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1.
Chem Commun (Camb) ; 55(79): 11944-11947, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31531457

RESUMO

A novel hexanuclear copper(ii)-based complex, [Cu6(tpbb)2(NO3)12] (1), was synthesized, which shows potent cytotoxicity to hepatoma carcinoma cells by inducing apoptosis and apoptosis-related processes. Furthermore, mechanistic investigations based on proteomes revealed that the induced apoptosis was mediated by acting on several targets and multiple pathways in a pleiotropic way.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Complexos de Coordenação/química , Cobre/química , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Dano ao DNA/efeitos dos fármacos , Desenho de Drogas , Humanos , Ligantes , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
2.
Bratisl Lek Listy ; 120(9): 646-649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475547

RESUMO

BACKGROUND: It has been demonstrated that proteasome inhibitors might be potential anticancer drugs. The copper complexes can be used as specific proteasome inhibitors in tumor cells able to induce apoptosis by the ubiquitin-proteasome pathway. The goal of our study was to test the cytotoxic and proteasome inhibitory effects of five Schiff base Cu(II) complexes - [Cu2(sal-D,L-glu)2(isoquinoline)2] . 2C2H5OH (1), [Cu(sal-5-met-L-glu)(H2O)].H2O (2), [Cu(ethanol)2(imidazole)4][Cu2(sal-D,L-glu)2(imidazole)2] (3), [Cu(sal-D,L-glu)(2-methylimidazole)] (4) on human lung carcinoma cells A549, cervix carcinoma cells HeLa and glioblastoma cells U-118MG. MATERIAL AND METHODS: For the cytotoxic analysis we used MTT test and for monitoring the proteasome inhibition western blot analysis. RESULTS: We have observed different cytotoxic effects of tested complexes on human cancer cells depending on the ligand present in their structure. Cu(II) complexes 4 and 5 were the most effective against A549 cells; all complexes were cytotoxic against HeLa cells and the complex 4 was the most effective against U-118MG. Moreover, we have detected the inhibition of the proteasome activity in human cancer cells A549 by Cu(II) complexes 1, 2 and 4 at IC50 concentration. CONCLUSION: Results of our study suggest that isoquinoline- and imidazole-based copper complexes could be used as inhibitors of the proteasome system in cancer cells A549 (Tab. 1, Fig. 1, Ref. 26).


Assuntos
Cobre/farmacologia , Inibidores de Proteassoma/farmacologia , Bases de Schiff/farmacologia , Células A549 , Antineoplásicos/farmacologia , Apoptose , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Complexo de Endopeptidases do Proteassoma
4.
Chem Commun (Camb) ; 55(73): 10972-10975, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31453611

RESUMO

Platinum-resistant cancer cells are sensitive to changes in the levels of reactive oxidative species (ROS). Herein, we design a biotin-modified Ru(ii) complex as a photosensitizer (denoted as Ru-Biotin). Ru-Biotin can selectively target cancer cells and produce vast amounts of singlet oxygen under two-photon excitation at 820 nm leading to cell apoptosis. Ru-Biotin is therefore an excellent candidate to overcome platinum resistance via two-photon photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Biotina/análogos & derivados , Biotina/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Biotina/síntese química , Biotina/efeitos da radiação , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Humanos , Raios Infravermelhos , Fotoquimioterapia/métodos , Fótons , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
5.
Inorg Chem ; 58(16): 10778-10790, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31386351

RESUMO

A new family of cyclometalated ruthenium(II) complexes [Ru(N^N)2(C^N)]+ derived from the π-extended benzo[h]imidazo[4,5-f]quinolone ligand appended with thienyl groups (n = 1-4, compounds 1-4) was prepared and its members were characterized for their chemical, photophysical, and photobiological properties. The lipophilicities of 1-4, determined as octanol-water partition coefficients (log Po/w), were positive and increased with the number of thienyl units. The absorption and emission bands of the C^N compounds were red-shifted by up to 200 nm relative to the analogous Ru(II) diimine systems. All of the complexes exhibited dual emission with the intraligand fluorescence (1IL, C^N-based) shifting to lower energies with increasing n and the metal-to-ligand charge transfer phosphorescence (3MLCT, N^N-based) remaining unchanged. Compounds 1-3 exhibited excited state absorption (ESA) profiles consistent with lowest-lying 3MLCT states when probed by nanosecond transient absorption (TA) spectroscopy with 532 nm excitation and had contributions from 1IL(C^N) states with 355 nm excitation. These assignments were supported by the lifetimes observed (<10 ns for the 1IL states and around 20 ns for the 3MLCT states) as well as a noticeable ESA for 3 with 355 nm excitation that did not occur with 532 nm excitation. Compound 4 was the only member of the family with two 3MLCT emissive lifetimes (15, 110 ns), and the TA spectra collected with both 355 and 532 nm excitation was assigned to the 3IL state, which was corroborated by its 4-6 µs lifetime. The ESA for 4 had a rise time of approximately 10 ns and an initial decay of 110 ns, which suggests a possible 3MLCT-3IL excited state equilibrium that results in delayed emission from the 3MLCT state. Compound 4 was nontoxic toward human skin melanoma cells (SKMEL28) in the dark (EC50 = >300 µM); 1-3 were cytotoxic and yielded EC50 values between 1 and 20 µM. The photocytotoxicites with visible light ranged from 87 nM with a phototherapeutic index (PI) of 13 for 1 to approximately 1 µM (PI = >267) for 4. With red light, EC50 values varied from 270 nM (PI = 21) for 3 to 12 µM for 4 (PI = >25). The larger PIs for 4, especially with visible light, were attributed to the much lower dark cytotoxicity for this compound. Because the dark cytotoxicity contributes substantially to the observed photocytotoxicity for 1-3, it was not possible to assess whether the 3IL state of 4 led to a much more potent phototoxic mechanism in the absence of dark toxicity. There was no stark contrast in cellular uptake and accumulation by laser scanning confocal and differential interference contrast microscopy to explain the large differences in dark toxicities between 1-3 and 4. Nevertheless, the study highlights a new family of Ru(II) C^N complexes where π-conjugation beyond a certain point results in low dark cytotoxicity with high photocytotoxicity, opposing the notion that cyclometalated Ru(II) systems are too toxic to be phototherapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Quinolonas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , 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 , Humanos , Ligantes , Luz , Estrutura Molecular , Processos Fotoquímicos , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Quinolonas/química , Rutênio/química
6.
Acta Crystallogr C Struct Chem ; 75(Pt 8): 1091-1101, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31380792

RESUMO

A new set of differently hydrated barium and strontium squarates, namely poly[[triaqua(µ-1,2-dioxocyclobut-3-ene-1,2-diolato)barium] monohydrate], {[Ba(C4O4)(H2O)3]·H2O}n (1), poly[[diaqua(µ-1,2-dioxocyclobut-3-ene-1,2-diolato)strontium] monohydrate], {[Sr(C4O4)(H2O)2]·H2O}n (2), and poly[[triaqua(µ-1,2-dioxocyclobut-3-ene-1,2-diolato)barium/strontium(0.85/0.15)] monohydrate], {[Ba0.85Sr0.15(C4O4)(H2O)3]·H2O}n (3), is reported. The study of their crystal structures indicates that all the complexes crystallize in the triclinic space group P-1. Complexes 1 and 3 have a rare combination of squarate units coordinated through monodentate O atoms to two different metal atoms and through two bidentate O atoms to three different metal atoms. Furthermore, they have three coordinated water molecules to give a coordination number of nine. The squarate ligands in complex 2 exhibit two different coordination modes: (i) monodentate O atoms coordinated to four different Sr atoms and (ii) two monodentate O atoms coordinated to two different metal atoms with the other two O atoms bidentate to four different Sr atoms. All the compounds decompose to give the respective carbonates when heated to 800 °C, as evidenced by thermogravimetry/differential thermal analysis (TG-DTA), which are clusters of nanoparticles. Complexes 1 and 3 show additional endothermic peaks at 811 and 820 °C, respectively, indicating the phase transition of BaCO3 from an orthorhombic (α-Pmcn) to a trigonal phase (ß-R3m). All three complexes have significant DNA-binding constants, ranging from 2.45 × 104 to 9.41 × 104 M-1 against EB-CT (ethidium bromide-calf thymus) DNA and protein binding constants ranging from 1.1 × 105 to 8.6 × 105 with bovine serum albumin. The in vitro cytotoxicity of the complexes is indicated by the IC50 values, which range from 128.8 to 261.3 µg ml-1. Complex 3 shows better BSA binding, antioxidant activity against the DPPH radical and cytotoxicity than complexes 1 and 2.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ciclobutanos/farmacologia , Depuradores de Radicais Livres/farmacologia , Substâncias Intercalantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Bário/química , Bovinos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Ciclobutanos/síntese química , Ciclobutanos/química , Ciclobutanos/metabolismo , DNA/metabolismo , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Humanos , Ligações de Hidrogênio , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/metabolismo , Ligantes , Células MCF-7 , Estrutura Molecular , Ligação Proteica , Soroalbumina Bovina/metabolismo , Estrôncio/química , Água/química
7.
Chem Biol Interact ; 311: 108789, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401089

RESUMO

The cytotoxicity of a dinuclear imine-copper (II) complex 2, and its analogous mononuclear complex 1, toward different melanoma cells, particularly human SKMEL-05 and SKMEL-147, was investigated. Complex 2, a tyrosinase mimic, showed much higher activity in comparison to complex 1, and its reactivity was verified to be remarkably activated by UVB-light, while the mononuclear compound showed a small or negligible effect. Further, a significant dependence on the melanin content in the tumor cells, both from intrinsic pigmentation or stimulated by irradiation, was observed in the case of complex 2. Similar tests with keratinocytes and melanocytes indicated a much lower sensitivity to both copper (II) complexes, even after exposition to UV light. Clonogenic assays attested that the fractions of melanoma cells survival were much lower under treatment with complex 2 compared to complex 1, both with or without previous irradiation of the cells. The process also involves generation of reactive oxygen species (ROS), as verified by EPR spectroscopy, and by using fluorescence indicators. Autophagic assays indicated a remarkable formation of cytoplasmic vacuoles in melanomas treated with complex 2, while this effect was not observed in similar treatment with complex 1. Monitoring of specific protein LC3 corroborated the simultaneous occurrence of autophagy. A balance interplay between different modes of cell death, apoptosis and autophagy, occurs when melanomas were treated with the dinuclear complex 2, in contrast to the mononuclear complex 1. These results pointed out to different mechanisms of action of such complexes, depending on its nuclearity.


Assuntos
Complexos de Coordenação/química , Cobre/química , Iminas/química , Monofenol Mono-Oxigenase/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Humanos , Melaninas/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/metabolismo , Raios Ultravioleta
8.
Chem Commun (Camb) ; 55(71): 10627-10630, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31429450

RESUMO

We report the synthesis of a novel hydroxyl-functionalised heteroleptic bis-NHC gold(i) complex that permits conjugation to various amines via carbamate bond formation. The resulting derivatives were studied in vitro using cell proliferation assays and fluorescent microscopic imaging of human cancer cell lines.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Carbamatos/química , Complexos de Coordenação/síntese química , Corantes Fluorescentes/síntese química , Ouro/química , Células A549 , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Doxorrubicina/química , Humanos , Imagem Óptica , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Triazóis/química
9.
Eur J Med Chem ; 179: 325-334, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255929

RESUMO

New palladacyclopentadienyl complexes with bis-N-heterocyclic carbenes as spectator ligands have been synthesized and exhaustively characterized. The crystal structure of complex 1a has been also determined by X-ray diffraction analysis. Their in vitro cytotoxicity and that of other palladacyclopentadienyl derivatives coordinating different ancillary ligands has been determined against different cancer cell lines. Many complexes have shown an antiproliferative activity toward tumor cells often definitely better than cisplatin, whereas they have resulted practically inactive against the non-cancer MRC-5 cell line. The mechanism of action of bis-NHC derivative 1a, particularly active against ovarian cancer cell lines was studied in depth. Through a longitudinally analysis, it is shown that compound 1a induces apoptosis via DNA damage and release of cytochrome C. We propose compound 1a as a powerful and specific drug for the therapy of a deadly disease such as high grade serous ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Heterocíclicos/farmacologia , Metano/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/química , Humanos , Ligantes , Metano/química , Metano/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
10.
Inorg Chem ; 58(15): 10129-10138, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31310108

RESUMO

A series of 16 "3 + 2" mixed-ligand complexes of the general composition [ReO(L1)(L2)] (H2L1a-H2L1d = tridentate thiosemicarbazones having a phenyl group with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents; HL2a-HL2d = bidentate N,N-diethyl-N'-benzoylthioureas with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents at the benzoyl groups) have been synthesized and characterized by spectroscopic methods and X-ray diffraction. Irrespective of the individual fluorine substitution, the complexes are stable and possess the same general structure. Some systematic electronic effects of the fluorine-substitution patterns of the ligands have been found on the 13C NMR chemical shifts of the N-C═N carbon atoms of the {L1}2- and the C═O carbon atoms of the {L2}- ligands. Antiparasitic properties of the rhenium complexes have been tested against epimastigotes and trypomastigotes forms of two Trypanosoma cruzi strains and the amastigotes form of one of them. The results of this study indicate that the activity of the rhenium complexes can clearly be modulated by fluorine substitution of their ligands. Some of the fluorinated compounds show a high activity against epimastigotes and trypomastigotes forms of the parasites. Reactions between (NBu4)[TcOCl4] and two representatives of the fluorinated ligands (H2L1b, 4-F-substituted, and H2L1c, 4-CF3-substituted) form stable complexes of the composition [TcOCl(L1b)] and [TcOCl(L1c)]. Subsequent reactions of these products with HL2b (4-F-substituted) give the corresponding [TcO(L1)(L2)] mixed-ligand complexes. Also, the technetium compounds are stable as solids and in solutions and have structures corresponding to those of their rhenium analogues.


Assuntos
Complexos de Coordenação/farmacologia , Halogenação , Rênio/farmacologia , Tiossemicarbazonas/farmacologia , Tioureia/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Haplorrinos , Ligantes , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Rênio/química , Tiossemicarbazonas/química , Tioureia/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
11.
Anticancer Res ; 39(7): 3687-3695, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262895

RESUMO

BACKGROUND: Neuroblastoma is the main solid extracranial tumor of childhood. The amplification of N-myc oncogene (MYCN) and 1p deletion are the main molecular alterations. These features are what make treatment impossible, especially in high-risk patients with metastases. MATERIALS AND METHODS: Our study investigated the processes undergone by CHP-212 neuroblastoma cells, after being treated with Casiopeínas® (Cas) IIgly, IIIEa, and IIIia for 2, 10, and 24 h. RESULTS: At 2 h, all the treatments Ied to apoptosis [defined by the presence of B-cell lymphoma 2 (BCL2), BCL2-associated X protein, cytochrome c, and caspase-3]. In addition, autophagy with specific molecules beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-II/LC3-I (ratio >1). Later at 10 h, autophagy-associated proteins were observed, and at 24 h, only survival proteins nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), and extracellular signal-regulated kinases (ERK)2/ERK1>1 were found. Another relevant finding was the presence of caspase-10 throughout the study, especially in cells treated with CasIIgly and CasIIIEa. CONCLUSION: These relationships indicate a possible mechanism of action of Casiopeínas on neuroblastoma.


Assuntos
Complexos de Coordenação/farmacologia , Neuroblastoma/metabolismo , Fenantrolinas/farmacologia , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Neuroblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-31148514

RESUMO

Three mononuclear, mixed ligand ternary Cu(II) complexes of 3-((Z)-1-(2-hydroxyphenylimino)ethyl)-4-hydroxy-6-methyl-2H-pyran-2-one (HEHMP) viz; [Cu-(Phen) (HEHMP)] (1a), [Cu-(Bpy)(HEHMP)] (1 b) and [Cu-Bpy(NCS)(HEHMP)] (1c) were synthesized and characterized by data obtained from various spectral techniques. The binding affinities of these complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) protein were explored by absorption and fluorescence quenching titrations. The results indicated strong affinity of the title compounds to bind with both CT-DNA and BSA. The antioxidant properties of the synthesized compounds evaluated by free-radical scavenging method using spectrophotometric technique indicated their affirmative potential activity. Gel electrophoresis experiments revealed the efficacy of metal complexes in resulting the cleavage of pBR322 supercoiled DNA. In vitro cytotoxicity studies of these complexes evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against HeLa and MCF-7 cancer cell lines indicated relatively high effectiveness of the complex 1c. Confocal microscopy signified the potential of the complexes to induce apoptosis in HeLa cell lines. In addition, the antibacterial activity of the compounds carried out by disc diffusion method revealed significantly enhanced antibacterial activity in Cu (II) ternary complexes compared to the activity of ligands in unbound form signifying the implicit role of metal ion in inducing lipophilic character.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Antioxidantes/química , Complexos de Coordenação/química , Cobre/química , DNA/química , Soroalbumina Bovina/química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Sobrevivência Celular , Complexos de Coordenação/farmacologia , Clivagem do DNA , Células HeLa , Humanos , Ligantes , Células MCF-7 , Simulação de Acoplamento Molecular , Processos Fotoquímicos , Ligação Proteica , Termodinâmica
13.
Eur J Med Chem ; 177: 350-361, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158749

RESUMO

The relationship between chemical structure and in vitro cytotoxic activities of a series of azastibocine-framework organoantimony(III) halide complexes against cancerous (HepG2, MDA-MB-231, MCF-7 and HeLa) and nonmalignant (HEK-293) cell lines was studied for the first time. A positive correlation between cytotoxic activity and the length of N→Sb coordinate bond on azastibocine framework of same nitrogen substituent was observed. By comparison, the organoantimony(III) complex 6-cyclohexyl-12-fluoro-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine (C4) exhibited the highest selectivity index, giving a IC50(nonmalignant)/IC50(cancerous) ratio of up to 8.33. The results of cell cycle analysis indicated that the inhibitory effect of C4 on the cellular viability was caused by cell cycle arrest mainly at the S phase. The necrosis induced by C4 was confirmed by the Trypan blue dye exclusion test and the increase of lactic dehydrogenase (LDH) released in the culture medium. Furthermore, evaluation of the levels of intracellular reactive oxygen species (ROS) in MDA-MB-231 cells, by quantifying the relative fluorescence units (RFU) using spectrofluorometer, indicated that cytotoxic activity of C4 is dependent on the production of ROS. This work established the correlation between cytotoxic activity and N→Sb inter-coordination, a finding that provided theoretical and experimental basis for in-depth design of antimony-based organometallic complexes as potential anticancer agents.


Assuntos
Antimônio/química , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , L-Lactato Desidrogenase/metabolismo , Estrutura Molecular , Necrose/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Chem Biodivers ; 16(8): e1900243, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207061

RESUMO

The new complex compounds [RuLCl(p-cymene)] ⋅ 3H2 O and [NiL2 (H2 O)2 ] ⋅ 3H2 O (L: 1-{4-[(2-hydroxy-3-methoxybenzylidene)amino]phenyl}ethanone) were prepared and characterized using FT-IR, 1 H- and 13 C-NMR, mass spectroscopy, TGA, elemental analysis, X-ray powder diffraction and magnetic moment techniques. Octahedral geometry for new Ni(II) and Ru(II) complexes was proposed. Thermal decomposition confirmed the existence of lattice and coordinated water molecule in the complexes. To determine the antioxidant properties of Schiff base ligand and its Ni(II), Ru(II) metal complexes, FRAP, CUPRAC, ABTS and DPPH methods of antioxidant assays were used. Moreover, enzyme inhibition of complexes was evaluated against carbonic anhydrase I and II isoenzymes (CA I and CA II) and acetylcholinesterase (AChE). For CA I and CA II, the best inhibition enzymes, was the Ni(II) complex with 62.98±18.41, 86.17±23.62 Ki values, whereas this inhibition effect showed ligand with 24.53±2.66 Ki value for the AChE enzyme.


Assuntos
Antioxidantes/química , Complexos de Coordenação/química , Inibidores Enzimáticos/química , Níquel/química , Rutênio/química , Bases de Schiff/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Espectrofotometria Infravermelho
15.
Inorg Chem ; 58(13): 8800-8819, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247881

RESUMO

Very few inorganic antineoplastic drugs have entered the clinic in the last decades, mainly because of toxicity issues. Because copper is an essential trace element of ubiquitous occurrence, decreased side effects could be expected in comparison with the widely used platinum anticancer compounds. In the present work, two novel hydrazonic binucleating ligands and their µ-hydroxo dicopper(II) complexes were prepared and fully characterized. They differ by the nature of the aromatic group present in their aroylhydrazone moieties: while H3L1 and its complex, 1, possess a thiophene ring, H3L2 and 2 contain the more polar furan heterocycle. X-ray diffraction indicates that both coordination compounds are very similar in structural terms and generate dimeric arrangements in the solid state. Positive-ion electrospray ionization mass spectrometry analyses confirmed that the main species present in a 10% dimethyl sulfoxide (DMSO)/water solution should be [Cu2(HL)(OH)]+ and the DMSO-substituted derivative [Cu2(L)(DMSO)]+. Scattering techniques [dynamic light scattering (DLS) and small-angle X-ray scattering] suggest that the complexes and their free ligands interact with bovine serum albumin (BSA) in a reversible manner. The binding constants to BSA were determined for the complexes through fluorescence spectroscopy. Moreover, to gain insight into the mechanism of action of the compounds, calf thymus DNA binding studies by UV-visible and DLS measurements using plasmid pBR322 DNA were also performed. For the complexes, DLS data seem to point to the occurrence of DNA cleavage to Form III (linear). Both ligands and their dicopper(II) complexes display potent antiproliferative activity in a panel of four cancer cell lines, occasionally even in the submicromolar range, with the complexes being more potent than the free ligands. Our data on cellular models correlate quite well with the DNA interaction experiments. The results presented herein show that aroylhydrazone-derived binucleating ligands, as well as their dinuclear µ-hydroxodicopper(II) complexes, may represent a promising structural starting point for the development of a new generation of highly active potential antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Hidrazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , DNA/química , Clivagem do DNA/efeitos dos fármacos , Cães , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/toxicidade , Isomerismo , Ligantes , Células Madin Darby de Rim Canino , Camundongos , Plasmídeos/química , Multimerização Proteica/efeitos dos fármacos , Soroalbumina Bovina/metabolismo
16.
Eur J Med Chem ; 178: 390-400, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202127

RESUMO

Two iridium(III) polypyridyl complexes [Ir(ppy)2(HPIP)](PF6) (Ir-1), [Ir(ppy)2(BHPIP)](PF6) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC50 values range from 5.2 ±â€¯0.8 to 22.3 ±â€¯1.8 µM. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca2+ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Irídio/farmacologia , Lipossomos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Polímeros/química , Polímeros/farmacologia , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 178: 401-416, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202128

RESUMO

This work mainly introduces the synthesis and characterization of three iridium(III) complexes [Ir(ppy)2(adppz)](PF6) (Ir-1), [Ir(bzq)2(addpz)](PF6) (Ir-2) and [Ir(piq)2(adppz)](PF6) (Ir-3). The complexes are more cytotoxic than cisplatin against tumor cell lines such as SGC-7901, A549, HeLa, Eca-109, HepG2 and BEL-7402. The toxicity test results indicated that complexes Ir-1, Ir-2 and Ir-3 can effectively inhibit the cell growth of SGC-7901 cells, and the measured IC50 values are 1.8 ±â€¯0.4, 1.6 ±â€¯0.3 and 0.8 ±â€¯0.1 µM, respectively. AO/EB staining and flow apoptosis confirmed that SGC-7901 cells were caused apoptosis after being treated with the complexes. Along with the increase of endogenous ROS and Ca2+ levels, mitochondrial membrane potential collapse and massive release of cytochrome c, it is fully demonstrated that these complexes induce apoptosis through ROS-mediated mitochondrial pathway. At the same time, the complex Ir-3 is outstanding in the inhibition of tumor growth in vivo. Combined with the above results, it provides a favorable foundation for the future development of more effective anti-tumor drugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , 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 , Humanos , Irídio/química , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade
18.
J Photochem Photobiol B ; 197: 111516, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170508

RESUMO

In the search for new therapeutic agents we have synthesized 13 new organotin(IV) carboxylate derivatives of (E)-4-((4-methoxy-2-nitrophenyl)amino)-4-oxobut-2-enoic acid. The synthesized complexes were characterized by several spectroscopic techniques. A chelating or bridging bidentate nature of the carboxylate ligand was suggested from the solid state FT-IR results. Solution state multinuclear NMR (1H, 13C and 119Sn) results reveal that the geometry around the Sn atom in triorganotin(IV) complexes is trigonal bipyramidal and in diorganotin(IV) complexes is octahedral. The ligand, (E)-4-((4-methoxy-2-nitrophenyl)amino)-4-oxobut-2-enoic acid, complex 1 and complex 2 were also analyzed by single crystal X-ray technique and the results fully supports the spectroscopic data. For 1 and 2 the geometry optimized by the single crystal X-ray analyses is distorted trigonal bipyramidal. The interaction of the studied compounds with SS-DNA was investigated by UV-Vis. Spectroscopy and Molecular docking showing an intercalative mode of binding. The evaluation of the screened compounds for cancer treatment displays even higher than that of the vincristine used as a standard drug. Similarly the performance of the tested compounds as an antileishmanial agent considers them very close in activity to the standard drug, amphotericin B. The antibacterial results show that the most of the compounds have a moderate sensitivity against the studied bacterial pathogens.


Assuntos
Complexos de Coordenação/química , Compostos Orgânicos de Estanho/química , Sítios de Ligação , Ácidos Carboxílicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Leishmania tropica/efeitos dos fármacos , Ligantes , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Eur J Med Chem ; 174: 216-225, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042617

RESUMO

The identification of a valid therapeutic treatment for Alzheimer's disease (AD) represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs) can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor) linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Fármacos Neuroprotetores/farmacologia , Rivastigmina/análogos & derivados , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Transformada , Quelantes/síntese química , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/toxicidade , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Rivastigmina/síntese química , Rivastigmina/toxicidade
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