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1.
Inorg Chem ; 59(1): 748-758, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808678

RESUMO

The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η5-CpR ring. The molecular structures for complexes Ir1-Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD+. The effect of the substituents in the η5-CpR ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Flúor/química , Irídio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Modelos Moleculares , Estrutura Molecular , Espécies Reativas de Oxigênio/análise
2.
Inorg Chem ; 58(23): 15917-15926, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31714764

RESUMO

A range of novel cyclometalated ruthenium(II) and iridium(III) complexes with a steroidal backbone based on androsterone were synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their cytotoxic properties in RT112 and RT112 cP (cisplatin-resistant) cell lines as well as in MCF7 and somatic fibroblasts were compared with those of the corresponding nonsteroidal complexes and the noncyclometalated pyridyl complexes as well as with cisplatin as reference. All steroidal complexes were more active in RT112 cP cells than cisplatin, whereby the cyclometalated pyridinylphenyl complexes based on 5c showed high cytotoxicity while maintaining low resistant factors of 0.33 and 0.50.


Assuntos
Androstenóis/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Rutênio/farmacologia , Androstenóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Rutênio/química , Relação Estrutura-Atividade
4.
Drug Deliv ; 26(1): 918-927, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31526064

RESUMO

Protein-based nanocarriers with inherent biocompatibility have been widely served as building blocks to construct versatile therapeutic nanoplatforms. Herein, bovine serum albumin-iridium oxide nanoparticles (denoted BSA-IrO2 NPs) are successfully synthesized via one-step biomineralization approach. The BSA-IrO2 NPs exhibits uniform size (40 nm), superb biocompatibility and high drug loading capacity for doxorubicin (27.4 wt%). Under near-infrared (NIR) laser irradiation, the as-prepared BSA-IrO2 NPs exhibited high photothermal conversion ability (54.3%) and good photostability. The in vitro drug release experiments displayed pH and NIR laser -triggered DOX release profiles, which could enhance the therapeutic anticancer effect. By utilizing this DOX loaded nanoplatform, effective synergistic chemo-photothermal therapy against human osteosarcoma can be realized, which has been systematically verified both in vitro and in vivo. Notably, in vivo pharmacokinetics studies showed that BSA-IrO2@DOX had prolonged blood circulation time due to the BSA component can improve the stealthiness of the nanoparticles during the blood circulation. Meanwhile, in vitro and in vivo toxicity studies demonstrated that the BSA-IrO2 NPs can act as biocompatible agents for drug delivery and cancer therapy. Therefore, this work presents a biomineralized iridium-based NPs with remarkable features and be used as a very potential therapeutic nanoplatform for cancer treatment.


Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Irídio/química , Irídio/farmacologia , Nanopartículas/química , Osteossarcoma/tratamento farmacológico , Soroalbumina Bovina/química , Células A549 , Animais , Neoplasias Ósseas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia/métodos , Dióxido de Silício/química
5.
Inorg Chem ; 58(20): 14175-14184, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31559820

RESUMO

A series of ferrocene-appended half-sandwiched iridium(III) phenylpyridine complexes have been designed and synthesized. These complexes show better anticancer activity than cisplatin widely used in clinic under the same conditions. Meanwhile, complexes could effectively inhibit cell migration and colony formation. Complexes could interact with protein and transport through serum protein, effectively catalyzing the oxidation of nicotinamide-adenine dinucleotid and inducing the accumulation of reactive oxygen species (ROS, 1O2), which confirmed the anticancer mechanism of oxidation. Furthermore, laser scanning confocal detection indicates that these complexes can enter cells followed by a non-energy-dependent cellular uptake mechanism, effectively accumulating in the lysosome (Pearson's colocalization coefficient: ∼0.90), leading to lysosome damage, and reducing the mitochondrial membrane potential (MMP). Taken together, ferrocene-appended iridium(III) complexes possess the prospect of becoming a new multifunctional therapeutic platform, including lysosome-targeted imaging and anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Ferrosos/farmacologia , Irídio/farmacologia , Metalocenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Ferrosos/química , Humanos , Irídio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metalocenos/química , Estrutura Molecular , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
6.
Eur J Med Chem ; 181: 111599, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408807

RESUMO

In this work, five naphthalimide-modified half-sandwich iridium and ruthenium complexes ([(η5-Cpx)Ir(NˆN)Cl]PF6, [(η6-p-cym)Ru(NˆN)Cl]PF6) have been presented. The anticancer activities of the complexes against various cancer cell lines were investigated, among them, complexes 2 and 4 showed better anticancer activity than cisplatin, and their anticancer activity is better than complex 5 without fluorophore. In addition, a series of biological tests of complex 2 were performed using flow cytometry, the results indicated that the complex could induce cell death in a variety of ways. By changing of the ligands, the complexes exhibited different photophysical properties, and the mechanism of action of the complexes entering the cell and inducing apoptosis are different. Moreover, complex 2 successfully targeted mitochondria, while complex 4 targeted lysosomes, causing mitochondrial damage and lysosomal damage to induce apoptosis. Excitingly, complex 2 has good antimetastatic ability to cancer cells. Furthermore, complexes 2 and 4 did not have a significant effect on the NADH binding reaction, but they had a moderate binding ability to BSA.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Naftalimidas/farmacologia , Rutênio/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Irídio/química , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Naftalimidas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Rutênio/química
7.
Chem Commun (Camb) ; 55(70): 10472-10475, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31411208

RESUMO

A mitochondria-targeted photodynamic therapy (PDT) agent was designed and synthesized. Upon light irradiation, it can produce photoacid and its photolysis products can further sensitize 1O2 generation, causing dual-mode (oxygen-independent and oxygen-dependent) photodynamic damage in mitochondria and killing cancer cells effectively even under hypoxic conditions.


Assuntos
Irídio/farmacologia , Mitocôndrias/metabolismo , Fotoquimioterapia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Oxigênio Singlete/metabolismo
8.
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
9.
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
10.
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
11.
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
13.
Photodiagnosis Photodyn Ther ; 26: 448-454, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31048016

RESUMO

BACKGROUND AND OBJECTIVE: Photodynamic therapy has emerged as a promising treatment for cancer and other malignancies. Design of photosensitizers with two different action mechanisms may be an essential strategy for the improvement of the efficacy of phototherapeutic drugs. The objective of this study was to evaluate the anticancer photo- and chemocytotoxic effects of the novel half-sandwich rhodium(III) and iridium(III) photosensitizers. MATERIALS AND METHODS: A series of novel half-sandwich Cp*-Rh(III) and Cp*-Ir(III) complexes containing 9-anthraldehyde thiosemicarbazones, (Cp*)M(L)Cl (M = Rh or Ir, L = 9-anthraldehyde thiosemicarbazones), were compared for cell uptake and photo- and chemocytotoxic effects against human prostate carcinoma (PC3) and human ovarian carcinoma (SKOV3) cell lines. RESULTS: Cp*-Ir(III) complexes, (Cp*)Ir(L)Cl, showed remarkable phototoxic behavior against human ovarian adenocarcinoma SKOV3 cells (IC50 = 2.7 and 2.3 µM, respectively, λirr > 400 nm), as well as the 7.4 and 5.3-fold lower toxicity in the dark, implying possibility of dual action as chemo- and phototherapeutic agents. CONCLUSION: The complexes, which present a synergistic effect with good properties of both the Cp*-Rh(III) and Cp*-Ir(III) chemotherapeutic effect and the anthracene photodynamic therapy efficiency, show great potential as a new generation of light activated dual-action anticancer agents for photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Irídio/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Ródio/farmacologia , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Feminino , Humanos , Técnicas In Vitro , Masculino , Neoplasias Ovarianas/tratamento farmacológico , Fármacos Fotossensibilizantes/síntese química , Neoplasias da Próstata/tratamento farmacológico
14.
Dalton Trans ; 48(26): 9692-9702, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-30949652

RESUMO

The synthesis, characterization, and photophysical properties of two novel cyclometalated iridium(iii) PEG complexes with a disulfide linkage [Ir(N^C)2(bpy-SS-PEG)](PF6) (bpy-SS-PEG = 4-(N-(2-((N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)amino)cabonylethoxy)dithiolethoxy)carbonylamino)methyl-4'-methyl-2,2'-bipyridine; HN^C = methyl 2-phenyl-4-quinolinecarboxylate (pqe) (1a), 2-phenylquinoline (pq) (2a)), their PEG-free counterparts [Ir(N^C)2(bpy-SS-py)](PF6) (HN^C = pqe (1b), pq (2b)), their disulfide-free counterparts [Ir(N^C)2(bpy-CONH-PEG)](PF6) (bpy-CONH-PEG = 4-N-(2-(ω-methoxypoly-(1-oxapropyl))ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine; (HN^C = pqe (1c), pq (2c)), and a bimetallic iridium(iii)-rhenium(i) complex [Ir(pqe)2(bpy-SS-py)Re(Me4-phen)(CO)3](PF6)(CF3SO3) (Me4-phen = 3,4,7,8-tetramethyl-1,10-phenathroline) (3) are reported. Upon irradiation, the complexes displayed intense green to red emission under ambient conditions. Complex 3 containing two communicating luminophores exhibited large spectral overlap and was found to have a theoretical FRET efficiency of 0.79. In the presence of GSH, the bimetallic disulfide-containing complex 3 would be cleaved which was followed by a 8-fold increase in emission intensity of the rhenium(i) moiety. The reaction was found to be specific toward Cys, GSH, and H2S compared to other biothiols. Cell-based assays on complex 1a demonstrated that the addition of GSH to induce cleavage of the disulfide linkage would provide a more cytotoxic agent due to the release of the appended PEG pendant. Cellular localization studies by laser-scanning confocal microscopy in live HeLa cells indicated that complexes 1a-c exhibited punctate staining in the mitochondria.


Assuntos
Complexos de Coordenação/farmacologia , Citotoxinas/farmacologia , Irídio/farmacologia , Polímeros/farmacologia , Piridinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Irídio/química , Microscopia Confocal , Mitocôndrias/química , Estrutura Molecular , Imagem Óptica , Polímeros/química , Piridinas/química , Relação Estrutura-Atividade
15.
Inorg Chem ; 58(9): 5956-5965, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-30986046

RESUMO

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-ß-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh3) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Iminas/química , Irídio/química , Rutênio/química , Células A549 , Aminação , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Células HeLa , Células Hep G2 , Humanos , Iminas/síntese química , Iminas/farmacologia , Irídio/farmacologia , Modelos Moleculares , Neoplasias/tratamento farmacológico , Rutênio/farmacologia
16.
Dalton Trans ; 48(15): 4788-4793, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30892340
17.
Chemistry ; 25(28): 7012-7022, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-30913329

RESUMO

The chemo-anti-inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti-inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long-lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase-dependent apoptosis and caspase-independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial-targeting and immunomodulatory activities is feasible to develop multifunctional metal-based anticancer agents.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Aspirina/uso terapêutico , Complexos de Coordenação/uso terapêutico , Imunomodulação/efeitos dos fármacos , Irídio/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Aspirina/química , Aspirina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Feminino , Humanos , Irídio/química , Irídio/farmacologia , Medições Luminescentes/métodos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Imagem Óptica/métodos
18.
Future Med Chem ; 11(2): 119-135, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30644327

RESUMO

Despite improvements in the 5-year survival rate to over 80% in cancers, such as Hodgkin lymphoma and testicular cancer, more aggressive tumors including pancreatic and brain cancer still have extremely low survival rates. The establishment of chemoresistance, responsible for the reduction in treatment efficiency and cancer relapse, is one possible explanation for this setback. Metal-based compounds, a class of anticancer drugs, are largely used in the treatment of cancer. Herein, we will review the use of metal-based small molecules in chemotherapy, focusing on recent studies, and we will discuss how new nonplatinum-based agents are prompting scientists to increase drug specificity to overcome chemoresistance in cancer cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Metais/química , Metais/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carboplatina/química , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Cisplatino/química , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Cobre/química , Cobre/farmacologia , Cobre/uso terapêutico , Descoberta de Drogas , Ouro/química , Ouro/farmacologia , Ouro/uso terapêutico , Humanos , Irídio/química , Irídio/farmacologia , Irídio/uso terapêutico , Ferro/química , Ferro/farmacologia , Ferro/uso terapêutico , Metais/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Rênio/química , Rênio/farmacologia , Rênio/uso terapêutico , Ródio/química , Ródio/farmacologia , Ródio/uso terapêutico , Rutênio/química , Rutênio/farmacologia , Rutênio/uso terapêutico
19.
Cancer Lett ; 447: 75-85, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30673591

RESUMO

Herein we present half-sandwich IrIII complexes [(η5-Cpxbiph)Ir(OˆC)Cl] containing OˆC(NHC)-chelating ligand as anticancer and antimetastasis agents. All the complexes displayed high potency in vitro against a wide range of cancer cells. In addition, Ir2 significantly curb tumor growth in a colon cancer mouse xenograft model in vivo. Further mechanism of action studies indicate that Ir2-initiated apoptosis occurs through ROS-mediated cross-talk between mitochondria and lysosomes.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Irídio/farmacologia , Lisossomos/efeitos dos fármacos , Metano/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Feminino , Células HCT116 , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Ligantes , Lisossomos/metabolismo , Metano/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo
20.
Appl Biochem Biotechnol ; 187(2): 556-569, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30003473

RESUMO

Half sandwich complexes of the type [(η5-C5Me5)M(L1-3)Cl]Cl.2H2O were synthesized using [{(η5-C5Me5)M(µ-Cl)Cl}2], where M = Rh(III)/Ir(III) and L1-3 = pyrimidine-based ligands. The complexes were characterized by spectral analysis. DNA interaction studies by absorption titration and hydrodynamic measurement and suggest intercalative mode of binding of complexes with CT-DNA. The molecular docking study also supports intercalation of the complexes between the stacks of nucleotide base pairs. The gel electrophoresis assay demonstrated the ability of the complexes to interact and cleave plasmid DNA. Minimum inhibitory concentrations (MIC) of the complexes were investigated by the microdilution broth method. The cytotoxic properties of the metal complexes were evaluated using brine shrimp lethality bioassay.


Assuntos
Complexos de Coordenação , Citotoxinas , Desoxirribonucleases , Irídio , Simulação de Acoplamento Molecular , Ródio , Animais , Artemia/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Desoxirribonucleases/síntese química , Desoxirribonucleases/química , Desoxirribonucleases/farmacologia , Irídio/química , Irídio/farmacologia , Ródio/química , Ródio/farmacologia
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