RESUMO
A catalyst-free gem-difluorination/spirocyclization reaction has been successfully developed for the synthesis of gem-difluorinated C2-spiroindoline derivatives from indole-2-carboxamides. The resulting gem-difluorinated C2-spiroindolines can be easily converted into 2-spiropseudoindoxyls through hydrolysis. This method offers the benefits of simple operation, convenient access to raw materials, and mild conditions. Dual function of Selectfluor in this reaction is noteworthy as it can serve as both a fluorinating agent and an alkaline accelerator precursor.
RESUMO
An unprecedented Csp3-H imination reaction using arylazo sulfones as the readily accessible and stable N source is reported. The synthetic virtues are demonstrated through mild conditions, simple operation, good air compatibility, and functional group tolerance, as well as suitability for gram-scale reaction. The resulting imines can be further converted to α-amino acids. The presented results shed light on an unusual usage of arylazo sulfones and will inspire novel experimental design by using arylazo sulfones as the N source.
RESUMO
We report an electrochemical intramolecular [3 + 2] cyclization of alkynyl enaminones in a user-friendly undivided cell under constant current conditions without an oxidant and catalyst, and indeno[1,2-c]pyrrole derivatives could be obtained in good to excellent yields. Notably, preliminary substituent-controlled selective transformation is also achieved under electrocatalysis alone, and indeno[1,2-c]pyrrole (R4 ≠ H) or indanone derivatives (R4 = H) could be prepared directly under electrocatalysis without adding a base and heating process.
Assuntos
Indanos , Pirróis , Catálise , Ciclização , Indanos/química , Pirróis/químicaRESUMO
A method for the rapid synthesis of polycyclic 3,3'-biindole derivatives has been developed through AgOTf-catalyzed nucleophilic addition and cycloisomerization processes. The cascade reaction employs readily accessible indoles and their N-2-formylphenyl derivatives and provides functionalized polycyclic 3,3'-biindoles in moderate to good yields under mild conditions. This reaction is highly efficient and takes only several minutes (â¼5 min). Notably, the method is also highlighted by a Selectfluor-mediated oxidation reaction that quickly generates the oxindole derivatives.
RESUMO
We report a PhB(OH)2-promoted electrochemical sulfuration-formyloxylation reaction of styrenes employing commercially available thiophenols/thiols as thiolating agents. Specifically, metal catalysts and external chemical oxidants are not needed in the reaction for the formation of ß-formyloxy sulfides, and these sulfides can be further converted to (E)-vinyl sulfones via the Selectfluor-mediated oxidation-olefination. Notably, on the basis of this electrochemical oxidation strategy, ß-hydroxy sulfide, ß-formyloxy sulfoxide, ß-formyloxy sulfone, and (E)-vinyl sulfoxide can also be easily prepared.
RESUMO
A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl- , Br- , I- ) and pyridine leaving groups ([(η5 -CpX )Ir(Phen)Z](PF6 )n , Cpx : electron-rich cyclopentadienyl group, Z: leaving group) have been prepared. Target complexes, especially the Cpxbiph (biphenyl-substituted cyclopentadienyl)-based one, showed favourable anticancer activity against human lung cancer (A549) cells; the best one (Ir8) was almost five times that of cisplatin under the same conditions. Compared with complexes involving halide ion leaving groups, the pyridine-based one did not display hydrolysis but effectively caused lysosomal damage, leading to accumulation in the cytosol, inducing an increase in the level of intracellular reactive oxygen species and apoptosis; this indicated an anticancer mechanism of oxidation. Additionally, these complexes could bind to serum albumin through a static quenching mechanism. The data highlight the potential value of half-sandwich iridium(III) phenanthroline complexes as anticancer drugs.
Assuntos
Complexos de Coordenação/síntese química , Halogênios/química , Irídio/química , Fenantrolinas/química , Piridinas/química , Complexos de Coordenação/química , Íons/química , Estrutura MolecularRESUMO
A series of configuration-controlled Fe(ii)-Ir(iii) heteronuclear metal complexes, including ferrocene and half-sandwich like iridium(iii) complex units, have been designed and prepared. These complexes show better anticancer activity than cisplatin under the same conditions, especially cis-configurational ones. Laser confocal microscopy analysis confirms that the complexes follow a non-energy-dependent cellular uptake mechanism, accumulate in lysosomes (pearson co-localization coefficient: â¼0.7), lead to lysosomal damage, and eventually induce apoptosis. These complexes can reduce the mitochondrial membrane potential, disturb the cell circle, catalyze the oxidation of nicotinamide-adenine dinucleotide (NADH) and increase the levels of intracellular reactive oxygen species (ROS), following an anticancer mechanism of oxidation. In addition, the complexes could bind to serum protein, and transport through it. Above all, the Fe(ii)-Ir(iii) heteronuclear metal complexes hold promise as potential anticancer agents for further study.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Irídio/química , Ferro/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NAD/metabolismo , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Four triphenylamine/carbazole-modified half-sandwich ruthenium(ii) compounds [(η6-p-cymene)Ru(N/O^N)Cl]0/+ with Schiff base chelating ligands (N/O^N) are synthesized and characterized. The introduction of Schiff base units effectively increases the antitumor activity of these compounds (IC50: 1.70 ± 0.56-17.75 ± 3.10 µM), which, meanwhile, can inhibit the metastasis of tumor cells effectively. These compounds follow an energy-dependent cellular uptake mechanism, mainly accumulate in lysosomes to destroy their integrity, and then eventually promote apoptosis. In addition, these compounds can induce an increase of intracellular reactive oxygen species (ROS) levels and provide an antitumor mechanism of oxidation, which is confirmed by the decrease of mitochondrial membrane potential (MMP) and the catalytic oxidation of the coenzyme nicotinamide-adenine dinucleotide (NADH). All these indicate that these ruthenium(ii) compounds are expected to be dual-functional antitumor agents: anti-metastasis and lysosomal damage.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Organelas/efeitos dos fármacos , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Arsenicais/química , Arsenicais/farmacologia , Carbazóis/química , Carbazóis/farmacologia , 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 , Células HeLa , Humanos , Conformação Molecular , Imagem Óptica , Organelas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Rutênio/farmacologia , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-AtividadeRESUMO
Six fluorescent half-sandwich iridium(iii) coumarin-salicylaldehyde Schiff base (O^N) compounds ([(η5-Cp*)Ir(O^N)Cl]) were prepared and characterized. The introduction of a coumarin unit increased the antitumor activity (IC50: 9.9 ± 0.1 µM-40.7 ± 12.9 µM) of these compounds, the best of which was nearly two times that of clinical cisplatin. The results of laser confocal microscopy demonstrated that these compounds possessed an energy-dependent cellular uptake mechanism, accumulated in the lysosomes (Pearson co-localization coefficient: â¼0.7), damaged the integrity of the lysosomes, and induced apoptosis. The compounds could also decrease the mitochondrial membrane potential, catalyze the oxidation of the coenzyme (nicotinamide-adenine dinucleotide) and improve the levels of the intracellular reactive oxygen species, following an antitumor mechanism of oxidation. Additionally, these compounds could block the metastasis of tumor cells. Above all, these iridium(iii) compounds show potential as antitumor agents with dual functions: lysosomal damage and anti-metastasis.
Assuntos
Aldeídos/farmacologia , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Corantes Fluorescentes/farmacologia , Irídio/farmacologia , Células A549 , Aldeídos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Irídio/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacosRESUMO
Six N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) 2-phenylpyridine complexes ([(η5-Cp*)Ir(C^N)Cl]) were prepared and characterized. Compared with cisplatin, these complexes exhibited potential antitumor activity against A549 and HeLa tumor cells, with IC50 values (half-maximum inhibitory concentration) that changed from 2.8 ± 0.8 µM to 39.5 ± 2.7 µM, and could block the migration of tumor cells. These complexes also effectively bound to protein (binding constant: ~104 M-1) and were transported through serum proteins, catalyzed the oxidation of coenzyme nicotinamide-adenine dinucleotide. Additionally, laser confocal microscopy and flow cytometry confirmed that these complexes possessed a non-energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (Pearson colocalization coefficient: ~0.74), damaged the integrity of acidic lysosomes, led to a change in the mitochondrial membrane potential, disrupted the cell cycle (G0/G1 phase), and eventually induced apoptosis. Above all, these complexes are potential antitumor agents with dual functions: metastasis inhibition and lysosomal damage.
Assuntos
Antineoplásicos , Complexos de Coordenação , Lisossomos/metabolismo , Neoplasias , Piridinas/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Células HeLa , Humanos , Irídio , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacosRESUMO
A formal [3 + 2] cycloaddition between ynamides and unprotected isoxazol-5-amines has been developed in the presence of catalytic AgNTf2 in an open flask. By the protocol, a variety of functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives can be obtained in up to 99% yield. The reaction mechanism might involve the generation of an unusual α-imino silver carbene intermediate (or a silver-stabilized carbocation) and subsequent cyclization/isomerization to build the significant pyrrole-3-carboxamide motif. The reaction features the use of an inexpensive catalyst, simple reaction conditions, simple work-up without column chromatographic purification for most of products and high yields.
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: â¼0.90), 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 fármacosRESUMO
Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) was utilized to analyze the influence of the ancillary ligands (TPA-modified bipyridine) to these complexes. The introduction of TPA units could effectively adjust the lipid solubility of complexes (logP), and endowed complexes with potential bioactivity (anticancer, antibacterial and bactericidal activity), especially in the field of anticancer (the best value of IC50 is 4.34±0.01µM). Interestingly, complexe 4 show some selectivity for cancer cells versus normal cells. Meanwhile, complexes could effectively prevent the metastasis of cancer cells. Complexes can be transported by serum albumin and followed by the static quenching mechanism (Kq: 1013M-1s-1), disturb cell cycle at G0/G1 phase, and induce apoptosis. The favorable fluorescence property confirmed these complexes followed by an energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (PCC: >0.95) and induced lysosomal damage, and eventually leaded to cell death. Our study demonstrates that these complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage.
Assuntos
Compostos de Anilina/química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Irídio/química , Células A549 , Animais , Antibacterianos/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Bovinos , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Luminescência , Lisossomos/efeitos dos fármacos , Potencial da Membrana Mitocondrial , Testes de Sensibilidade Microbiana , Soroalbumina Bovina/química , Relação Estrutura-AtividadeRESUMO
Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four IrIII complexes of the types [(η5 -Cpx )Ir(N^N)Cl]PF6 (complexes 1 and 2) and [Ir(Phpy)2 (N^N)]PF6 (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC50 =(3.56±0.5)â µm], which was nearly six times as effective as cisplatin [(21.31±1.7)â µm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×105 to 81.71×105 m-1 ). IrIII complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD+ (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these IrIII complexes as emerging cancer therapeutics.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Irídio/química , Estilbenos/química , Células A549 , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Modelos Químicos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , EspectrofotometriaRESUMO
A novel methodology for the stereoselective synthesis of dihydroisobenzofuran derivatives is described in this paper. The procedure was realized by the bifunctional TBAF catalyzed selective O-nucleophilic cyclization of enaminone with intramolecular alkyne under mild and non-metal-mediated conditions. The results of control experiments suggested that the cation-π interaction and basicity, offered by TBAF, might be indispensable for the isomerization of enaminone and the formation of carbon-oxygen bond.
RESUMO
Four new triphenyltin(IV) acylhydrazone compounds of the type Ph3SnCH2CH2CONHN=R (where Phâ¯=â¯phenyl; Râ¯=â¯isopropyl, isobutyl, cyclopentyl and cyclooctyl) were synthesized and characterized by elemental analysis, infrared spectrum (IR), nuclear magnetic resonance spectrum (NMR) and mass spectrum (MS). The crystal structures were determined and showed that tin atoms were four-coordinated and adopted a pseudo-tetrahedron configuration. Tin(IV) compounds show excellent bovine serum albumin (BSA) binding properties, and can oxidize nicotinamide-adenine dinucleotid (NADH) to generate reactive oxygen species (ROS), which inducing apoptosis effectively. Bioassay results indicated that tin(IV) compounds have stronger cytotoxic activity against A549 human lung cancer cells compared with cis-platin used clinically, and showing some selectivity.
Assuntos
Hidrazonas/química , Hidrazonas/farmacologia , Compostos Orgânicos de Estanho/química , Células A549 , Apoptose/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Hidrazonas/síntese química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD+ and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent.
Assuntos
Compostos Ferrosos/farmacologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Lisossomos/metabolismo , Metalocenos/farmacologia , Imagem Óptica , Compostos Organometálicos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Células A549 , Antineoplásicos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Ferrosos/química , Humanos , Metalocenos/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Orgânicos de Estanho/químicaRESUMO
4-(1H-Isochromen-1-yl)isoquinoline derivatives were synthesized in high yields via the AgBF4-catalyzed self-reaction of ortho-alkynylarylaldehydes to give isochromene intermediates, followed by the dehydration of the 1,5-dicarbonyl motif with NH3. Compared with electron-rich aromatic substituents, this strategy can provide the desired isochromene products with an electron-deficient isoquinoline unit. The reactions feature simple experimental operations, mild reaction conditions and high product yields.
RESUMO
Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes of the type [(η5-Cpx)Ir(C^C)Cl]PF6, where Cpx is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cpxph = C5Me4C6H5) or biphenyl (Cpxbiph = C5Me4C6H4C6H5) derivatives, and the C^C-chelating ligands are different N-heterocyclic carbene (NHC) ligands, have been synthesized and characterized. Three X-ray crystal structures have been determined. Except for Cp* complex 1A, the other eleven complexes 1B-4C all showed potent cytotoxicity, with IC50 values ranging from 2.9 to 46.3 µM toward HeLa human cervical cancer cells. The potency toward HeLa cells increased with additional phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*, and increased with the size of chain substitution on the C^C-ligand in the order: ph > butyl > ethyl > methyl. Complex [(η5-C5Me4C6H4C6H5)Ir(L4)Cl]PF6 (4C) displayed the highest potency, and was about 3 times more active than the clinical platinum drug cisplatin. Complexes 1A-4C all undergo hydrolysis and their kinetics was studied. DNA binding appears not to be the major mechanism of action. The ability of these iridium complexes to catalyze hydride transfer from the coenzyme NADH to NAD+ was studied. Complexes [(η5-C5Me4C6H4C6H5)Ir(L2)Cl]PF6 (2C) and [(η5-C5Me4C6H4C6H5)Ir(L3)Cl]PF6 (3C) cause cell apoptosis and arrest the cell cycle at the G1 phase and G2/M phase when HeLa cancer cells are treated with different IC50 concentrations of the complexes, and increase the amount of reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.
RESUMO
A silver-catalyzed domino reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with conjugated dienes is described here. Through this reaction, the synthesis of a variety of indanone-fused cyclohexene derivatives can be achieved efficiently. The formation of these tricyclic products could involve a key Diels-Alder reaction of in situ generated indanenone dienophiles with conjugated dienes. Particularly, the products can be accomplished in a high endo/exo selective way.