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1.
Chem Biol Interact ; 330: 109231, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853594

RESUMO

Hetero mononuclear rhenium(I) metal complexes (I-V) using different substituted indole-pyrazoline based ligands were synthesized and characterized by spectroscopic and analytical methods. The binding of the rhenium complexes to Herring sperm DNA was monitored by UV spectroscopy, viscosity measurements, and molecular docking studies; groove binding was suggested as the most possible mode and the DNA-binding constants of the complexes were evaluated. In vivo and in vitro cytotoxicity of compounds were evaluated against the brine shrimp and S. cerevisiae cells. An antimicrobial study was carried out by estimating MIC (Minimum Inhibitory Concentration) against two Gram-positive and three Gram-negative bacteria. All synthesized complexes are biologically more active than the corresponding ligands. The anti-proliferation activity of complexes was evaluated on MCF-7, HCT116, and A549 cancer cells by MTT assay. The toxicity profile of synthesized compounds was confirmed by H2O2 production by reactive oxygen species. The increased concentration of lipid peroxidation end products increased free radicals, which enhancing the oxidative stress level in living organisms and results in cell death.


Assuntos
Complexos de Coordenação/farmacologia , Indóis/química , Pirazóis/química , Rênio/química , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Artemia/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citotoxinas/toxicidade , DNA/metabolismo , Humanos , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos
2.
Proc Natl Acad Sci U S A ; 117(30): 17535-17542, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32661159

RESUMO

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl2 (Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ródio , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Pareamento Incorreto de Bases/efeitos dos fármacos , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Células HCT116 , Humanos , Camundongos , Estrutura Molecular , Ródio/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Biofouling ; 36(3): 351-367, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32401555

RESUMO

Pseudomonas aeruginosa and Serratia marcescens are prominent members belonging to the group of ESKAPE pathogens responsible for Urinary Tract Infections (UTI) and nosocomial infections. Both the pathogens regulate several virulence factors, including biofilm formation through quorum sensing (QS), an intercellular communication mechanism. The present study describes the anti-biofilm and QS quenching effect of thiazolinyl-picolinamide based palladium(II) complexes against P. aeruginosa and S. marcescens. Palladium(II) complexes showed quorum sensing inhibitory potential in inhibiting swarming motility behaviour, pyocyanin production and other QS mediated virulence factors in both P. aeruginosa and S. marcescens. In addition, the establishment of biofilms was prevented on palladium (II) coated catheters. Overall, the present study demonstrates that thiazolinyl-picolinamide based palladium (II) complexes will be a promising strategy to combat device-mediated UTI infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Paládio/farmacologia , Ácidos Picolínicos/química , Tiazóis/química , Cateteres Urinários/microbiologia , Antibacterianos/química , Antibacterianos/toxicidade , Biofilmes/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Infecção Hospitalar/prevenção & controle , Humanos , Células MCF-7 , Paládio/química , Paládio/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Piocianina/metabolismo , Percepção de Quorum/efeitos dos fármacos , Serratia marcescens/efeitos dos fármacos , Serratia marcescens/metabolismo , Infecções Urinárias/microbiologia , Infecções Urinárias/prevenção & controle , Virulência , Fatores de Virulência/metabolismo
4.
PLoS One ; 15(4): e0231147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287324

RESUMO

This paper reports the synthesis, characterization, anticancer screening and quantum chemical calculation of a tetradentate Schiff base 2,2'-((1E,1'E)-((2,2-dimethylpropane-1,3-diyl)bis- (azanylylidene))bis(methanylylidene))bis(4-fluorophenol) (L2F) and its Pd (II) complex (PdL2F). The compounds were characterized via UV-Visible, NMR, IR spectroscopy and single crystal x-ray diffraction. Density Functional Theory (DFT) and time-dependent DFT calculations in gas and solvent phases were carried out using B3LYP, B3P86, CAM-B3LYP and PBE0 hybrid functionals combined with LanL2DZ basis set. Complexation of L2F to form PdL2F was observed to cause a bathochromic shift of the maximum absorption bands of n-π* from 327 to 410 nm; an upfield shift for δ (HC = N) from 8.30 to 7.96 ppm and a decreased wavenumber for ν(C = N) from 1637 to 1616 cm-1. Overall, the UV-Vis, NMR and IR spectral data are relatively well reproduced through DFT and TD-DFT methods. L2F and PdL2F showed IC50 of 90.00 and 4.10 µg/mL, respectively, against human colorectal carcinoma (HCT116) cell lines, signifying increased anticancer activity upon complexation with Pd (II).


Assuntos
Complexos de Coordenação/farmacologia , Paládio/farmacologia , Bases de Schiff/farmacologia , Técnicas de Química Sintética/métodos , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração Inibidora 50 , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Paládio/química , Bases de Schiff/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
5.
Biofouling ; 36(2): 210-221, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32292058

RESUMO

Surfactin is a type of cyclic lipopeptide biosurfactant implicated in a wide range of applications. Although its antimicrobial activity has been characterized, its effect on Candida albicans physiology remains to be elucidated. The present study evaluated the influence of surfactin-C15 (SF) and its complexes with divalent counterions on C. albicans biofilm formation and preformed biofilms. The SF and metal(II)-SF complexes inhibited biofilm formation and reduced the metabolic activity of mature biofilms in a concentration-dependent manner. The same concentrations of the compounds studied dislodged preexisting biofilms grown on polystyrene plates. Moreover, SF and its metal(II) complexes reduced the mRNA expression of hypha-specific genes HWP1, ALS1, ALS3, ECE1 and SAP4 without exhibiting significant growth inhibition. Further research showed that the compounds tested reduced cellular surface hydrophobicity (CSH). These results suggest that SF and metal(II)-SF complexes could be used as anti-biofilm agents against C. albicans hypha-related infections in clinical practice.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Hifas/efeitos dos fármacos , Tensoativos/metabolismo , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Candida albicans/metabolismo , Proteínas Fúngicas/genética , Proteínas de Fluorescência Verde/genética , Hifas/crescimento & desenvolvimento
6.
Inorg Chem ; 59(8): 5728-5741, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32242663

RESUMO

[44/47Sc]Sc3+, [68Ga]Ga3+, and [111In]In3+ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, H3glyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc(glyox)(H2O)] and [In(glyox)(H2O)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10-5 M) and indium-111 (RCY > 99%, [L] = 10-8 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/µmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [44Sc]ScCl3 (RCY > 99%, [L] = 10-6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [68Ga]Ga(glyox) and [111In]In(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H3glyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc(glyox) in addition to the in-batch UV-vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc(glyox) and Ga(glyox), confirming the viability of the cells. These initial investigations suggest H3glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Corantes Fluorescentes/farmacologia , Oximas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Quelantes/síntese química , Complexos de Coordenação/sangue , Complexos de Coordenação/química , Estabilidade de Medicamentos , Corantes Fluorescentes/química , Radioisótopos de Gálio/química , Células HeLa , Humanos , Radioisótopos de Índio/química , Marcação por Isótopo , Ligantes , Microscopia de Fluorescência/métodos , Oximas/síntese química , Estudo de Prova de Conceito , Radioisótopos/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/química , Escândio/química , Termodinâmica
7.
J Med Chem ; 63(8): 4005-4021, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32207946

RESUMO

Six complexes of formula [Ir(η5:κ1-C5Me4CH2py)(C,N)]PF6, where C5Me4CH2py is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η5:κ1-C5Me4CH2pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1-6, are exceptionally more potent (1-2 orders of magnitude). Additionally, 1-6 disrupt mitochondrial membrane potential (ΔΨm) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.


Assuntos
Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Irídio/química , Antineoplásicos/farmacologia , Proliferação de Células/fisiologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X/métodos , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Irídio/farmacologia , Células MCF-7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
8.
Chem Commun (Camb) ; 56(20): 3069-3072, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32049075

RESUMO

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Niacina/farmacologia , Platina/farmacologia , Rutênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Niacina/química , Platina/química , Rutênio/química , Relação Estrutura-Atividade
9.
Chem Commun (Camb) ; 56(20): 3047-3049, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32048688

RESUMO

A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-ß-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.


Assuntos
Ácido Aspártico/análogos & derivados , Complexos de Coordenação/farmacologia , Proteínas de Escherichia coli/antagonistas & inibidores , Etilenodiaminas/farmacologia , Succinatos/farmacologia , Zinco/farmacologia , Inibidores de beta-Lactamases/farmacologia , Aminoácidos/química , Aminoácidos/farmacologia , Ácido Aspártico/química , Ácido Aspártico/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Proteínas de Escherichia coli/metabolismo , Etilenodiaminas/química , Estrutura Molecular , Relação Estrutura-Atividade , Succinatos/química , Zinco/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química , beta-Lactamases/metabolismo
10.
Chemistry ; 26(22): 4997-5009, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32065454

RESUMO

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP)2 (sq)](PF6 ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)2 (mal)](PF6 ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)2 (mal)](PF6 ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP)2 (mal)](PF6 ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Pironas/farmacologia , Rutênio/química , Antineoplásicos/química , Cisplatino/química , Complexos de Coordenação/química , Células HeLa , Humanos , Ligantes , Estrutura Molecular , Pironas/química , Rutênio/farmacologia
11.
Dalton Trans ; 49(10): 3243-3252, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32096513

RESUMO

A series of cationic Ru(ii)(η6-p-cymene) complexes with thioether-functionalised N-heterocyclic carbene ligands have been prepared and fully characterized. Steric and electronic influence of the R thioether substituent on the coordination of the sulfur atom was investigated. The molecular structure of three of them has been determined by means of X-ray diffractrometry and confirmed the bidentate (κ2-C,S) coordination mode of the ligand. Interestingly, only a single diastereomer, as an enantiomeric couple, was observed in the solid state for complexes 1c, 1i and 1j. DFT calculations established a low energy inversion barrier between the two diastereomers through a sulfur pyramidal inversion pathway with R donating group while a dissociative/associative mechanism is more likely with R substituents that contain electron withdrawing group, thus suggesting that the only species observed by the 1H-NMR correspond to an average resonance position of a fluxional mixtures of isomers. All these complexes were found to catalyse the oxydant-free double dehydrogenation of primary amine into nitrile. Ru complex bearing NHC-functionalised S-tBu group was further investigated in a wide range of amines and was found more selective for alkyl amine substrates than for benzylamine derivatives. Finally, preliminary results of the biological effects on various human cancer cells of four selected Ru complexes are reported.


Assuntos
Complexos de Coordenação/química , Rutênio/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Humanos , Ligantes , Rutênio/farmacologia , Sulfetos/química
12.
Inorg Chem ; 59(5): 2978-2987, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32037809

RESUMO

We have synthesized and structurally characterized three tetra-(p-tolyl)antimony(III)-containing heteropolytungstates, [{(p-tolyl)SbIII}4(A-α-XW9O34)2]n- [X = PV (1-P), AsV (1-As), or GeIV (1-Ge)], in aqueous solution using conventional, one-pot procedures. The polyanions 1-P, 1-As, and 1-Ge were fully characterized in the solid state and in solution and were shown to be soluble and stable in aqueous medium at pH 7. Biological studies demonstrated that all three polyanions possess significant antibacterial and antitumor activities. The minimum inhibitory concentrations of 1-P, 1-As, and 1-Ge were determined against four kinds of bacteria, including the two pathogenic bacteria strains, Vibrio parahaemolyticus and Vibrio vulnificus. The three novel polyanions also showed high cytotoxic potency in the human cell lines A549 (non-small cell lung cancer), CH1/PA-1 (ovarian teratocarcinoma), and SW480 (colon carcinoma).


Assuntos
Antibacterianos/farmacologia , Antimônio/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Tungstênio/farmacologia , Células A549 , Antibacterianos/síntese química , Antibacterianos/química , Antimônio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Células Tumorais Cultivadas , Tungstênio/química , Vibrio parahaemolyticus/efeitos dos fármacos , Vibrio vulnificus/efeitos dos fármacos
13.
Inorg Chem ; 59(5): 3281-3289, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32073260

RESUMO

Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N-heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of RhIII- and IrIII(Cp*)(NHC)Cl2 (Cp* = η5-pentamethylcyclopentadienyl) compounds and comparison of their properties to the RuII- and OsII(cym) analogues (cym = η6-p-cymene). Like the RuII- and OsII(cym) complexes, the RhIII- and IrIII(Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC50) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC50 values of ∼1 µM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl2 complexes may be a scaffold for the development of TrxR inhibitors.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Ligantes , Metais Pesados/química , Metais Pesados/farmacologia , Metano/análogos & derivados , Metano/química , Metano/farmacologia , Conformação Molecular , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/metabolismo
14.
Chemistry ; 26(31): 7092-7108, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32037581

RESUMO

Many cancer cells critically rely on antioxidant systems for cell survival and are vulnerable to further oxidative impairment triggered by agents generating reactive oxygen species (ROS). Therefore, the classical design and development of inhibitors that target antioxidant defense enzymes such as thioredoxin reductase (TrxR) can be a promising anticancer strategy. Herein, it is shown that a gold(I) complex containing an oleanolic acid derivative (4 b) induces apoptosis of ovarian cancer A2780 cells by activating endoplasmic reticulum stress (ERS). It can inhibit TrxR enzyme activity to elevate ROS, mediate ERS and mitochondrial dysfunction, and finally leads to cell cycle arrest and apoptosis of A2780 cells. Notably, this complex inhibits A2780 xenograft tumor growth accompanied by increased ERS level and decreased TrxR activity in tumor tissues.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Ouro/química , Ácido Oleanólico/química , Neoplasias Ovarianas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Estresse do Retículo Endoplasmático , Feminino , Ouro/farmacologia , Humanos , Oxirredução , Tiorredoxina Dissulfeto Redutase/química
15.
Dalton Trans ; 49(4): 972-976, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31894797

RESUMO

An HCBP1 peptide-ruthenium conjugate (Ru-ß-Ala-FQHPSFI) as a potential candidate for targeted therapy of hepatoma was synthesized. Ru-ß-Ala-FQHPSFI shows drastically enhanced cytotoxicity and high selectivity for hepatoma cells versus noncancer liver cells. Raman imaging shows that this peptide-based drug can be taken up well by the hepatoma cells compared with the bare ruthenium complex (Ru) and the opposite sequence peptide-ruthenium conjugate (Ru-ß-Ala-IFSPHQF). This study presents a new strategy for the construction of tumor-targeting metal-based anticancer therapeutics.


Assuntos
Carcinoma Hepatocelular/patologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Neoplasias Hepáticas/patologia , Oligopeptídeos/química , Rutênio/química , Sequência de Aminoácidos , Células Hep G2 , Humanos
16.
Dalton Trans ; 49(4): 1143-1156, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31894801

RESUMO

A series of 2-phenyl and 2-pyridyl tris-benzimidazole ligands was reacted with the [Ru(p-cymene)Cl2]2 dimer to yield the corresponding neutral cyclometallated and cationic organoruthenium(ii) complexes. All of the synthesized compounds were characterized using an array of spectroscopic and analytical techniques, including 1H, 13C nuclear magnetic resonance (NMR), infrared spectroscopy and mass spectrometry. The trinuclear compounds were screened for their cytotoxicy against the MCF-7 breast cancer cell line and the triple negative MDA-MB-231 breast cancer cell line at concentrations of 10 and 20 µM. Overall, the 2-pyridyl ligands 10 and 11, and their corresponding trinuclear complexes [16][PF6]3 and [17][PF6]3, show the most promising activity as these compounds significantly reduce the percentage cell survival of MCF-7 and MDA-MB-231 breast cancer cell lines at the aforementioned fixed concentrations. It was observed that 10 and [16][PF6]3 show potency greater than that of cisplatin against the MCF-7 breast cancer cell line, and [17][PF6]3 shows potency comparable to that of cisplatin against the MCF-7 cell line. Additionally, the synthesized compounds were observed to have relatively low cytotoxicty towards MCF-12A breast epithelial cells and relatively higher selectivity towards MCF-7 breast cancer cells compared to cisplatin.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Quelantes/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Complexos de Coordenação/síntese química , Humanos , Células MCF-7 , Modelos Moleculares , Conformação Molecular
17.
Dalton Trans ; 49(4): 1232-1240, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903474

RESUMO

Three asymmetric tridentate acyl hydrazone Schiff base ligands namely L1, L2 and L3 were prepared via condensation of 4-methoxybenzohydrazide with picolinaldehyde, 1-(pyridin-2-yl)ethanone and phenyl(pyridin-2-yl)methanone respectively. Three bio-relevant mononuclear zinc(ii) complexes [Zn(L1)Cl2]·2H2O (1), [Zn(L2)Cl2] (2) and [Zn(L3)Cl2] (3) were synthesized by treatment of zinc(ii) chloride with the corresponding Schiff base ligands and characterised by the usual physicochemical techniques. The solid state structures of complexes 1 and 3 were evaluated by single crystal X-ray analysis. All complexes were able to hydrolyse the P-O bond of the phosphate monoester in 90% (v/v) DMSO-water medium using 4-nitrophenylphosphate (4-NPP) as the model substrate and the trend in their activity is 1≈2 > 3. On considering the highly efficient hydrolysis properties, complexes 1-3 were tested as potential therapeutic agents for cancer using HCT116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and A549 (human non-small lung carcinoma) cells. Complex 2 showed the highest IC50 values for anti-cancer activity towards all three cell lines among the three complexes and complex 3 showed the least activity as observed in the phosphatase activity study. The internucleosomal degradation of DNA during apoptosis can be detected by cell death detection ELISA. DNA fragmentation that leads to cell death was examined and when induced by complex 2 in HepG2 cells a significant level of DNA fragmentation was observed at regular intervals of time.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Hidrazonas/química , Monoéster Fosfórico Hidrolases/metabolismo , Zinco/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Cinética , Bases de Schiff/química
18.
Dalton Trans ; 49(4): 1207-1219, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903475

RESUMO

Two types of ruthenium(ii) complexes containing 1,2,4-triazolo[1,5-a]pyrimidines of the general formulas [RuCl2(dmso)3(L)] ((1)-(3)) and [RuCl2(dmso)2(L)2] ((4)-(6)), where L represents 1,2,4-triazolo[1,5-a]pyrimidine (tp for (1)), 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp for (2)), 7-isobutyl-5-methyl-1,2,4-trizolo[1,5-a]pyrimidine (ibmtp for (3)), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for (4)), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp for (5)) and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp for (6)), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, and 15N), and X-ray (for (3), (4), and (5)). All these complexes have been thoroughly screened for their in vitro cytotoxicity against melanoma cell lines A375 and Hs294T, indicating cis,cis,cis-[RuCl2(dbtp)2(dmso)2] (5) as the most active representative, in addition to being non-toxic to normal human fibroblasts (NHDF) and not inducing hemolysis of human erythrocytes. In order to develop an intravenous formulation for (5), liposomes composed of soybean phosphatidylcholine (SPC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) were prepared and subsequently characterized. (5)-Loaded liposomes, with spherical morphology, assessed by transmission electron microscope (TEM), exhibited satisfactory encapsulation efficiency and stability. In in vitro experiments, PEG-modified (5)-loaded liposomes were more effective (10-fold) than free (5) for growth inhibition of both human melanoma cell lines. Furthermore, such an approach resulted in the reduction of cancer cell viability that was even 10-fold greater than that observed for free cisplatin.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Lipossomos/química , Melanoma/patologia , Nanoestruturas/química , Pirimidinas/química , Rutênio/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Cápsulas , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Humanos , Interações Hidrofóbicas e Hidrofílicas , Triazóis/química
19.
Chem Commun (Camb) ; 56(10): 1509-1512, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31917383

RESUMO

Gallium(iii) complexes with polypridyl ligands are shown to kill bulk osteosarcoma cells and osteosarcoma stem cells (OSCs) with up to nanomolar potency. The most effective complex induces apoptosis in osteosarcoma cells by damaging genomic DNA. To the best of our knowledge this is the first investigation into metal-based anti-OSC agents.


Assuntos
Complexos de Coordenação/farmacologia , Gálio/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/química , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Humanos , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia
20.
Chemistry ; 26(9): 1947-1952, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31909511

RESUMO

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Resistencia a Medicamentos Antineoplásicos , Platina/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Complexos de Coordenação/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Conformação Molecular , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Espectrometria de Fluorescência
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