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1.
J Org Chem ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31984747

RESUMO

A copper-catalyzed decarboxylative cycloaddition of propiolic acids, azides, and arylboronic acids is described. The present reaction provides an efficient and convenient method for the synthesis of various fully substituted 1,2,3-triazoles from readily available starting materials. A possible mechanism is proposed.

2.
J Inorg Biochem ; 203: 110909, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31689591

RESUMO

Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclometalated iridium(III) complexes have been demonstrated as the potential anticancer agents, however, their antitumor efficacies against GSCs are still unknown. Herein, we investigated the antitumor activity of two cyclometalated iridium(III) complexes [Ir(ppy)2L](PF6) (Ir1) and [Ir(thpy)2L](PF6) (Ir2) (ppy = 2-phenylpyridine, thpy = 2-(2-thienyl)pyridine and L = 4,4'-Bis(hydroxymethyl)-2,2'-bipyridine) against GSCs. The results clearly indicate that Ir1 and Ir2 kill GSCs selectively with IC50 values ranging from 5.26-9.05 µM. Further mechanism research display that Ir1 and Ir2 can suppress the proliferation of GSCs, penetrate into GSCs efficiently, localize to mitochondria, and induce mitochondria-mediated apoptosis, including the loss of mitochondrial membrane (MMP), elevation of intracellular reactive oxygen species (ROS) and caspases activation. Moreover, Ir1 and Ir2 can destroy the GSCs self-renewal and unlimited proliferation capacity by affecting the GSCs colony formation. According our knowledge, this is the first study to investigate the anti-GSCs properties of cyclometalated iridium(III) complexes.

3.
Chemistry ; 23(60): 15166-15176, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28833658

RESUMO

Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated IrIII complexes have emerged as potential anticancer agents. By conjugation of VPA to IrIII complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1 a-3 a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1 a-3 a can overcome cisplatin resistance effectively and are about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin-resistant human lung carcinoma (A549R) cells. Mechanistic studies indicate that 1 a-3 a can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, accumulate in mitochondria, and induce a series of cell-death-related events mediated by mitochondria. This study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents.


Assuntos
Antineoplásicos/toxicidade , Complexos de Coordenação/química , Irídio/química , Mitocôndrias/efeitos dos fármacos , Ácido Valproico/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cisplatino/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Humanos , Microscopia de Fluorescência por Excitação Multifotônica , Conformação Molecular , Espécies Reativas de Oxigênio/metabolismo
4.
Dalton Trans ; 46(2): 445-454, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27942635

RESUMO

New TEMPO-functionalized Ru(ii) polypyridyl complexes were synthesized as efficient theranostic photosensitizers for cancer treatment. Interestingly, due to the presence of a redox sensitive TEMPO moiety, an enhancement in the intracellular fluorescence of TEMPO-functionalized Ru(ii) complexes was observed during photodynamic treatment in both confocal microscopy and flow cytometry. This can be explained by the conversion of the TEMPO radical moiety to diamagnetic non-radical species in cells upon PDT-induced oxidative stress. To the best of our knowledge this is the first ruthenium complex capable of simultaneously inducing and monitoring the oxidative stress. The tethered TEMPO moiety decreased the inherent dark-cytotoxicity and increased the photo-toxicity simultaneously, both of which contributed to the greatly improved photodynamic therapy (PDT) efficacy, ultimately resulting in cancer cell apoptosis. The phototoxicity index value for TEMPO-functionalized Ru(ii) complexes was selective towards cancer cell lines (280.5 for HeLa cells vs. 30.2 for LO2 cells) and ca. 40-fold higher than that for TEMPO-free Ru(ii) analogues (6.7 for HeLa cells). The main contributor for such a greatly enhanced PDT efficacy was the effect of the TEMPO moiety on the cellular uptake and intracellular ROS levels. We therefore demonstrate that the combination of TEMPO with the photosensitizers may be an emerging strategy to develop novel photosensitizer-based theranostic platforms, which can induce and monitor the PDT response simultaneously.

5.
Chem Commun (Camb) ; 53(5): 842-845, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-27917426

RESUMO

We report here a supramolecular strategy to assemble a cyclodextrin-functionalized anticancer Ru(ii) complex with an adamantane-appended tumor-targeting peptide into discrete and stable phosphorescent nanostructures that can induce cell death in integrin αvß3-rich tumor cells with high selectivity. This strategy presents new opportunities for the construction of tumor-targeting metallo-anticancer therapeutics.

6.
Sci Rep ; 6: 38954, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27958338

RESUMO

Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2'-bipyridine-4,4'-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties. The quantum yields and emission lifetimes are influenced by variation of the ester substituents on the Ir(III) complexes. The cytotoxicity of these Ir(III) complexes is correlated with the length of their ester groups. Among them, 4a and 4b are found to be highly active against a panel of cancer cells screened, including cisplatin-resistant cancer cells. Mechanism studies in vitro indicate that they undergo hydrolysis of ester bonds, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. Furthermore, 4a and 4b can induce pro-death autophagy and apoptosis simultaneously. Our study indicates that ester modification is a simple and feasible strategy to enhance the anticancer potency of Ir(III) complexes.


Assuntos
Antineoplásicos , Complexos de Coordenação , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Irídio , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Células Hep G2 , Humanos , Irídio/química , Irídio/farmacologia , Células MCF-7 , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia
7.
Dalton Trans ; 45(33): 13042-51, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27139504

RESUMO

Theranostic anticancer agents incorporating anticancer properties with capabilities for real-time treatment assessment are appealing candidates for chemotherapy. The design of mitochondria-targeted cytotoxic drugs represents a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three coumarin-appended phosphorescent cyclometalated iridium(iii) complexes 1-3 have been explored as mitochondria-targeted theranostic anticancer agents. These complexes display rich photophysical properties, which facilitate the study of their intracellular fate. All three complexes can specifically target mitochondria and show much higher antiproliferative activities than cisplatin against various cancer cells including cisplatin-resistant cells. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphological changes in mitochondria. Mechanism studies show that 1-3 exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Genome-wide transcriptional and Connectivity Map analyses reveal that the cytotoxicity of complex 3 is associated with pathways involved in mitochondrial dysfunction and apoptosis.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cumarínicos/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cumarínicos/química , Perfilação da Expressão Gênica , Humanos , Irídio/química , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina Teranóstica
8.
Chemistry ; 22(23): 7800-9, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27106876

RESUMO

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1-Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase-independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase-independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rênio/química , Rênio/farmacologia , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Compostos Organometálicos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Rênio/farmacocinética , Transcriptoma/efeitos dos fármacos
9.
Chem Commun (Camb) ; 51(39): 8353-6, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25882790

RESUMO

In this report, we designed a histone deacetylase-targeted phosphorescent Re(I) complex ReLMito. Colocalization studies suggested that ReLMito could specially localize to mitochondria. We also demonstrated that ReLMito could induce paraptosis in cancer cells. These features endowed the complex with potential to induce and monitor mitochondrial morphological changes during the paraptosis simultaneously.


Assuntos
Complexos de Coordenação/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Mitocôndrias/metabolismo , Piridinas/farmacologia , Rênio/farmacologia , Amidas/química , Amidas/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/química , Células HeLa , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Piridinas/química , Rênio/química
10.
Chem Sci ; 6(10): 5409-5418, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29861886

RESUMO

Stimuli-activatable photosensitizers (PSs) are highly desirable for photodynamic therapy (PDT) to selectively demolish tumor cells. On the other hand, lysosomes are emerging as attractive anticancer targets. Herein, four cyclometalated iridium(iii)-ß-carboline complexes with pH-responsive singlet oxygen (1O2) production and lysosome-specific imaging properties have been designed and synthesized. Upon visible light (425 nm) irradiation, they show highly selective phototoxicities against cancer cells. Notably, complex 2 ([Ir(N^C)2(N^N)](PF6) in which N^C = 2-phenylpyridine and N^N = 1-(2-benzimidazolyl)-ß-carboline) displays a remarkably high phototoxicity index (PI = IC50 in the dark/IC50 in light) of >833 against human lung carcinoma A549 cells. Further studies show that 2-mediated PDT induces caspase-dependent apoptosis through lysosomal damage. The pH-responsive phosphorescence of complex 2 can be utilized to monitor the lysosomal integrity upon PDT, which provides a reliable and convenient method for in situ monitoring of therapeutic effect and real-time assessment of treatment outcome. Our work provides a strategy for the construction of highly effective multifunctional subcellular targeted photodynamic anticancer agents through rational structural modification of phosphorescent metal complexes.

11.
Angew Chem Int Ed Engl ; 53(45): 12137-41, 2014 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-25244053

RESUMO

During autophagy, the intracellular components are captured in autophagosomes and delivered to lysosomes for degradation and recycling. Changes in lysosomal trafficking and contents are key events in the regulation of autophagy, which has been implicated in many physiological and pathological processes. In this work, two iridium(III) complexes (LysoIr1 and LysoIr2) are developed as theranostic agents to monitor autophagic lysosomes. These complexes display lysosome-activated phosphorescence and can specifically label lysosomes with high photostability. Simultaneously, they can induce autophagy potently without initiating an apoptosis response. We demonstrate that LysoIr2 can effectively implement two functions, namely autophagy induction and lysosomal tracking, in the visualization of autophagosomal-lysosomal fusion. More importantly, they display strong two-photon excited fluorescence (TPEF), which is favorable for live cell imaging and in vivo applications.


Assuntos
Autofagia , Irídio/química , Lisossomos/metabolismo , Linhagem Celular Tumoral , Proteínas de Fluorescência Verde/metabolismo , Humanos , Fótons , Espectroscopia de Prótons por Ressonância Magnética
13.
Chemistry ; 19(31): 10160-9, 2013 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-23828334

RESUMO

Histone deacetylases inhibitors (HDACis) have gained much attention as a new class of anticancer agents in recent years. Herein, we report a series of fluorescent ruthenium(II) complexes containing N(1)-hydroxy-N(8)-(1,10-phenanthrolin-5-yl)octanediamide (L), a suberoylanilide hydroxamic acid (SAHA) derivative, as a ligand. As expected, these complexes show interesting chemiphysical properties, including relatively high quantum yields, large Stokes shifts, and long emission lifetimes. The in vitro inhibitory effect of the most effective drug, [Ru(DIP)2L](PF6)2 (3; DIP: 4,7-diphenyl-1,10-phenanthroline), on histone deacetylases (HDACs) is approximately equivalent in activity to that of SAHA, and treatment with complex 3 results in increased levels of the acetylated histone H3. Complex 3 is highly active against a panel of human cancer cell lines, whereas it shows relatively much lower toxicity to normal cells. Further mechanism studies show that complex 3 can elicit cell cycle arrest and induce apoptosis through mitochondria-related pathways and the production of reactive oxygen species. These data suggest that these fluorescent ruthenium(II)-HDACi conjugates may represent a promising class of anticancer agents for potential dual imaging and therapeutic applications targeting HDACs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Rutênio/química , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ligantes , Estrutura Molecular , Compostos Organometálicos/química , Espécies Reativas de Oxigênio/análise , Vorinostat
14.
Chemistry ; 19(36): 12152-60, 2013 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-23878093

RESUMO

A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate ß-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that ß-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/antagonistas & inibidores , Carbolinas/química , Carbolinas/síntese química , Cisplatino/química , Inibidores Enzimáticos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Antineoplásicos/química , Carbolinas/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Compostos Organometálicos/farmacologia , Rutênio/química
15.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 4): o769, 2010 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-21580613

RESUMO

In the the title compound, C(19)H(18)BrNO(3), the furan-one ring is almost planar [maximum atomic deviation = 0.019 (3) Å] and is nearly perpendicular to the two phenyl rings, making dihedral angles of 88.96 (17) and 87.71 (17)°. Inter-molecular C-H⋯O hydrogen bonding is present in the crystal structure.

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