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1.
Nat Commun ; 12(1): 26, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397915

RESUMO

Mitochondrial oxidation-induced cell death, a physiological process triggered by various cancer therapeutics to induce oxidative stress on tumours, has been challenging to investigate owing to the difficulties in generating mitochondria-specific oxidative stress and monitoring mitochondrial responses simultaneously. Accordingly, to the best of our knowledge, the relationship between mitochondrial protein oxidation via oxidative stress and the subsequent cell death-related biological phenomena has not been defined. Here, we developed a multifunctional iridium(III) photosensitiser, Ir-OA, capable of inducing substantial mitochondrial oxidative stress and monitoring the corresponding change in viscosity, polarity, and morphology. Photoactivation of Ir-OA triggers chemical modifications in mitochondrial protein-crosslinking and oxidation (i.e., oxidative phosphorylation complexes and channel and translocase proteins), leading to microenvironment changes, such as increased microviscosity and depolarisation. These changes are strongly related to cell death by inducing mitochondrial swelling with excessive fission and fusion. We suggest a potential mechanism from mitochondrial oxidative stress to cell death based on proteomic analyses and phenomenological observations.


Assuntos
Irídio/farmacologia , Mitocôndrias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Morte Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Transferência de Energia , Células HEK293 , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Oxirredução/efeitos dos fármacos , Proteoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Viscosidade
2.
Dalton Trans ; 49(11): 3562-3569, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123890

RESUMO

The combination of chemotherapeutic and photodynamic activities in an iridium-based molecular compound is less reported. Herein, two iridium complexes (IrC1 and IrC2) with ß-carboline alkaloid ligands were designed and synthesized. Both complexes exhibited high anticancer activities with IC50 values of around 1 µM in the dark against several cell lines tested. Notably, the cytotoxicity of these two complexes against lung cancer (A549) cells increased significantly under light (425 nm) irradiation, with phototoxicity index (PI) values of 120 and 93, respectively. They were specifically enriched in the mitochondria. Cell-based assays demonstrated that IrC1 induced an increase in intracellular reactive oxygen species (ROS) levels, reduction in ATP production, mitochondrial DNA damage, an increase in lipid peroxidation levels, and proteasomal activity inhibition. Under light conditions (in some cases a two-photon laser was also applied), these effects were greatly enhanced. Overall, we have demonstrated that these iridium complexes have dual activities of chemotherapy and photodynamic therapy, which may help to design new metal-based anticancer agents for combined chemo-photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Dano ao DNA , DNA Mitocondrial/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química
3.
Dalton Trans ; 49(14): 4491-4501, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32191249

RESUMO

Reaction between 2-(2'-pyridyl)benzimidazole derivatives and [{IrCl(η5-C5Me5)}2(µ-Cl)2] afforded mono- and binuclear "piano-stool" Ir(iii) compounds of type [IrnCln(η5-C5Me5)n(L)]Cln (n = 1, L = LET (1) and LSO3H (2); n = 2, L = LBN (3)), which were fully characterized, including the X-ray crystallographic analysis of 1. While the free ligands and compound 3 exhibited no toxicity to the tested microbes, compound 1 was highly potent against bacteria (MIC = 12.9-25.8 nM) and fungi (MIC < 0.40 nM). However, complex 1 induced damage to non-malignant cell lines (human embryonic kidney (HEK293), CC50 = 0.995 µg mL-1) and human RBCs (HC10 = 10.9 µg mL-1 and HC50 > 32 µg mL-1). Interestingly, complex 2, bearing the benzimidazole ligand with an alkylated sulfonate side chain (LSO3H), was selectively potent against C. neoformans with MIC value of 11.2 nM and was non-toxic to HEK293. According to DNA binding studies, compounds 1-3 could be considered as moderate metallo intercalators with a binding constant of 5.0 × 104-1.0 × 105 M-1. Alternatively, evidence was obtained, from ESI-MS measurements, for the non-covalent mode of binding of 2 to hen egg white lysozyme, while compounds 1 and 3 decomposed during the interaction with that protein. This may be attributed to the electrostatic and H-bonding interactions between the polar sulfonate group and charged protein side-chains.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Candida albicans/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cryptococcus neoformans/efeitos dos fármacos , Cristalografia por Raios X , Ciclopentanos/química , Ciclopentanos/farmacologia , Teoria da Densidade Funcional , Escherichia coli/efeitos dos fármacos , Irídio/química , Irídio/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
4.
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
5.
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
6.
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
7.
ACS Nano ; 13(11): 12694-12702, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31644267

RESUMO

Noble-metal-based nanomaterials made of less toxic metals have been utilized as potential antibacterial agents due to their distinctive oxidase-like activity. In this study, we fabricated core-shell structured Pd@Ir bimetallic nanomaterials with an ultrathin shell. Pd@Ir nanostructures show morphology-dependent bactericidal activity, in which Pd@Ir octahedra possessing higher oxidase-like activity exert bactericidal activity stronger than that of Pd@Ir cubes. Furthermore, our results reveal that the presence of natural organic matter influences the antibacterial behaviors of nanomaterials. Upon interaction with humic acid (HA), the Pd@Ir nanostructures induce an elevated level of reactive oxygen species, resulting in significantly enhanced bactericidal activity of the nanostructures. Mechanism analysis shows that the presence of HA efficiently enhances the oxidase-like activity of nanomaterials and promotes the cellular internalization of nanomaterials. We believe that the present study will not only demonstrate an effective strategy for improving the bactericidal activity of noble-metal-based nanomaterials but also provide an understanding of the antibacterial behavior of nanomaterials in the natural environment.


Assuntos
Antibacterianos , Substâncias Húmicas , Nanopartículas Metálicas/química , Paládio , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Irídio/química , Irídio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Paládio/química , Paládio/farmacologia , Espécies Reativas de Oxigênio/metabolismo
8.
J Am Chem Soc ; 141(46): 18486-18491, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31644286

RESUMO

Among all molecules developed for anticancer therapies, photodynamic therapeutic agents have a unique profile. Their maximal activity is specifically triggered in tumors by light, and toxicity of even systemically delivered drug is prevented in nonilluminated parts of the body. Photosensitizers exert their therapeutic effect by producing reactive oxygen species via a light-activated reaction with molecular oxygen. Consequently, the lowering of pO2 deep in solid tumors limits their treatment and makes essential the design of oxygen-independent sensitizers. In this perspective, we have recently developed Ir(III)-based molecules able to oxidize biomolecules by type I processes under oxygen-free conditions. We examine here their phototoxicity in relevant biological models. We show that drugs, which are mitochondria-accumulated, induce upon light irradiation a dramatic decrease of the cell viability, even under low oxygen conditions. Finally, assays on 3D tumor spheroids highlight the importance of the light-activation step and the oxygen consumption rate on the drug activity.


Assuntos
Complexos de Coordenação/farmacologia , Irídio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Fotoquimioterapia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Células Tumorais Cultivadas
10.
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
11.
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
12.
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
13.
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
14.
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
15.
Metallomics ; 11(8): 1344-1352, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31347624

RESUMO

Iridium complexes have recently attracted increasing interest in developing metallodrugs. Herein, we have synthesized and characterized a clickable iridium hydride complex 2-N3. The cytotoxity and production of reactive oxygen species study in A2780 cancer cells indicated a potent anticancer activity of 2-N3. The ICP-MS analysis and the cellular imaging via Cu(i) catalyzed azide-alkyne cycloaddition suggested the accumulation of 2-N3 in the nucleus and cytoplasm. Further label-free quantitative proteomic analysis indicated that the ECM-receptor interaction pathway was activated by 2-N3. The analysis of down-regulated proteins suggested that 2-N3 affected cellular DNA transcription, post-translational glycosyl modification, and redox homeostasis. Besides, 2-N3 also damaged several crucial proteins and enzymes in the mitochondria and nucleus, leading to the disorder of the cellular processes. Our results provide a new approach to mechanism studies of metallodrugs combining click chemistry and proteomic analysis.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Alquinos/química , Antineoplásicos/química , Azidas/química , Linhagem Celular Tumoral , Química Click , Complexos de Coordenação/química , Reação de Cicloadição , Feminino , Humanos , Irídio/química , Modelos Moleculares , Imagem Óptica , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Proteínas/metabolismo , Proteômica , Espécies Reativas de Oxigênio/metabolismo
16.
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
17.
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 Fármacos , 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
18.
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
20.
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
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