Significant differences in the reactivity of the trans complexes with respect to cisplatin were observed. In general, adduct formation with the selected peptide is favored for the trans compounds, whereas cisplatin shows a preference for oligonucleotides, especially if adjacent G-G residues are present. The results are discussed in relation to the possible mechanism of action of the trans-Pt(II) complexes.

trans-Pt(II) Complexes with aliphatic amines and planar amines such as (hydroxymethyl)pyridines, and pyridine-3- and pyridine-4-carboxylic acids were synthesized and screened for their potential cytotoxic activity in different cancer cell lines used at the NCI for in vitro screens, i.e., MCF7, NCIH460, and SF268. The complexes studied were designed to differ in geometrical parameters such as the position of the phenyl-group substituents and the nature of the substituents themselves for gathering information about the structure-activity relationships in the trans-complexes. The variation of the substituents turns to be crucial for their biological activity, as both pyridine-3- and pyridine-4-carboxylic acids in trans-position to both amine and isopropylamine ligands provided complexes which displayed no specificity toward any type of cell tested, while (hydroxymethyl)pyridine in trans-position to isopropylamine ligands led to complexes that were clearly more effective against the cell lines tested.

The preparation and characterization of the new complexes trans-[PtCl4(NH3)(3-picolinic acid)] (1), trans-[PtCl4{NH2CH(CH3)2}(3-picolinic acid)] (2), trans-[PtCl4(NH3)(4-picolinic acid)] (3), and trans-[PtCl4{NH2CH(CH3)2}(4-picolinic acid)] (4) are described. The main structural feature of these complexes is the presence of ligands capable of multiple hydrogen-bonding interactions. Crystals of 1, 2, 3, and 4 suitable for single-crystal X-ray diffraction were grown, and the molecular structures of these compounds are discussed. In contrast to the inactive parent PtII complexes, the PtIV complexes displayed cytotoxic activity against various cancer cell lines used at the National Cancer Institute (NCI) for in vitro screens. Once more, the isopropylamine derivatives showed the best cytotoxicity values. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The investigation of the formation and reactivity of Pd and Pt thiosemicarbazone complexes has revealed an unstudied intermediate derived from p-nitroacetophenone 4-methylthiosemicabazone (L1H2). The L1H2 ligand leads to a new complex [Pt(L1)(L1H2)] that supports the postulated mechanism of how cyclometallation reactions take place. All the newly synthesized complexes, [(Pd(L1)4], [(Pt(L1)4], and [Pt(L1)(L1H2)] (3), have been characterized and tested against MCF7, SF268, and NCI H460 cell lines. The crystal structure of [Pt(L1)(L1H2)]·dmso is reported. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

7 páginas, 5 figuras, 1 tabla -- PAGS nros. 104-110, In an attempt to design new antitumoral drugs based on transplatin complexes, we determined the experimental conditions for the preparation of trans-[Pt((CH3)2CNOH)((CH3)2CHNH2)Cl2], and solved the crystal structure. The cytotoxicity of the novel complex, the cis counterpart, cisplatin, and a trans complex with aliphatic amines, as well as the capacity of some of these complexes to cause either apoptotic or necrotic cell death, was comparatively examined in NRK-52E rat renal tubular cells and HepG2 human hepatoma cells. The results indicate that the oxime complex with trans geometry, but not the one with cis geometry, causes death by apoptosis, making the complex potentially suitable for therapeutic purposes. However cytotoxicity values are higher in the case of cis geometry than in trans geometry in both tumoral and non-tumoral cell lines, Authors thank the Spanish Ministry of Science and Education, Spanish CICYT Grants: SAF2003-01700 and SAF2004-01250

The investigation of cis-PtI2(NH3)2, the diiodido analogue of cisplatin (cisPtI2 hereafter), has been unjustly overlooked so far mainly because of old claims of pharmacological inactivity. Some recent - but still fragmentary - findings prompted us to reconsider more systematically the chemical and biological profile of cisPtI2 in comparison with cisplatin. Its solution behaviour, interactions with DNA and cytotoxic properties versus selected cancer cell lines were thus extensively analysed through a variety of biophysical and computational methods. Notably, we found that cisPtI2 is highly cytotoxic in vitro toward a few solid tumour cell lines and that its DNA platination pattern closely reproduces that of cisplatin; cisPtI2 is also shown to completely overcome resistance to cisplatin in a platinum resistant cancer cell line. The differences in the biological actions of these two Pt complexes are most likely related to slight but meaningful differences in their solution behaviour and reactivity. Overall, a very encouraging and unexpected pharmacological profile emerges for cisPtI2 with relevant implications both in terms of mechanistic knowledge and of prospective clinical application. An ab initio DFT study is also included to support the interpretation of the solution behaviour of cisPtI2 under physiological and slightly acidic pH conditions, TM and LM acknowledge Beneficentia Stiftung (Vaduz), COST Action CM1105 and AIRC (IG-16049) for generous financial support. JK and VB acknowledge the support from the Czech Science Foundation (Grant 14-21053S)

Trans diiodido platinum(II) complexes bearing the same as well as different aliphatic amines (mixed-amines) have interesting biological activity; cytotoxicity and interactions with some important biological models have already been demonstrated. Herein we described the interaction of such compounds with ct-DNA, supercoiled and linearized plasmid DNA and 5-GMP. Interestingly, UV irradiation of these compounds results in an increase in reactivity towards DNA and 5-GMP in such model systems. Additionally, the cytotoxicity of the trans-Pt(II) complexes towards human cancer cells is noticeably increased when treatment is combined for 90min with UVA-irradiation. With this work we provide evidence that trans diiodido compounds can be activated by UV-light over relatively short treatment times.

Wood wool cement composites (WWCC) are widely used materials constituted of wood wool and Portland cement. The material presents excellent mechanical, chemical and biological properties. However, the understanding of its mechanical behavior is rather limited. In this contribution, a hierarchically structured model is presented to describe the mechanical behavior of WWCC under compressive stress. The material is modeled as 3D rigid open cellular structured material, 2D randomly oriented triple laminated material and particulated + fibrous material in the cm, mm and lm scales, respectively. The outcome of the model is a set of mathematical expressions permitting to predict the stress–strain behavior of the material in two cases: wood strands parallel and perpendicularly oriented to the stress direction. Mechanistically, the model predicts failure by buckling at the mesoscale. A statistical experimental work is included and used to validate the model. Fil: Quiroga, A.. Universidad Tecnológica Nacional. Facultad Regional Santa Fe; Argentina Fil: Rintoul, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); Argentina

Platinum complexes, bearing aliphatic amines and phosphine ligands in trans configuration with iodide as leaving groups, are synthesized and characterized. The crystal structure of trans-PtI2(isopropylamine)(PPh3) is reported. The complex bearing isopropylamine is demonstrated to be the best candidate as its cytotoxic activity is comparable to or better than cisplatin. A remarkably higher interaction of the complexes with DNA is reported as compared to the parent chlorido series. Cell cycle studies of the complexes in six human cell lines are performed and also compared with the previous series, The Spanish Ministerio de Economia y Competitividad has supported this work with the grant: SAF2012-34424. This work was also supported by a School of the Sciences, Stevenson University Seed Grant

The r eactivity o f cis - diamminediiodidoplatinum(II), cis-PtI2(NH3)2, the iodo analogue of cisplatin, with hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry and X-ray crystallography. Interestingly, the study compound forms a stable 1:1 protein adduct for which the crystal structure was solved at 1.99 A resolution. In this adduct, the Pt II center, upon release of one ammonia ligand, selectively coordinates to the imidazole of His15. Both iodide ligands remain bound to platinum, with this being a highly peculiar and unexpected feature. Notably, two equivalent modes of Pt II binding are possible that differ only in the location of I atoms with respect to ND1 of His15. The structure of the adduct was compared with that of HEWL−cisplatin, previously described; differences are stressed and their important mechanistic implications discussed.

This article reviews the chemical and antitumoral properties of thiosemicarbazone complex-based drugs containing platinum(II) or palladium(II). Tetranuclear orthometallated complexes are the preferentially formed by most of the selected TSCNs. The core of these complexes consists of a flexible eight-member ring of alternating M–S atoms, causing in some cases, formation of two different geometric isomers. The different isomers display different cytotoxic activity, which was significant especially with platinum derivatives. Moreover, they display cytotoxic activity in tumor cell lines resistant to cis -DDP; the analysis of the interaction with DNA indicates interhelical cross-link formation. Binuclear complexes of thiosemicarbazones are chloro-bridged complexes where no orthometallation occurs, but their cytotoxic testing shows activity against resistant cell lines. Mononuclear complexes, which show an analogous structure to cisplatin, have shown promising “in vitro” antitumor properties. In addition, the interaction with DNA indicates that they have an enhanced capacity to form DNA interstrand cross-links, by comparison with cis -DDP. The final purpose is to evaluate the coordination chemistry of selected thiosemicarbazone complexes of palladium and platinum in order to provide guidance and determine structure and antitumor activity relationships for continuing studies of these systems.

Reaction of ZnCl2 with an excess of isopropylamine ligand in water gives [ZnCl2(isopropylamine)2]. This novel zinc complex has been characterized by elemental analysis and 1H-NMR. Interestingly, we have found that [ZnCl2(isopropylamine)2] markedly retards the decay in activity of catalase extracts. In fact, catalase extracts (0.075 mg of protein ml−1) may retain more than 80% of their initial enzymatic activity within the first 10 hours of incubation with 0.10 μM [ZnCl2(isopropylamine)2] while the activity of control extracts decreases to less than 50% of the initial value. Moreover, after 24 hours of treatment with [ZnCl2(isopropylamine)2] under the above-mentioned conditions, 70% of the initial enzymatic activity is still retained by catalase extracts while the activity of control untreated extracts drops to 17% of the initial value. On the other hand, our results show that after incubation of catalase extracts with [ZnCl2(isopropylamine)2] the supernatants obtained by centrifugation of the extracts contain a higher amount of active catalase than the supernatants of control untreated catalase extracts. Moreover, [ZnCl2(isopropylamine)2] induces precipitation of a large amount of contaminant proteins present in the catalase extracts. Altogether, these data indicate that treatment of catalase extracts with [ZnCl2(isopropylamine)2] both increases the pureness of catalase solutions and slows down the decay in catalase activity. We believe that [ZnCl2(isopropylamine)2] may be useful as a stabilizing agent for enzyme activity assays with crude catalase extracts.

A series of bis([(9-oxo-9,10-dihydroacridine-4-carbonyl)amino]alkyl) alkylamines have been prepared and their antiproliferative properties have been tested against HT-29 cell lines. Compounds 6b and 6d showed an interesting cytotoxic profile and were subjected to further cytotoxic evaluation, DNA binding properties and molecular modelling studies. The evaluation of the cytotoxic activity of compounds 6b and 6d against pairs of cisplatin-sensitive and -resistant ovarian tumour cells shows that both compounds may be endowed with interesting antitumour properties because they are able to circumvent cisplatin resistance in A2780cisR, CH1cisR and Pam 212-ras tumour cells. On the other hand, DNA binding data indicate that compounds 6b and 6d are able to intercalate stronger than acridine within the double helix. Both compounds displace ethidium bromide with an efficiency ten times higher than acridine from several linear double-stranded DNAs and induce 43 degrees unwinding in supercoiled pBR322 DNA while acridine unwinds pBR322 DNA by only 24 degrees. Altogether these data indicate that the significant conformational changes induced by compounds 6b and 6d in the double helix are due to a bis-intercalative DNA binding mode. We propose that binding to DNA through bisintercalation might be at least in part responsible for the remarkable cytotoxic properties of these acridine derivatives. The complex of 6b with d(GCGCGC)(2) in the four possible orientations that the ligand can adopt when binding to the DNA hexamer have been modelled and subjected to molecular dynamics simulations with the aim of evaluating the binding preferences of this bisintercalating agent into the DNA molecule. The predictions suggest that 6b binds to d(GCGCGC)(2) with a parallel orientation of the chromophores relative to each other and with a preference for binding through the minor groove of the hexamer. The possible relevance of these findings to the process of bisintercalation and the antitumour profile of these compounds is discussed in this paper.

The adducts formed between trans-(dimethylamino)(methylamino)dichloridoplatinum(II), [t-PtCl2(dma)(ma)], and two model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease, were independently characterized by X-ray crystallography and electrospray ionization mass spectrometry. In these adducts, the Pt(II) center, upon chloride release, coordinates either to histidine or aspartic acid residues while both alkylamino ligands remain bound to the metal. Comparison with the cisplatin derivatives of the same proteins highlights for [t-PtCl2(dma)(ma)] a kind of biomolecular metalation remarkably different from that of cisplatin.

Trans-[PtCl2(N,N-dimethylamine)(isopropylamine)] is a novel trans-platinum compound that shows cytotoxic activity in several cisplatin resistant cell lines. The aim of this paper was to analyse, by means of molecular cell biology techniques and total reflection X-ray fluorescence (TXRF), the cytotoxic activity, the induction of apoptosis, the cellular uptake and the DNA binding of trans-[PtCl2(N,N-dimethylamine)(isopropylamine)] in the cisplatin resistant cell line A2780cisR. The results show that this drug is more cytotoxic and induces a higher amount of apoptotic cells than cisplatin in A2780cisR cells. However, the intracellular accumulation and extent of binding to DNA of trans-[PtCl2(N,N-dimethylamine)( isopropylamine)] is lower than that of cis-DDP. Moreover, trans-[PtCl2(N,N-dimethylamine)(isopropylaminae)] is partially inactivated by intracellular levels of glulathione. The result suggest that circumvention of ciplatin resistance by trans-[PtCl2(N,N-dimethylamine)(isopropylamine)] in A2780cisR cells might be related with the ability of this drug to induce apoptosis.

Cytotoxicity tests in tumor cells sensitive to cis-DDP (HL-60, JURKAT, Hela and 3T3) and in tumor cells transformed by ras oncogenes and resistant to cis-DDP (Pam 212-ras) show that cyclometallated complexes 1a [Pd(p-is.TSCN-NHMe)]4, 2b [Pt(p-is.TSCN-NMe2)]4 and 4a [Pd(p-is.TSCN-NHex)]4 may be endowed with specific cytotoxic properties. In fact, these three novel metal-thiosemicarbazone compounds kill Pam 212-ras cells through apoptosis induction. These results, together with others recently published, indicate that the design and synthesis of metallated-thiosemicarbazone compounds may lead to the discovery of novel antitumor agents able to circumvent cis-DDP resistance, in particular tumor cell lines.

p-Isopropylbenzaldehyde thiosemicarbazone (p-is.TSCN) (1) reacts with [Pt(μ-Cl)(η 3 -C 4 H 7 )] 2 to form a dinuclear [Pt(μ-Cl)(p-is.TSCN)] 2 complex (2) and a cyclometallated cluster [Pt(p-is.TSCN)] 4 (3). Biological testing of these complexes against HL-60 and U-937 human leukemic cells suggest that complexes 2 and 3 may be endowed with important cytotoxic activity properties since they exhibit IC 50 values (50% inhibition of cell growth) in the micromolar range, as does the clinically used drug cisplatin (cis-DDP). Analysis of the interaction of compounds 2 and 3 with DNA indicates that the kinetics of DNA platination due to compounds 2 and 3 is faster than that of cisplatin and that after 24 h of incubation most of the platinum centers are bound to DNA. Thus, it is likely that the cytotoxic activity displayed by compounds 2 and 3 may be correlated with their high level of DNA platination.

In this communication, we present the synthesis of new platinum complexes based on hydroxyquinoline ligands. We demonstrate the importance and the role of the halogen substitution as well as the chelation, which are essential structural characteristics for finding good cytotoxicities.

The synthesis, characterization and cytotoxicity studies of two novel platinum(iv) complexes, trans-PtCl4(dma)(PPh3), 1, and trans-PtCl4(ipa)(PPh3), 2, where dma is dimethylamine and ipa is isopropylamine, have been carried out. Both complexes contain aliphatic amines trans to phosphane ligands as a good alternative to take advantage of the phosphane group lipophilicity and the stability of platinum(iv) to obtain more effective drugs. Moreover, the complexes are stable in solution and such stability allowed their antitumoral action and DNA interaction to be checked and proved. © 2013 The Royal Society of Chemistry.

The antitumoral potential for a series of platinum iodido complexes, all bearing the same aliphatic amines (first iodido complexes generation), was demonstrated in a previous study. Concretely, cis complexes were shown to have a peculiar and different reactivity compared to cisplatin with sulfur donors models and Cyt C. In this work we have synthesized and studied iodido complexes bearing different aliphatic amines in trans configuration (the second generation) to investigate their potential antitumor activity in a panel of cell lines. Their interaction with biological models such as pBR322 and smaller biomolecules (5′-GMP, 9EtG, N-AcMet and N-AcCys) have been studied and compared to cisplatin and to the first iodido series. Their cytotoxicity, on the other hand, turned out to be especially active towards cell lines where cisplatin has no effect. © 2013 Elsevier Inc., Authors would like to thank the Spanish Ministry of Science and Education, Spanish CICYT Grants: SAF-2009-09431 and SAF2012-34424.

We report the synthesis, characterization and cytotoxic assays of new trans-platinum compounds, trans-[PtCl2NH3(3-(hydroxymethyl)-pyridine)] and trans-[PtCl2NH3(4-(hydroxymethyl)-pyridine)]. In the present work, we found that the replacement of the ammine ligand in “classical” transplatinum with the two new ligands does not increase the cytotoxic activity, maybe because these complexes do not produce a stability of the intrastrand cross-links in DNA.

This focused review is devoted to our advances in developing trans platinum complexes as antitumoral complexes, in particular those bearing aliphatic amines. It includes some fundamental aspects of the understanding of non conventional metallodrug mechanism. The perspective is arranged by those fundamental aspects and within each section only the most successful examples have been included and also those in which clearly SAR's (structure activity relationships) have been observed.