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1.
Nat Commun ; 10(1): 4765, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628366

RESUMO

Spin-orbit coupling (SOC) has gained much attention for its rich physical phenomena and highly promising applications in spintronic devices. The Rashba-type SOC in systems with inversion symmetry breaking is particularly attractive for spintronics applications since it allows for flexible manipulation of spin current by external electric fields. Here, we report the discovery of a giant anisotropic Rashba-like spin splitting along three momentum directions (3D Rashba-like spin splitting) with a helical spin polarization around the M points in the Brillouin zone of trigonal layered PtBi2. Due to its inversion asymmetry and reduced symmetry at the M point, Rashba-type as well as Dresselhaus-type SOC cooperatively yield a 3D spin splitting with αR ≈ 4.36 eV Å in PtBi2. The experimental realization of 3D Rashba-like spin splitting not only has fundamental interests but also paves the way to the future exploration of a new class of material with unprecedented functionalities for spintronics applications.


Assuntos
Anisotropia , Bismuto/química , Eletrônica/métodos , Compostos de Platina/química , Platina/química , Algoritmos , Simulação por Computador , Cristalografia por Raios X , Eletricidade , Modelos Químicos , Modelos Moleculares , Nanoestruturas/química , Compostos de Platina/síntese química
2.
ACS Appl Mater Interfaces ; 11(35): 31832-31843, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31433151

RESUMO

Naturally available microclays are well-known materials with great adsorption capabilities that are available in nature in megatons quantities. On the contrary, artificial nanostructures are often available at high cost via precision manufacturing. Such precision nanomanufacturing is also typically used for fabrication of self-propelled micromotors and nanomachines. Herein, we utilized naturally available Cloisite microclays to fabricate autonomous self-propelled microrobots and demonstrated their excellent performances in pesticide removal due to their excellent adsorption capability. Six different modified Cloisite microrobots were investigated by sputtering their microclays with platinum (Pt) for the fabrication of platinum-Cloisite (Pt-C) microrobots. The obtained microrobots displayed fast velocities (v > 110 µm/s) with fast and efficient enhanced removal of the pesticide fenitrothion, which is also considered as improvised nerve agent. The fabricated Pt-C microrobots exhibited low cytotoxicity even at high concentrations when incubated with human lung carcinoma epithelial cells, which make them safe for human handling.


Assuntos
Argila/química , Fenitrotion/química , Inseticidas/química , Nanoestruturas/química , Agentes Neurotóxicos/química , Compostos de Platina/química , Robótica , Células A549 , Adsorção , Fenitrotion/toxicidade , Humanos , Inseticidas/toxicidade , Agentes Neurotóxicos/toxicidade
3.
Inorg Chem ; 58(14): 9067-9075, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31268715

RESUMO

The binuclear platinum(II) boron-dipyrromethene (BODIPY) complex [{Pt(dach)}2(µ-Dcrb)] (DP), where dach is 1,2-diaminocyclohexane and H4Dcrb is a morpholine-conjugated BODIPY-linked dicatechol bridging ligand, was prepared for lysosome organelle targeting and near-IR (NIR) light (600-720 nm) induced photocytotoxic activity. The platinum complex [Pt(dach)(cat)] (CP), where H2cat is catechol, was synthesized and used as a control complex without bearing the BODIPY unit. The complex DP displayed a band at 660 nm (ε = 2.1 × 104 M-1 cm-1) in the red region of the UV-visible spectrum recorded in 10% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (DMSO/DMEM, pH 7.2). The complex DP and the BODIPY ligand displayed emission in 10% DMSO-DMEM (pH 7.2) giving an λem value of 668 nm (λex = 650 nm) with a ΦF value of 0.02 for DP and 0.16 for H4Dcrb (ΦF, fluorescence quantum yield). Titration experiments using 1,3-diphenylisobenzofuran (DPBF) indicated that the complex DP and H4Dcrb on irradiation with near-IR light of 600-720 nm generated singlet oxygen (1O2) as the ROS (reactive oxygen species). The complex DP showed significant lysosomal localization and remarkable apoptotic photodynamic therapy (PDT) effects, giving half-maximal inhibitory concentration values (IC50) within 0.6-3.4 µM in HeLa cervical cancer, A549 lung cancer, and MDA-MB231 multidrug resistant cancer cells, while being essentially nontoxic in the dark and in the HPL1D immortalized lung epithelial normal cells. The acridine orange assay using A549 cells showed lysosomal membrane permeabilization by the complex DP under near-IR light (600-720 nm). This complex on near-IR light (600-720 nm) activation in A549 cells induced apoptotic cell death, as observed from an Annexin-V FITC assay.


Assuntos
Compostos de Boro/química , Lisossomos/química , Fotoquimioterapia , Compostos de Platina/química , Pirróis/química , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Potenciais da Membrana/efeitos dos fármacos , Estrutura Molecular , Compostos de Platina/farmacologia
4.
Inorg Chem ; 58(10): 6804-6810, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31046253

RESUMO

The substitution-inert polynuclear platinum complexes (SI-PPCs) are now recognized as a distinct subclass of platinum anticancer drugs with high DNA binding affinity. Here, we investigate the effects of SI-PPCs containing dangling amine groups in place of NH3 as ligands to increase the length of the molecule and therefore overall charge and its distribution. The results obtained with the aid of biophysical techniques, such as total intensity light scattering, gel electrophoresis, and atomic force microscopy, show that addition of dangling amine groups considerably augments the ability of SI-PPCs to condense/aggregate nucleic acids. Moreover, this enhanced capability of SI-PPCs correlates with their heightened efficiency to inhibit DNA-related enzymatic activities, such as those connected with DNA transcription, catalysis of DNA relaxation by DNA topoisomerase I, and DNA synthesis catalyzed by Taq DNA polymerase. Thus, the addition of the dangling amine groups resulting in structures of SI-PPCs, which differ so markedly from the derivatives of cisplatin used in the clinic, appears to contribute to the overall biological activity of these molecules.


Assuntos
Aminas/química , Complexos de Coordenação/química , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA/química , Compostos de Platina/química , RNA/química , Taq Polimerase/antagonistas & inibidores , Antineoplásicos/química , Microscopia de Força Atômica , Inibidores da Topoisomerase I
5.
Eur J Med Chem ; 167: 377-387, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30784875

RESUMO

The great interest in epithelial-to-mesenchymal transition (EMT) programme lies in its association with process of metastasis and invasion, which is a crucial cause of cancer-related death. Herein, we designed and reported three new NSAID-Pt(IV) prodrugs, taking Non-Steroid Anti-Inflammatory Drugs (NSAIDs) to disrupt EMT programme and assist genotoxic platinum-based drugs as a cytotoxicity booster, to offer a class of potential anticarcinogens with a multi-functional action mechanism. The NSAID-Pt(IV) prodrugs, especially Eto-Pt(IV), highly enhanced cellular uptake with amount up to 42-fold at 3 h compared with CDDP, and greatly increased DNA damage and cell apoptosis, showing much higher cytotoxicity than cisplatin in the tested cancer cells even in A549/cis cells. Among of them, Eto-Pt(IV) and Car-Pt(IV) exhibited more excellent activity than Sul-Pt(IV), arising from their reduction-labile and favorable lipophilicity. Most strikingly, Eto-Pt(IV) markedly inhibited metastasis and invasion of MCF-7 cells, owing to its COX-2 suppression that down-regulated active MMP-2, vimentin protein and up-regulated E-cadherin. In vivo, Eto-Pt(IV) displayed potent antitumor activity and no observable toxicity in BALB/c nude mice bearing MCF-7 tumors.


Assuntos
Anti-Inflamatórios não Esteroides/química , Antineoplásicos/química , Desenho de Fármacos , Compostos de Platina/química , Pró-Fármacos/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/farmacologia
6.
Cancer Chemother Pharmacol ; 83(4): 681-692, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30661096

RESUMO

Platinum-based drugs, mainly cisplatin, are used for the treatment of several solid tumors such as OS. However, cisplatin treatment often results in the development of chemoresistance, leading therapeutic failure. We have previously reported that platinum complexes containing 8-hydroxyquinoline ligands have good antitumor activity against different cancer cell lines and with a different and better cytotoxic profile than cisplatin. Here, the anticancer properties of two different quinoline-platinum complexes [Pt(Cl)2(quinoline)(dmso)] (1) [PtCl(8-O-quinoline)(dmso)] (2) on in vitro (2D and 3D) and in vivo models (xenograft tumor of human osteosarcoma in mice) are presented. In this order, [PtCl(8-O-quinoline)(dmso)] (2) impaired cell viability to have a more pronounced antitumor effect than cisplatin on MG-63 osteosarcoma cells (IC50 4 µM vs. 39 µM). Besides, [PtCl(8-O-quinoline)(dmso)] (2) increased ROS production in a dose-manner response and this compound induced early and late apoptotic fractions of human osteosarcoma cells. Finally, [PtCl(8-O-quinoline)(dmso)] (2) decreased the cell viability of multicellular spheroids and reduced the tumor volume on athymic nude mice N:NIH(S) Fox1nu without inducing side effects. In this way, [PtCl(8-O-quinoline)(dmso)] (2) did not alter the normal cytoarchitecture of liver and kidney and the blood biomarkers (GPT, GOT, uremia, and creatinine) did not suffer modifications. Taken together, our data indicate that these compounds showed a better anticancer performance than cisplatin on in vitro and in vivo studies. These results showed the importance of chelation in the antitumor properties, suggesting that the [PtCl(8-O-quinoline)(dmso)] (2) might be a promising agent for the treatment of human osteosarcoma tumors resistant to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Compostos de Platina/farmacologia , Quinolinas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias Ósseas/patologia , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Nus , Osteossarcoma/patologia , Compostos de Platina/administração & dosagem , Compostos de Platina/química , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Phys Chem Chem Phys ; 21(8): 4162-4175, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30656331

RESUMO

Complementary structural and dynamical information on drug-DNA interplay has been achieved at a molecular level, for Pt/Pd-drugs, allowing a better understanding of their pharmacodynamic profile which is crucial for the development of improved chemotherapeutic agents. The interaction of two cisplatin-like dinuclear Pt(ii) and Pd(ii) complexes with DNA was studied through a multidisciplinary experimental approach, using quasi-elastic neutron scattering (QENS) techniques coupled with synchrotron-based extended X-ray absorption fine structure (SR-EXAFS) and Fourier-Transform Infrared Spectroscopy-Attenuated Total Reflectance (SR-FTIR-ATR). DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231) was used, with a view to evaluate the effect of the unconventional antineoplastic agents on this low prognosis type of cancer. The drug impact on DNA's dynamical profile, via its hydration layer, was provided by QENS, a drug-triggered enhanced mobility having been revealed. Additionally, an onset of anharmonicity was detected for dehydrated DNA, at room temperature. Far- and mid-infrared measurements allowed the first simultaneous detection of the drugs and their primary pharmacological target, as well as the drug-prompted changes in DNA's conformation that mediate cytotoxicity. The local environment of the absorbing Pd(ii) and Pt(ii) centers in the drugs' adducts with adenine, guanine and glutathione was attained by EXAFS.


Assuntos
Antineoplásicos/química , DNA/química , Paládio/química , Compostos de Platina/química , Adenina/química , Linhagem Celular Tumoral , Glutationa/química , Guanina/química , Humanos , Nêutrons , Conformação de Ácido Nucleico , Espectroscopia de Infravermelho com Transformada de Fourier , Síncrotrons , Espectroscopia por Absorção de Raios X
8.
J Inorg Biochem ; 191: 112-118, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30496946

RESUMO

Novel bisphosphonate platinum complexes: [Pt(isopropylamine)2(BP)]NO3 (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.


Assuntos
Difosfonatos/química , Compostos de Platina/química , Animais , Bovinos , Linhagem Celular Tumoral , Cristalografia por Raios X , DNA/efeitos dos fármacos , Difosfonatos/farmacologia , Humanos , Compostos de Platina/farmacologia
9.
Biomater Sci ; 6(12): 3345-3355, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30357140

RESUMO

Conventional chemotherapy has been impeded by the inherent characteristics of cancer including fast mutagenesis and drug resistance; thus a combination therapy consisting of multiple therapeutic strategies has attracted much attention. However, the loading processes of multiple therapeutic molecules affect each other; thus the development of a nanocarrier that enables independent loading of the cargo molecules has been demanded. Herein, we report an ingeniously designed Pt(iv)-mediated polymeric architecture (Pt-PA) for combinatorial gene and chemotherapy to address the issue, prepared by crosslinking a cationic polymer (polyethylenimine, PEI) with a Pt(iv) prodrug. Therapeutic siRNA (anti-BCL2) was simply loaded by electrostatic interaction to form a stable nanocomplex. In the cellular study, the simultaneous release of both the active Pt(ii) drug and siRNA was monitored under the intracellular reducing environment, driven by dissociation of the polymer architecture due to an inherent characteristic of the Pt(iv) crosslinker. Therefore, an enhanced gene silencing effect and an anticancer effect were observed. Furthermore, in the animal study, an improved therapeutic effect of the nanocomplex was observed, which can be explained by tumor targeting via the EPR effect, and enhanced drug and siRNA release at the intracellular environment simultaneously. Taken together, the overall results from in vitro and in vivo studies strongly suggest the therapeutic potential of our precisely designed Pt(iv)-mediated polymer architecture.


Assuntos
Antineoplásicos/química , Inativação Gênica , Nanopartículas/química , Compostos de Platina/química , Terapêutica com RNAi/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/uso terapêutico , Neoplasias Experimentais/terapia , Compostos de Platina/administração & dosagem , Compostos de Platina/uso terapêutico , Polietilenoimina/química , Pró-Fármacos/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Eletricidade Estática
10.
Artigo em Inglês | MEDLINE | ID: mdl-30230996

RESUMO

Square planar mononuclear platinum(II) complexes having general formula [Pt(Ln)Cl2], (where, Ln = L1-4) were synthesized with neutral bidentate heterocyclic 1,3,5-trisubstituted bipyrazole based ligands. The synthesized compounds were characterized by physicochemical method such as TGA, molar conductance, micro-elemental analysis and magnetic moment, and spectroscopic method such as, FT-IR, UV-vis, 1H NMR, 13C NMR and mass spectrometry. Biological applications of the compounds were carried out using in vitro brine shrimp lethality bioassay, in vitro antimicrobial study against five different pathogens, and cellular level cytotoxicity against Schizosaccharomyces pombe (S. Pombe) cells. Pt(II) complexes were tested for DNA interaction activities using electronic absorption titration, viscosity measurements study, fluorescence quenching technique and molecular docking assay. Binding constants (Kb) of ligands and complexes were observed in the range of 0.23-1.07 × 105 M-1 and 0.51-3.13 × 105 M-1, respectively. Pt(II) complexes (I-IV) display an excellent binding tendency to biomolecule (DNA) and possess comparatively high binding constant (Kb) values than the ligands. The DNA binding study indicate partial intercalative mode of binding in complex-DNA. The gel electrophoresis activity was carried out to examine DNA nuclease property of pUC19 plasmid DNA.


Assuntos
Antibacterianos/farmacologia , DNA/metabolismo , Compostos de Platina/química , Compostos de Platina/farmacologia , Animais , Antibacterianos/química , Artemia/efeitos dos fármacos , Técnicas de Química Sintética , Citotoxinas/química , Citotoxinas/farmacologia , Desoxirribonucleases/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Eletroforese/métodos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Compostos de Platina/síntese química , Schizosaccharomyces/efeitos dos fármacos , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria
11.
Inorg Chem ; 57(20): 12641-12649, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30260643

RESUMO

Deficiencies in DNA mismatch repair (MMR) machinery result in greater incidence of DNA base pair mismatches in many types of cancer cells relative to normal cells. Consequently, luminescent probes capable of signaling the presence of mismatched DNA hold promise as potential cancer diagnostic and therapeutic tools. In this study, a series of cyclometalated platinum(II) complexes with sterically expansive tetraarylethylene ligands were synthesized and examined for selective detection of mismatched DNA. Increased steric bulk of the tetraarylethylene ligands in these complexes was observed to correlate with greater preferential luminescence enhancement in the presence of hairpin DNA oligonucleotides containing a mismatched site compared to well-matched oligonucleotides, with the most effective complex displaying ∼14-fold higher emission upon binding CC mismatched oligonucleotides compared to well-matched oligonucleotides. The results indicate binding to mismatched sites in DNA oligonucleotides occurs through metalloinsertion, and the luminescence response increases as a function of thermodynamic destabilization of the mismatch. Luminescence quenching experiments with Cu(phen)22+ and NaI further indicate mismatch binding from the minor groove, consistent with metalloinsertion. Binding to CC mismatched oligonucleotides was also investigated by isothermal titration calorimetry and UV-melting studies. These results demonstrate the efficacy of tetraarylethylene-based platinum(II) complexes for detection of mismatched DNA and establish a new molecular platform for development of organometallic DNA binding agents.


Assuntos
Dano ao DNA , Etilenos/química , Compostos de Platina/química , Reparo de Erro de Pareamento de DNA , Ligantes , Modelos Moleculares , Estrutura Molecular
12.
Metallomics ; 10(7): 1003-1015, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29978878

RESUMO

The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4]-, [AuCl2(dmso)2]+, [AuCl2(bipy)]+) and Pt(ii) ([PtCl2(dmso)2]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized. By using the solvent accessible surface area (SASA) applied on specific inhibitory sites (ion channel and intracellular domains) the nature of these sites was described. Docking studies were used to determine the theoretical probability of the non-covalent metal binding site positions. Inhibition studies implied that all the investigated complexes decreased the activity of the enzyme while the kinetic analysis indicated an uncompetitive mode of inhibition for the selected complexes. Docking results suggested that the main inhibitory site of all these complexes is located in the ion translocation pathway on the extracellular side in the E2P enzyme conformation, similar to the case of cardiac glycosides, specific Na/K-ATPase inhibitors. Also, based on our knowledge, the hydrolyzed forms of [AuCl4]- and [PtCl2(dmso)2] complexes were investigated for the first time by theoretical calculations in this paper. Thereby, a new inhibitory site situated between the M2 and M4 helices was revealed. Binding in this site induces conformational changes in the enzyme domains and perturbs the E1-E2P conformational equilibrium, causing enzyme inhibition.


Assuntos
Complexos de Coordenação/metabolismo , Compostos de Ouro/metabolismo , Modelos Teóricos , Compostos de Platina/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Sítios de Ligação , Complexos de Coordenação/química , Compostos de Ouro/química , Humanos , Cinética , Modelos Moleculares , Simulação de Acoplamento Molecular , Compostos de Platina/química , Conformação Proteica , ATPase Trocadora de Sódio-Potássio/química
13.
J Inorg Biochem ; 185: 10-16, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29730232

RESUMO

We synthesized and validated five Schiff base Pt(II) complexes derived from 2-hydroxy-1-naphthaldehyde benzoyl hydrazone and its derivatives, which are modified at the benzohydrazide structures (L1-L5). The complexes were [Pt(L1)(DMSO)Cl] (C1), [Pt(L2)(DMSO)Cl] (C2), [Pt(L3)(DMSO)Cl] (C3), [Pt(L4)(DMSO)Cl] (C4), and [Pt(L5)(DMSO)Cl] (C5). Crystal structures showed that the Pt centers of all complexes were tetra-coordinated with other atoms. The structure-activity relationships and anticancer mechanisms of the complexes were explored. These five Pt(II) complexes were toxic at micromolar doses and exhibited cytotoxicity similar to or somewhat higher than that of cisplatin, with IC50 values ranging from 4.38 µM to 25.16 µM. The complexes exerted chemotherapeutic effects via inhibition of telomerase by targeting the c-myc promoter and down-regulating the expression of human telomerase reverse transcriptase, consequently triggering cell apoptosis. In addition, Pt(II) complexes also caused cell cycle arrest at S-phase, leading to the down-regulation of cdc25 A, cyclin A2, and CDK2 and up-regulation of p53, p27, and p21 proteins. Other complex-associated events were reactive oxygen species production, transformation of the mitochondrial membrane potential (Δψm), release of cytochrome c, regulation of Bcl-2 family protein expression, facilitated release of apoptotic active substances, and activation of caspases to induce apoptosis.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Compostos de Platina/química , Compostos de Platina/farmacologia , Neoplasias Gástricas/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Bases de Schiff/química , Espectrofotometria Infravermelho , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Relação Estrutura-Atividade , Telomerase/metabolismo
14.
Inorg Chem ; 57(9): 5575-5584, 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29688719

RESUMO

Thioredoxin (Trx) is an important enzyme in the redox signaling pathway and is usually overexpressed in tumor cells. We demonstrate herein that the photoactive platinum(IV) anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(Py)2] (1) can bind to His, Glu, and Gln residues of Trx upon the irradiation of blue light. More importantly, complex 1 can also induce the oxidation of Met, Trp, and the Cys catalytic sites to form disulfide bonds by generating reactive oxygen species (ROS) upon photoactivation. These eventually lead to inhibition of activity of Trx enzyme and the Trx system and further increase in the cellular ROS level. We speculate that the oxidative damage not only inhibits Trx activity but also greatly contributes to the anticancer action of complex 1.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos de Platina/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxinas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Oxirredução/efeitos dos fármacos , Compostos de Platina/síntese química , Compostos de Platina/química , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/metabolismo
15.
Dalton Trans ; 47(14): 4902-4908, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29546259

RESUMO

The [Cu(L)Cl2]2 and [Pt(L)Cl2] complexes were prepared from the simple Schiff-base ligand (E)-phenyl-N-((pyridin-2-yl)methylene)methanamine (L) and respectively, CuCl2 and cis-[PtCl2(DMSO)2]. DNA-interaction studies revealed that the copper complex most likely acts as a DNA cleaver whereas the platinum complex binds to the double helix. Remarkably, cell-viability experiments with HeLa, MCF7 and PC3 cells showed that [Cu(L)Cl2]2 is an efficient cytotoxic agent whereas [Pt(L)Cl2] is not toxic, illustrating the crucial role played by the nature of the metal ion in the corresponding biological activity.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Compostos de Platina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/metabolismo , Células HeLa , Humanos , Concentração Inibidora 50 , Ligantes , Células MCF-7 , Estrutura Molecular , Plasmídeos/metabolismo , Bases de Schiff/química
16.
PLoS One ; 13(3): e0193668, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29509784

RESUMO

We report microsecond timescale molecular dynamics simulation of the complex formed between Pt(II)-phenanthroline and the 16 N-terminal residues of the Aß peptide that is implicated in the onset of Alzheimer's disease, along with equivalent simulations of the metal-free peptide. Simulations from a variety of starting points reach equilibrium within 100 ns, as judged by root mean square deviation and radius of gyration. Platinum-bound peptides deviate rather more from starting points, and adopt structures with larger radius of gyration, than their metal-free counterparts. Residues bound directly to Pt show smaller fluctuation, but others actually move more in the Pt-bound peptide. Hydrogen bonding within the peptide is disrupted by binding of Pt, whereas the presence of salt-bridges are enhanced.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Simulação de Dinâmica Molecular , Fenantrolinas/química , Compostos de Platina/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Humanos , Ligação de Hidrogênio , Platina/química , Ligação Proteica
17.
Met Ions Life Sci ; 182018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29394021

RESUMO

Polynuclear platinum complexes (PPCs) represent a discrete structural class of DNA-binding agents with excellent antitumor properties. The use of at least two platinum coordinating units automatically means that multifunctional DNA binding modes are possible. The structural variability inherent in a polynuclear platinum structure can be harnessed to produce discrete modes of DNA binding, with conformational changes distinct from and indeed inaccessible to, the mononuclear agents such as cisplatin. Since our original contributions in this field a wide variety of dinuclear complexes especially have been prepared, their DNA binding studied, and potential relevance to cytotoxicity examined. This chapter focuses on how DNA structure and reactivity is modulated through interactions with PPCs with emphasis on novel aspects of such structure and reactivity. How these major changes are further reflected in damaged DNA-protein binding and cellular effects are reviewed. We further review, for the first time, the great structural diversity achieved in PPC complex design and summarize their major DNA binding effects.


Assuntos
Antineoplásicos/uso terapêutico , DNA de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Compostos de Platina/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Complexos de Coordenação , DNA de Neoplasias/química , DNA de Neoplasias/genética , Quadruplex G , Humanos , Modelos Moleculares , Estrutura Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Compostos de Platina/química , Compostos de Platina/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
18.
Met Ions Life Sci ; 182018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29394023

RESUMO

Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation. HS is identified as a ligand receptor for polynuclear platinum complexes (PPCs) defining a new mechanism of cellular accumulation for platinum drugs with implications for tumor selectivity. The covalent and noncovalent interaction of PPCs with GAGs and the functional consequences of strong binding with HS are explained in detail. Sulfate cluster anchoring shields the sulfates from recognition by charged protein residues preventing the exercise of the HS-enzyme/protein function, such as growth factor recognition and the activity of heparanase on HS. The cellular consequences are inhibition of invasion and angiogenesis. Metalloglycomics is a potentially rich new area of endeavor for bioinorganic chemists to study the relevance of intrinsic metal ions in heparin/ HS-protein interactions and for development of new compounds for therapeutic, analytical, and imaging applications.


Assuntos
Antineoplásicos/química , Glicômica/métodos , Proteoglicanas de Heparan Sulfato/química , Heparina/química , Compostos Organometálicos/química , Compostos de Platina/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Sítios de Ligação , Configuração de Carboidratos , Complexos de Coordenação , Proteoglicanas de Heparan Sulfato/metabolismo , Heparina/metabolismo , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organometálicos/metabolismo , Compostos Organometálicos/uso terapêutico , Compostos de Platina/metabolismo , Compostos de Platina/uso terapêutico , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
19.
Int J Food Microbiol ; 269: 64-74, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29421360

RESUMO

Human noroviruses (NoV) are major agents of foodborne outbreaks. Because of the lack of a standardized cell culture method, real-time reverse transcriptase PCR is now commonly used for the detection of NoV in foodstuffs and environmental samples. However, this approach detects the viral nucleic acids of both infectious and non-infectious viruses and needs to be optimized to predict infectivity for public health risk assessment. The aim of this study was to develop a viability PCR method to discriminate between native and heat-treated virus, for both NoV and its surrogate, murine norovirus (MNV). To this end, screening of viability markers (monoazide dyes, platinum and palladium compounds) was performed on viral RNA, native virus or heat-treated virus, and incubation conditions were optimized with PtCl4, the most efficient viability marker. Multiple MNV molecular models were designed: no impact of amplicon length was observed on inactivated MNV genomic titer; but the 5'NTR, ORF1 and 3'UTR regions resulted in higher reductions than central genomic regions. The optimal viability PCR conditions developed (incubation with 2.5 mM PtCl4 in PBS for 10 min at 5 °C) were finally applied to MNV by performing heat inactivation studies and to native and heat-treated NoV clinical strains. The viability PCR discriminated efficiently between native and heat-inactivated MNV at 72 °C and 80 °C, and efficiently reduced the genomic titer of heat-treated NoV strains. This viability PCR method could be useful to study heat inactivation kinetics of NoV and MNV. It could also be evaluated for the identification of infectious enteric viruses in foodstuffs and environmental samples.


Assuntos
Contaminação de Alimentos/análise , Norovirus/isolamento & purificação , Compostos de Platina/química , RNA Viral/química , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Animais , Infecções por Caliciviridae/prevenção & controle , Infecções por Caliciviridae/virologia , Microbiologia de Alimentos/métodos , Gastroenterite/prevenção & controle , Gastroenterite/virologia , Temperatura Alta , Humanos , Camundongos , Norovirus/classificação , Norovirus/genética , RNA Viral/genética , Inativação de Vírus
20.
Curr Med Chem ; 25(4): 437-461, 2018 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-28554319

RESUMO

BACKGROUND: The inherent problems accompanying chemotherapy necessitate the development of new anticancer approaches. The development of compounds that can disrupt cancerous cellular machinery by novel mechanisms, via interactions with proteins and non-canonical DNA structures (e.g. G-quadruplexes), as well as by alteration of the intracellular redox balance, is nowadays focus of intense research. In this context, organometallic compounds of the noble metals Pt and Au have become prominent experimental therapeutic agents. This review provides an overview of the Pt(II) and Au(III) cyclometalated compounds with a chelating ring containing a strong C-M σ -bond to improve the stability of the compounds with respect to ligand exchange reactions and biological reduction. Furthermore, these properties can be easily tuned by modification of either the anionic cyclometalated or the ancillary ligands. Special focus has been set to C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological mechanisms of action as anticancer agents. METHODS: A structured search of both chemical and medicinal databases for peerreviewed research literature has been conducted. The quality of retrieved papers was appraised using standard tools. The synthesis as well as the chemical and biological properties of the described compounds were carefully reviewed and described. The findings were outlined using a conceptual framework. RESULTS: In this review we included 155 papers, the majority originating from high-impact papers on the synthesis and biological modes of platinum(II) and gold(III) compounds. Among them, 17 papers were highlighted to give an introduction to the use of Pt and Au compounds with medicinal properties, mainly focussing on coordination compounds. The synthesis and medicinal properties of organometallic compounds of various metals (such as Fe, Ru, Ti) were outlined in 51 papers. These compounds included metallocenes, metallo- arenes, metallo-carbonyls, metallo-carbenes (e.g. N-heterocyclic carbenes), and alkynyl complexes. The C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum( II) (46 papers) and gold(III) (44 papers) were discussed concerning their synthesis, stability and advantages to develop therapeutic compounds. We strove to show the consistent development of C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological modes from the early beginnings to the most recent findings. CONCLUSION: This review supplies a profound overview of the development of organometallic compounds for medicinal purposes, setting special focus to the synthesis and stability of C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum(II) and gold(III) and their use as anticancer agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Ouro/química , Compostos de Ouro/farmacologia , Compostos de Platina/química , Compostos de Platina/farmacologia , Animais , Humanos , Estrutura Molecular
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