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1.
J Inorg Biochem ; 224: 111591, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34450410

RESUMO

Alzheimer's disease (AD) is known as a complex multifactorial syndrome and both metal chelators and amyloid ß peptide (Aß) inhibitors show promise against AD. Herein, four small hybrid compounds have been designed and synthesized utilizing 8-hydroxyquinoline, pyridine or imidazole as chelators and benzimidazole as the recognition moiety for AD treatment. These conjugates can capture Cu2+ from Aß and become dimers upon Cu2+ coordination and show high efficiency for both Cu2+ elimination and Aß assembly inhibition. Besides, these designed complexes can inhibit the production of Aß-induced reactive oxygen species (ROS), protect mitochondria from damage, and improve the survival rate of neuron cells. Our work provides a new strategy to combine hydrophobic interaction and metal ion chelation to design amyloid inhibitors.

2.
Adv Sci (Weinh) ; 8(17): e2004566, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34197052

RESUMO

Oncosis, depending on DNA damage and mitochondrial swelling, is an important approach for treating cancer and other diseases. However, little is known about the behavior of mitochondria during oncosis, due to the lack of probes for in situ visual illumination of the mitochondrial membrane and mtDNA. Herein, a mitochondrial lipid and mtDNA dual-labeled probe, MitoMN, and a continuous add-on assay, are designed to image the dynamic process of mitochondria in conditions that are unobservable with current mitochondrial probes. Meanwhile, the MitoMN can induce oncosis in a light-activated manner, which results in the enlargement of mitochondria and the death of cancer cells. Using structured illumination microscopy (SIM), MitoMN-stained mitochondria with a dual-color response reveals, for the first time, how swelled mitochondria interacts and fuses with each other for a nonlinear enlargement to accelerate oncosis into an irreversible stage. With this sign of irreversible oncosis revealed by MitoMN, oncosis can be segregated into three stages, including before oncosis, initial oncosis, and accelerated oncosis.

3.
J Am Chem Soc ; 143(30): 11370-11381, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34291952

RESUMO

Phase separation of DNA is involved in chromatin packing for the regulation of gene transcription. Visualization and manipulation of DNA phase separation in living cells present great challenges. Herein, we present a Ru(II) complex (Ru1) with high DNA binding affinity and DNA "light-switch" behavior that can induce and monitor DNA phase separation both in vitro and in living cells. Molecular dynamics simulations indicate that the two phen-PPh3 ligands with positively charged lipophilic triphenylphosphine substituents and flexible long alkyl chains in Ru1 play essential roles in the formation of multivalent binding forces between DNA molecules to induce DNA phase separation. Importantly, the unique environmental sensitive emission property of Ru1 enables direct visualization of the dynamic process of DNA phase separation in living cells by two-photon phosphorescent lifetime imaging. Moreover, Ru1 can change the gene expression pattern by modulating chromatin accessibility as demonstrated by integrating RNA-sequencing and transposase-accessible chromatin with high-throughput sequencing. In all, we present here the first small-molecule-based tracer and modulator of DNA phase separation in living cells and elucidate its impact on the chromatin state and transcriptome.

4.
Chem Sci ; 12(7): 2357-2367, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-34164000

RESUMO

Phosphorescent metal complexes are a new kind of multifunctional antitumor compounds that can integrate imaging and antitumor functions in a single molecule. In this minireview, we summarize the recent research progress in this field, concentrating on the theranostic applications of phosphorescent iridium(iii), ruthenium(ii) and rhenium(i) complexes. The molecular design that affords these complexes with tumour- or subcellular organelle-targeting properties is elucidated. The potential of these complexes to induce and monitor the dynamic behavior of subcellular organelles and the changes in microenvironment during the process of therapy is demonstrated. Moreover, the potential and advantages of applying new technologies, such as super-resolution imaging and phosphorescence lifetime imaging, are also described. Finally, the challenges faced in the development of novel theranostic metallo-anticancer complexes for possible clinical translation are proposed.

5.
Dalton Trans ; 50(26): 9068-9075, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34113944

RESUMO

Over the past few decades, the landscape of inorganic medicinal chemistry has been dominated by investigations on platinum or ruthenium, while the research based on other metal centers such as rhodium has been relatively insufficient. In this work, a series of cyclometalated rhodium(iii) complexes with imidazo[4,5-f][1,10]phenanthroline containing different aromatic rings were synthesized and characterized. Notably, all the complexes displayed stronger anticancer activity against various cancer cells compared with cisplatin. A mechanism study revealed that the rhodium complexes accumulated in the mitochondria, elevated the levels of mitochondrial reactive oxygen species (ROS) and released cytochrome c, indicating severe mitochondrial damage during the anticancer activity. Further studies illustrated that the rhodium complexes caused cell cycle arrest at the G2/M phase, upregulated the expression of p53 and reduced the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated x (Bax), which ultimately resulted in cellular apoptosis. Overall, through mitochondrial pathways, these Rh(iii) complexes could induce cellular apoptosis to a larger extent than cisplatin and should be paid close attention as promising chemotherapeutic drugs in anticancer research.

6.
Angew Chem Int Ed Engl ; 60(27): 15095-15100, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33835669

RESUMO

Ferroptosis regulates cell death through reactive oxygen species (ROS)-associated lipid peroxide accumulation, which is expected to affect the structure and polarity of lipid droplets (LDs), but with no clear evidence. Herein, we report the first example of an LD/nucleus dual-targeted ratiometric fluorescent probe, CQPP, for monitoring polarity changes in the cellular microenvironment. Due to the donor-acceptor structure of CQPP, it offers ratiometric fluorescence emission and fluorescence lifetime signals that reflect polarity variations. Using nucleus imaging as a reference, CQPP was applied to report the increase in LD polarity and the homogenization of polarity between LDs and cytoplasm in the ferroptosis model. This LD/nucleus dual-targeted fluorescent probe shows the great potential of using fluorescence imaging to study ferroptosis and ferroptosis-related diseases.


Assuntos
Núcleo Celular/metabolismo , Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Ferroptose , Corantes Fluorescentes/síntese química , Humanos , Gotículas Lipídicas/química , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo
7.
Chem Commun (Camb) ; 57(41): 5040-5042, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33881416

RESUMO

Herein, we report a neutral iridium complex, [Ir(4-(2-pyridinyl)benzaldehyde)2(acetylacetone)] (Ir-ER), with viscosity-responsive phosphorescent emission intensity and lifetime. Quantitative measurement by two-photon phosphorescent lifetime imaging shows that the viscosity of ER increases significantly in the process of erastin-induced ferroptosis. Our work provides an effective strategy for quantitative measurement of the micro-environmental alternations of subcellular organelles during a specific cell death process.


Assuntos
Complexos de Coordenação/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Irídio/farmacologia , Imagem Óptica , Complexos de Coordenação/química , Retículo Endoplasmático/metabolismo , Humanos , Irídio/química , Células MCF-7 , Estrutura Molecular , Fótons , Piperazinas/farmacologia , Viscosidade
8.
J Inorg Biochem ; 218: 111400, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33684684

RESUMO

Recently, rhodium complexes have received intensive attentions due to their tunable chemical and biological properties as well as attractive antitumor activity. In this work, two imidazole triphenylamino rhodium complexes [Rh(ppy)2L1]PF6 (Rh1) and [Rh(ppy)2L2]PF6 (Rh2) (ppy = 2-phenylpyridine, L1 = 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N,N-diphenylaniline, L2 = N-(4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenyl)-4-methyl-N-(p-tolyl)aniline) have been synthesized and characterized. Both complexes display stronger anticancer activity against a various of cancer cells than cisplatin and they can effectively localize to mitochondria. Further mechanism studies show that Rh1 induce caspase-dependent apoptosis through mitochondrial damage, down-regulate the expression of B-cell lymphoma-2 (Bcl-2)/Bcl2-associated x (Bax) and reactive oxygen species (ROS) elevation. Our work provides a strategy for the construction of highly effective anticancer agents targeting mitochondrial metabolism through rational modification of rhodium complexes.

9.
Small ; 17(1): e2005086, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33284508

RESUMO

The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N6 -methyladenosine (m6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsSx -PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O2 modulator is developed to improve tumor hypoxia. OsSx -PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsSx -PEG NPs elevate RNA m6 A methylation levels to cause the m6 A-dependent mRNA degradation of the hypoxia-related genes. Moreover, OsSx -PEG NPs can regulate the expression of RNA m6 A methyltransferases and demethylases. Finally, DOX@OsSx -PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m6 A methylation of hypoxia-related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia-modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance.


Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina , Humanos , Hipóxia , Metilação , Polietilenoglicóis
10.
Inorg Chem ; 59(17): 12632-12642, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32838518

RESUMO

Multifunctional platinumIV anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinumII anticancer agents. Herein, we develop dual and triple action platinumIV complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As a result, PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from PFL. Furthermore, treatment with PFL impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that PFL can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that PFL intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Inibidores Enzimáticos/química , Platina/química , Pró-Fármacos/metabolismo , Timidilato Sintase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Liberação Controlada de Fármacos , Fluoruracila/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Transcrição Genética/efeitos dos fármacos
11.
Angew Chem Int Ed Engl ; 59(42): 18755-18762, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32634290

RESUMO

The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.


Assuntos
Complexos de Coordenação/química , Ferro/metabolismo , Mitocôndrias/metabolismo , Rênio/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Deferasirox/química , Avaliação Pré-Clínica de Medicamentos , Epigenômica , Histonas/metabolismo , Humanos , Quelantes de Ferro/química , Metilação/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , RNA Polimerase II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Biochem Pharmacol ; 175: 113848, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044354

RESUMO

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Chalconas/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/química , Linhagem Celular Tumoral , Chalconas/química , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética
13.
Adv Sci (Weinh) ; 7(1): 1901992, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31921566

RESUMO

Ruthenium complexes are promising photosensitizers (PSs), but their clinical applications have many limitations. Here, a multifunctional nano-platform PDA-Pt-CD@RuFc formed by platinum-decorated and cyclodextrin (CD)-modified polydopamine (PDA) nanoparticles (NPs) loaded with a ferrocene-appended ruthenium complex (RuFc) is reported. The NPs can successfully deliver RuFc to the tumor sites. The release of RuFc from the NPs can be triggered by low pH, photothermal heating, and H2O2. The combined photodynamic and photothermal therapy (PDT-PTT) mediated by PDA-Pt-CD@RuFc NPs can overcome the hypoxic environment of tumors from several aspects. First, the platinum NPs can catalyze H2O2 to produce O2. Second, vasodilation caused by photothermal heating can sustain the oxygen supplement. Third, PDT exerted by RuFc can also occur through the non-oxygen-dependent Fenton reaction. Due to the presence of PDA, platinum NPs, and RuFc, the nanosystem can be used in multimodal imaging including photothermal, photoacoustic, and computed tomography imaging. The NPs can be excited by the near-infrared two-photon light source. Moreover, the combined treatment can improve the tumor microenvironments to obtain an optimized combined therapeutic effect. In summary, this study presents a tumor-microenvironment-adaptive strategy to optimize the potential of ruthenium complexes as PSs from multiple aspects.

14.
Eur J Med Chem ; 179: 849-862, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302589

RESUMO

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Dicetopiperazinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
Chem Sci ; 10(11): 3315-3323, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30996918

RESUMO

Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.

16.
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
17.
Dalton Trans ; 48(13): 4398-4404, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30864598

RESUMO

Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing ß-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carbolinas/farmacologia , Complexos de Coordenação/farmacologia , Lisossomos/efeitos dos fármacos , Rênio/química , Células A549 , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carbolinas/síntese química , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Complexos de Coordenação/síntese química , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Camundongos Nus , Relação Estrutura-Atividade
18.
ACS Appl Mater Interfaces ; 11(14): 13123-13133, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30888144

RESUMO

Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re2(CO)6(dip)2L](PF6)2 (dip = 4,7-diphenyl-1,10-phenanthroline; L = 4,4'-azopyridine (ReN) or 4,4'-dithiodipyridine (ReS)) were synthesized and characterized. ReN and ReS can react with glutathione (GSH). They exhibit good in vitro anticancer activity against cancer cell lines screened. Besides, they can target mitochondria, cause oxidative stress, and disturb GSH metabolism. Both ReN and ReS can induce necroptosis and caspase-dependent apoptosis simultaneously. We also demonstrate that ReN and ReS can inhibit tumor growth in nude mice bearing carcinoma xenografts. Our study shows the potential of Re(I) complexes as chemotherapeutic agents to kill cancer cells via a mitochondria-to-cellular redox strategy.


Assuntos
Carcinogênese/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Rênio/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/química , Rênio/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Med Chem ; 62(7): 3311-3322, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30816710

RESUMO

Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Dano ao DNA , DNA Mitocondrial/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Irídio/química , Células A549 , Animais , Complexos de Coordenação/química , Cristalografia por Raios X , DNA Mitocondrial/metabolismo , Células HeLa , Humanos , Ligantes , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Chem Sci ; 10(5): 1285-1293, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30809342

RESUMO

Precise quantitative measurement of viscosity at the subcellular level presents great challenges. Two-photon phosphorescence lifetime imaging microscopy (TPPLIM) can reflect micro-environmental changes of a chromophore in a quantitative manner. Phosphorescent iridium complexes are potential TPPLIM probes due to their rich photophysical properties including environment-sensitive long-lifetime emission and high two-photon absorption (TPA) properties. In this work, a series of iridium(iii) complexes containing rotatable groups are developed as mitochondria-targeting anticancer agents and quantitative viscosity probes. Among them, Ir6 ([Ir(ppy-CHO)2(dppe)]PF6; ppy-CHO: 4-(2-pyridyl)benzaldehyde; dppe: cis-1,2-bis(diphenylphosphino)ethene) shows satisfactory TPA properties and long lifetimes (up to 1 µs). The emission intensities and lifetimes of Ir6 are viscosity-dependent, which is mainly attributed to the configurational changes in the diphosphine ligand as proved by 1H NMR spectra. Ir6 displays potent cytotoxicity, and mechanism investigations show that it can accumulate in mitochondria and induce apoptotic cell death. Moreover, Ir6 can induce mitochondrial dysfunction and monitor the changes in mitochondrial viscosity simultaneously in a real-time and quantitative manner via TPPLIM. Upon Ir6 treatment, a time-dependent increase in viscosity and heterogeneity is observed along with the loss of membrane potential in mitochondria. In summary, our work shows that multifunctional phosphorescent metal complexes can induce and precisely detect microenvironmental changes simultaneously at the subcellular level using TPPLIM, which may deepen the understanding of the cell death mechanisms induced by these metallocompounds.

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