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1.
Inorg Chem ; 58(17): 11294-11299, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31411862

RESUMO

The first two examples of polyoxopalladates(II) (POPs) containing tetravalent metal ion guests, [MO8Pd12(PO4)8]12- (M = SnIV, PbIV), have been prepared and structurally characterized in the solid state, solution, and gas phase. The interactions of the metal ion guests and the palladium-oxo shell were studied by theoretical calculations. The POPs were shown to possess anticancer activity by causing oxidative stress inducing caspase activation and consecutive apoptosis of leukemic cells.


Assuntos
Antineoplásicos/farmacologia , Metais Pesados/química , Compostos Organometálicos/farmacologia , Polímeros/química , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Íons/química , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química
2.
Photochem Photobiol Sci ; 18(8): 2012-2022, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31282525

RESUMO

Organic-metal complexes are promising molecules for use in photodynamic therapy (PDT). The aim of this study was to investigate in vitro effects of novel Ru(ii) and Ir(iii) BODIPY complexes for PDT. These hybrid organic-metal molecules (Ru-BD and Ir-BD) have been synthesized via reactions of a BODIPY precursor (BD) with a phenanthroline unit bearing Ru(ii) (3) and novel Ir(iii) (4) compounds. The crystal structures of the new distyryl BODIPY (BD) and Ru(ii) complex (3) are also reported. The photophysical and singlet oxygen generation properties of Ru-BD and Ir-BD were investigated in comparison with unsubstituted BODIPY (BD). Moreover, Ru-BD and Ir-BD have been biologically evaluated in vitro in chronic myeloid leukemia and cervical cancer cell lines in terms of photodynamic therapy efficacy in the presence of BD control. These complexes were not toxic in the dark but red light was needed to induce cell death. These data support the fact that Ru-BD could be accepted as a valuable photosensitizer-drug for further PDT treatment.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Corantes/farmacologia , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Irídio/farmacologia , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Rutênio/química , Rutênio/farmacologia , Oxigênio Singlete/análise , Oxigênio Singlete/metabolismo , Células Tumorais Cultivadas
3.
Eur J Med Chem ; 179: 246-256, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255925

RESUMO

Ruthenium complexes have attracted a surge of interest as anticancer drug candidates because of their low toxicity, diversity in mode-of-actions and non-cross drug resistance with conventional platinum-based agents. Despite remarkable advances, only a limited number of ruthenium complexes have been demonstrated to kill cancer cells and suppress metastasis simultaneously. Here, two organometallic tetranuclear Ru(II) arene complexes (Ru-1 and Ru-2) have been synthesized and evaluated for their in vitro activity against a panel of human cancer cell lines, including a cisplatin-resistant human lung cancer A549 cell line. A superior cytotoxic activity of the ruthenium complexes compared to cisplatin across distinct cell lines was observed. Further examination of the mechanism indicated that anticancer activity was accomplished by inducing apoptosis in cancer cells. In addition, we found that such compounds exhibited promising antimetastatic activity and reduced the invasiveness of cancer cells. Importantly, choosing Ru-1 as a target compound, a significantly enhanced safety profile relative to cisplatin in animals was validated, suggesting that these complexes can be used as promising candidates for cancer therapy and deserve further investigation.


Assuntos
Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Células RAW 264.7 , Rutênio/química , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
4.
Eur J Med Chem ; 179: 26-37, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233920

RESUMO

PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC50 > 100 µM) to HepG2 cells, but the value decreased by 387-fold to 0.36 µM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.


Assuntos
Antineoplásicos/farmacologia , Guanidina/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Imagem Óptica , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanidina/química , Células Hep G2 , Humanos , Irídio/química , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Mitocôndrias/patologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade
5.
Molecules ; 24(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052604

RESUMO

Salen ligands are a class of Schiff bases simply obtained through condensation of two molecules of a hydroxyl-substituted aryl aldehyde with an achiral or chiral diamine. The prototype salen, or N,N'-bis(salicylidene)ethylenediamine has a long history, as it was first reported in 1889, and immediately, some of its metal complexes were also described. Now, the salen ligands are a class of N,N,O,O tetradentate Schiff bases capable of coordinating many metal ions. The geometry and the stereogenic group inserted in the diamine backbone or aryl aldehyde backbone have been utilized in the past to efficiently transmit chiral information in a variety of different reactions. In this review we will summarize the important and recent achievements obtained in stereocontrolled reactions in which Al(salen) metal complexes are employed. Several other reviews devoted to the general applications and synthesis of chromium and other metal salens have already been published.


Assuntos
Etilenodiaminas/química , Compostos Organometálicos/química , Catálise , Técnicas de Química Sintética , Reação de Cicloadição , Etilenodiaminas/síntese química , Estrutura Molecular , Compostos Organometálicos/síntese química , Polimerização , Estereoisomerismo , Uridina Difosfato N-Acetilglicosamina/análogos & derivados
6.
Chem Commun (Camb) ; 55(32): 4695-4698, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30942201

RESUMO

This report demonstrates that changing the position of the carbon-metal bond in a polypyridyl cyclopalladated complex, i.e. going from PdL1 (N^N^C^N) to PdL2 (N^N^N^C), dramatically influences the photodynamic properties of the complex in cancer cells. This effect is primarily attributed to the significantly difference in absorbance and singlet oxygen quantum yields between the two isomers.


Assuntos
Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Paládio/química , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Teoria da Densidade Funcional , Humanos , Isomerismo , Luz , Modelos Químicos , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
7.
Eur J Med Chem ; 171: 364-371, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928708

RESUMO

The present work describes the synthesis and spectroscopic characterization of ten different metal complexes of sulfabenzamide and sulfamethoxazole as ligands (M-SBZ, M-SMZ). Spectroscopic methods such as 1H NMR, UV-Vis spectroscopy analysis, FTIR and XRD confirmed the coordination of both ligands to metals through the nitrogen and oxygen atoms of the sulfonamide group. Both sulfabenzamide and sulfamethoxazole metal complexes were active against Gram-positive and negative bacterial strains. Sulfamethoxazole complexes showed their MIC values from 0.125 to 2.000 g ml-1 and sulfabenzamide complexes exhibited related MIC values from 1.000 to 2.000 g ml-1. Finally Zn (II) sulfamethoxazole with an inexpensive and common metal displayed more activity than its free ligand drug.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Sulfametoxazol/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfametoxazol/química , Sulfonamidas/química , Sulfonamidas/farmacologia
8.
Nat Chem ; 11(6): 571-577, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30988418

RESUMO

One of the core barriers to developing C-H activation reactions is the ability to distinguish between multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp2)-H bonds have been selectively activated in the presence of proximate ones. Yet achieving such unconventional site selectivity with C(sp3)-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid-derived directing group and a 2-pyridone ligand that enables the preferential activation of the distal γ-C(sp3)-H bond over the proximate ß-C(sp3)-H bonds for a wide range of alcohol-derived substrates. A competition experiment between the five- and six-membered cyclopalladation step, as well as kinetic experiments, demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp3)-H activation.


Assuntos
Álcoois/química , Carbono/química , Técnicas de Química Sintética/métodos , Hidrogênio/química , Álcoois/síntese química , Derivados de Benzeno/síntese química , Ciclização , Estrutura Molecular , Compostos Organometálicos/síntese química , Paládio/química , Piridonas/química , Piruvatos/química
9.
Dalton Trans ; 48(12): 3990-3997, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30839995

RESUMO

Abnormal levels of biological viscosity are closely associated with some diseases and malfunction (e.g. cancer, diabetes). Sensitive viscosity probes are of significant importance in disease diagnosis and remain an unmet need. In this research, we present a novel viscosity-sensitive dinuclear Ir(iii) complex (1), which freely rotates and shows weak phosphorescence in a low-viscosity environment, while in viscous media, both the phosphorescence intensity and lifetime are enhanced significantly. 1 can further be applied for phosphorescence lifetime imaging (PLIM) and measure lysosomal microviscosity with high accuracy and reliability. Interestingly, this PLIM property can distinguish between tumorous and nontumorous cells. Importantly, the probe shows much stronger phosphorescence in the fresh blood of diabetic mice than that of normal mice. This work offers a potential efficient probe for diagnosing viscosity related diseases.


Assuntos
Viscosidade Sanguínea , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Irídio/análise , Irídio/química , Medições Luminescentes , Lisossomos/química , Células A549 , Animais , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Imagem Óptica , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Temperatura Ambiente , Viscosidade
10.
Photochem Photobiol Sci ; 18(5): 1218-1227, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30839974

RESUMO

Zinc bacteriochlorophyll-d analogs possessing a methylene group at the 132-position were prepared by chemical modification of naturally occurring chlorophyll-a. The synthetic 31-epimers were successfully separated by reverse phase HPLC to give diastereomerically pure samples. The stereochemistry of the chiral C31-center in the separated bacteriochlorophyll-d analogs was determined by HPLC analysis of the authentic stereoisomers prepared stereospecifically. Both the epimers were monomeric in tetrahydrofuran to give sharp absorption bands, while they self-aggregated to form chlorosomal oligomers with red-shifted bands in an aqueous Triton X-100 micelle solution. The resulting large oligomers deaggregated by addition of Triton X-100 to give monomeric species. Their aggregation and deaggregation were dependent on the 31-stereochemistry, indicating that each epimer produced self-aggregates that were supramolecularly different. The substitution with the 132-methylene group enhanced their self-aggregation abilities and the stability of their resulting self-aggregates.


Assuntos
Proteínas de Bactérias/química , Bacterioclorofilas/química , Compostos Organometálicos/síntese química , Zinco/química , Dicroísmo Circular , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/química , Espectrofotometria Ultravioleta , Estereoisomerismo
11.
Eur J Med Chem ; 168: 123-133, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30818174

RESUMO

The 1:1 stoichiometric reactions of 3-methoxy salicylaldehyde-4(N)-substituted thiosemicarbazones (H2L1-4) with [RuCpCl(PPh3)2] was carried out in methanol. The obtained complexes (1-4) were characterized by analytical, IR, absorption and 1H NMR spectroscopic studies. The structures of ligand [H2-3MSal-etsc] (H2L3) and complex [RuCp(Msal-etsc) (PPh3)] (3), were characterized by single crystal X-ray diffraction studies. The interaction of the ruthenium(II) complexes (1-4) with calfthymus DNA (CT-DNA) has been explored by absorption and emission titration methods. Based on the observations, an intercalative binding mode of DNA has been proposed. The protein binding abilities of the new complexes were monitored by quenching the tryptophan and tyrosine residues of BSA, as model protein. From the studies, it was found that the new ruthenium metallacycles exhibited better affinity than their precursors. The free radical scavenging assay suggests that all complexes effectively scavenged the DPPH radicals as compared to that of standard control ascorbic acid and scavenging activities of complexes are in the order of 4 > 2 > 3 > 1. In addition, ruthenium(II) complexes (2-4) also exhibited an excellent in vivo antioxidant activity as it was able to increase the survival of worms exposed to lethal oxidative and thermal stresses possibly through reducing the intracellular ROS levels. It was interesting to note that complexes 2-4 failed to increase the lifespan of mev-1 mutant worms having shortened lifespan due to the over production of free radicals. This data confirmed that complexes 2-4 conferred stress resistance in C. elegans, but they also require an endogenous detoxification mechanism for doing so. The genetic and reporter gene expression analysis revealed that complexes 2-4 maintained the intracellular redox status and offered stress protection through transactivation of antioxidant defence machinery genes gst-4 and sod-3 which are directly regulated by SKN-1 and DAF-16 transcription factors, respectively. Altogether, our results suggested that complexes 2-4 might play a crucial role in stress modulation and they perhaps exert almost similar effects in higher models, which is an important issue to be validated in future.


Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Caenorhabditis elegans/metabolismo , Relação Dose-Resposta a Droga , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Relação Estrutura-Atividade
12.
J Pept Sci ; 25(4): e3158, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784138

RESUMO

Redox-active ruthenium complexes have been widely used in various fields; however, the harsh conditions required for their synthesis are not always conducive to their subsequent use in biological applications. In this study, we demonstrate the spontaneous formation of a derivative of tris(bipyridine)ruthenium at 37°C through the coordination of three bipyridyl ligands incorporated into a peptide to a ruthenium ion. Specifically, we synthesized six bipyridyl-functionalized peptides with randomly chosen sequences. The six peptides bound to ruthenium ions and exhibited similar spectroscopic and electrochemical features to tris(bipyridine)ruthenium, indicating the formation of ruthenium complexes as we anticipated. The photo-excited triplet state of the ruthenium complex formed in the peptides exhibited an approximately 1.6-fold longer lifetime than that of tris(bipyridine)ruthenium. We also found that the photo-excited state of the ruthenium complexes was able to transfer an electron to methyl viologen, indicating that the ruthenium complexes formed in the peptides had the same ability to transfer charge as tris(bipyridine)ruthenium. We believe that this strategy of producing ruthenium complexes in peptides under mild conditions will pave the way for developing new metallopeptides and metalloproteins containing functional metal-complexes.


Assuntos
Compostos Organometálicos/síntese química , Peptídeos/química , Peptídeos/síntese química , Rutênio/química , Estrutura Molecular , Compostos Organometálicos/química , Oxirredução , Processos Fotoquímicos
13.
Biomater Sci ; 7(4): 1652-1660, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30724288

RESUMO

INTRODUCTION: Ovarian cancer is often diagnosed at a late stage, when disease has spread to extra-pelvic regions such as the omentum. There are limited treatment options available for women with extensive disease and tumours often relapse after current chemotherapy regimens. Therefore, novel drugs should be investigated for the treatment of ovarian cancer. A 3D organotypic model of ovarian cancer can provide a specific platform for the evaluation of nano-drugs. Using patient derived primary cells, the 3D model mimics the ovarian metastatic microenvironment allowing efficient and reproducible testing of many nanoparticles. Dichlororuthenium(ii) (p-cymene) (1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) conjugated fructose-micelles have been used as the promising nano-drug for the treatment of metastatic cancer. Therefore we aimed to investigate the anti-metastatic properties of RAPTA-C conjugated micelles in ovarian cancer metastasis. METHODS: Ovarian cancer cell adhesion and invasion into a model of omentum were analyzed with and without RAPTA-C conjugated micelles in a range of conditions. RESULTS: We observed that RAPTA-C showed low general toxicity to both primary healthy and cancer cell lines. RAPTA-C loaded micelles significantly enhance the internalization of ruthenium inside the cells compared to free drugs. RAPTA-C did not affect adhesion of OVCAR4 ovarian cancer cells; however, it significantly inhibited invasion of these cells within the omentum model, either in its free form or as cargos inside the micelles. However, when OVCAR4 were treated prior to implantation, invasion was not inhibited. CONCLUSION: A 3D organotypic model provides a clinically relevant and simple method to evaluate the efficiency of nano-drug treatment of ovarian cancer. The ability to inhibit metastasis of RAPTA-C delivered in fructose coated nanoparticles was investigated for the first time via this model. These results provide a good basis to continue the development of this nano-drug in vivo.


Assuntos
Antineoplásicos/farmacologia , Modelos Biológicos , Compostos Organometálicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Frutose/química , Humanos , Micelas , Nanopartículas/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas
14.
Biomater Sci ; 7(4): 1716-1728, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30758381

RESUMO

Polycationic gene carriers are attracting increasing attention for their use as gene delivery systems. Herein, a novel and high-performance polycationic gene carrier (i.e., Zn-DPPA2) was constructed by introducing a dipicolylamine compound along with zinc ion coordination onto polyethylenimine (PEI1.8k) via Schiff base bonds. Zn-DPPA2 exhibited efficient transfection and negligible cytotoxicity. Zn-DPPA2/DNA complexes possessed significant endocytosis efficiency and excellent endosomal escape ability. Additionally, this polycaitionic gene carrier showed an excellent ability as an antiserum. The nanoscale size and good size stability ensured that Zn-DPPA2/DNA could accumulate in tumor tissue through the enhanced permeability and retention (EPR) effect. Moreover, Zn-DPPA2/DNA complexes exhibited efficient transfection in tumor tissue after intravenous injection. This strategy provided a new idea for polycationic gene carrier construction, which has prospects for widespread application in the field of gene therapy.


Assuntos
DNA/química , Técnicas de Transferência de Genes , Heterozigoto , Compostos Organometálicos/farmacologia , Polietilenoimina/farmacologia , Zinco/farmacologia , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetulus , DNA/genética , Células HEK293 , Células HeLa , Humanos , Íons/química , Íons/farmacologia , Células MCF-7 , Estrutura Molecular , Peso Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Polietilenoimina/química , Transfecção , Zinco/química
15.
J Enzyme Inhib Med Chem ; 34(1): 388-393, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734595

RESUMO

Two acetazolamide (AAZ) complexes with ruthenium(II) η6-p-cymene chloride were synthesised, characterised and tested for their inhibitory effects on several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with pharmacological applications. Against human (h) isoform hCA I, the two complexes showed inhibition constants in the range of 8.5-23.4 nM (AAZ has a KI of 250 nM), against hCA II of 0.48-4.2 nM, whereas against hCA IX of 0.63-3.8 nM and against hCA XII of 0.04-0.52 nM, respectively. These highly effective ruthenium acetazolamide derivatives against the tumour-associated CA isoforms IX and XII warrant further in vivo studies, in hypoxic tumours overexpressing these enzymes.


Assuntos
Acetazolamida/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Acetazolamida/química , Antígenos de Neoplasias , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Rutênio/química , Relação Estrutura-Atividade
16.
Chemistry ; 25(30): 7232-7242, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30730065

RESUMO

Overuse and misuse of antibacterial drugs has resulted in bacteria resistance and in an increase in mortality rates due to bacterial infections. Therefore, there is an imperative necessity of new antibacterial drugs. Bio-organometallic derivatives of antibacterial agents offer an opportunity to discover new active antibacterial drugs. These compounds are well-characterized products and, in several examples, their antibacterial activities have been studied. Both inhibition of the antibacterial activity and strong increase in the antibiotic activity of the parent drug have been found. The synthesis of the main classes of bio-organometallic derivatives of these drugs, as well as examples of the use of structure-activity relation (SAR) studies to increase the activity and to understand the mode of action of bio-organometallic antimicrobial peptides (BOAMPs) and platensimicyn bio-organometallic mimics is presented in this article.


Assuntos
Antibacterianos/síntese química , Materiais Biocompatíveis/síntese química , Compostos Organometálicos/síntese química , Adamantano/síntese química , Adamantano/farmacologia , Aminobenzoatos/síntese química , Aminobenzoatos/farmacologia , Anilidas/síntese química , Anilidas/farmacologia , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Materiais Biocompatíveis/farmacologia , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Humanos , Metais/química , Estrutura Molecular , Compostos Organometálicos/farmacologia , Relação Estrutura-Atividade
17.
Ultrason Sonochem ; 55: 207-216, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30745233

RESUMO

The dandelion-shaped nanostructure of an organotin complex with formula Sn(CH3)2Cl2}NC5H4C(O)NHP(O)[NHC6H11]2}2 (C1) was synthesized by means of a sonochemical method. Nano-structures were characterized by elemental analysis, NMR, SEM-EDS, XRD, UV-Vis, and FT-IR spectroscopy. The thermal stability of the complex C1 has been studied by thermal gravimetric analysis (TGA), and compared to the bulk form (C2). Both the morphology and the size of the ultrasound-assisted synthesized organotin complex have been investigated using scanning electron microscopy (SEM) by changing such parameters as the concentration of initial reactants and the sonication frequency. Two different forms of the organotin complex (C1, C2) and the corresponding ligand (L) were evaluated by a modified Ellman's method on acetyl- and butyrylcholinesterase enzymes. Nanodendalion C1 and ligand L showed the best activity against AChE and BChE, respectively, with the IC50 values being 326.59 µg/ml and 426.68 µg/ml. Further, Lineweaver Burk plots indicated that these compounds are mixed inhibitors. The synthesized compounds and cholinesterase enzymes were simulated by molecular docking for more details concerning the conformation and the orientations of these compounds in the active site of the receptor.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Fosfatos/química , Estanho/química , Ondas Ultrassônicas , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ligantes , Modelos Moleculares , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo
18.
Molecules ; 24(4)2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30795515

RESUMO

We use molecular mechanics and DFT calculations to analyze the particular electronic behavior of a giant nanoball. This nanoball is a self-assembled M12L24 nanoball; with M equal to Pd+2; Cr; and Mo. These systems present an extraordinarily large cavity; similar to biological giant hollow structures. Consequently, it is possible to use these nanoballs to trap smaller species that may also become activated. Molecular orbitals, molecular hardness, and Molecular Electrostatic Potential enable us to define their potential chemical properties. Their hardness conveys that the Mo system is less reactive than the Cr system. Eigenvalues indicate that electron transfer from the system with Cr to other molecules is more favorable than from the system with Mo. Molecular Electrostatic Potential can be either positive or negative. This means that good electron donor molecules have a high possibility of reacting with positive regions of the nanoball. Each of these nanoballs can trap 12 molecules, such as CO. The nanoball that we are studying has large pores and presents electronic properties that make it an apposite target of study.


Assuntos
Cromo/química , Elétrons , Molibdênio/química , Nanoestruturas/química , Compostos Organometálicos/química , Paládio/química , Monóxido de Carbono/química , Catálise , Modelos Químicos , Compostos Organometálicos/síntese química , Porosidade , Piridinas/química , Teoria Quântica , Termodinâmica
19.
Biomater Sci ; 7(4): 1386-1392, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30656318

RESUMO

Octahedral molybdenum cluster complexes have recently come forth as pertinent singlet oxygen photosensitizers towards biological applications. Still, their phototoxic efficiency in the absence of nanocarriers remains limited due to their poor cellular uptake. Here, two cationic octahedral molybdenum cluster complexes, bearing carboxylate ligands with triphenylphosphonium (1) or N-methyl pyridinium (2) mitochondria-targeting terminal functions, have been designed and synthesized. Their photophysical properties in water and in vitro biological activity were investigated in the context of blue-light photodynamic therapy of cancer and photoinactivation of bacteria. Upon blue light irradiation, complex 1 displays red luminescence with a quantum yield of 0.24 in water, whereas complex 2 is much less emissive (ΦL < 0.01). Nevertheless, both complexes efficiently produce singlet oxygen, O2(1Δg). Complex 1 is rapidly internalized into HeLa cells and accumulated in mitochondria, followed by relocation to lysosomes and clearance at longer times. In contrast, the more hydrophilic 2 is not internalized into HeLa cells, highlighting the effect of the apical ligands on the uptake properties. The treatment with 1 results in an intensive phototoxic effect under 460 nm irradiation (IC50 = 0.10 ± 0.02 µM), which exceeds by far those previously reported for octahedral cluster-based molecular photosensitizers. The ratio between phototoxicity and dark toxicity is approximately 50 and evidences a therapeutic window for the application of 1 in blue-light photodynamic therapy. Complex 1 also enters and efficiently photoinactivates Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus, documenting its suitability as a blue-light photosensitizer for antimicrobial applications.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Molibdênio/farmacologia , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Molibdênio/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo , Relação Estrutura-Atividade
20.
Inorg Chem ; 58(3): 2208-2217, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30675781

RESUMO

Subtle ligand modifications on ruthenium arene complexes can lead to different mechanisms of action and result in significant changes in the anticancer efficacy. Herein, four novel dinuclear ruthenium(II) arene complexes were designed and prepared. In vitro tests indicated that complexes 1-3 displayed moderate antiproliferative activity against the tested cancer cells, while the cytotoxicity of complex 4 is superior or comparable to that of cisplatin. Further studies indicated that complexes 1-4 induce cell death through DNA interaction and a reactive-oxygen-species-mediated endoplasmic reticulum (ER) stress pathway, which is the first example of an organometallic ruthenium(II) arene complex to induce ER stress as well as DNA interaction. This kind of dinuclear ruthenium(II) arene complex has unique biological characteristics and is a promising model for new anticancer drug development.


Assuntos
Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Rutênio/química , Eletricidade Estática , Relação Estrutura-Atividade
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