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2.
Chem Commun (Camb) ; 55(67): 9919-9922, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31328197

RESUMO

Reported herein is a relebactam-derived fluorogenic reagent for covalent labeling of serine ß-lactamases (SBLs), which are the major causes of bacterial resistance to ß-lactam antibiotics. This highly selective imaging reagent generates over 300-fold stronger near-infrared fluorescence signals upon covalently bonding to SBLs, allowing wash-free visualization of live antimicrobial-resistant bacteria.


Assuntos
Marcadores de Afinidade/farmacologia , Compostos Azabicíclicos/farmacologia , Enterobacter cloacae/isolamento & purificação , Corantes Fluorescentes/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/química , Marcadores de Afinidade/síntese química , Marcadores de Afinidade/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Enterobacter cloacae/enzimologia , Fluoresceínas/síntese química , Fluoresceínas/química , Fluoresceínas/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química
3.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2532-2537, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359720

RESUMO

According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Podofilotoxina/farmacologia , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Indóis/síntese química , Células K562 , Podofilotoxina/síntese química , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 177: 414-424, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158754

RESUMO

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 µM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aß1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.


Assuntos
Azepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Azepinas/síntese química , Azepinas/química , Azepinas/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
7.
Comput Biol Chem ; 80: 512-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31185422

RESUMO

A new series of N'-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 µM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.


Assuntos
Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Indóis/farmacologia , Tiazolidinas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Hidrazinas/metabolismo , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Células MCF-7 , Simulação de Acoplamento Molecular , Ligação Proteica , Tiazolidinas/síntese química , Tiazolidinas/química , Tiazolidinas/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
8.
Talanta ; 201: 185-193, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122410

RESUMO

A novel, simple, sensitive, and precise spectrofluorometric assay of cancer antigen [CA 125] is described. This modality is based on monitoring the quenching of the luminescence intensity at 790 nm of the phthalocyanine fluorophore, in a nanocomposite comprising the fluorophore and cationic polystyrene, which results from interaction with CA 125. The remarkable quenching of the luminescence intensity of the Ni-phthalocyanine complex doped in PS matrix by various concentrations of CA 125 was successfully utilized as an optical sensor for the determination of CA 125 in different serum samples of ovarian disease. The performance of the designed biosensor is determined through monitoring the quenching of the luminescence intensity at 790 nm by cancer antigen 125 after excitation at 685 nm, pH 7.3 in water. The calibration plot was achieved over the concentration range 1.0 × 10-2 - 127 U mL-1 CA-125 with a correlation coefficient of 0.99 and detection limit of 1.0 × 10-4 U mL-1. The mechanism of the interaction between the nano thin film nickel(II)phthalocyanine and CA-125 was discussed. A significant correlation between the proposed method for the assessment of CA 125 and the standard method was applied to patients and controls.


Assuntos
Técnicas Biossensoriais/métodos , Antígeno Ca-125/sangue , Corantes Fluorescentes/química , Indóis/química , Proteínas de Membrana/sangue , Nanocompostos/química , Poliestirenos/química , Biomarcadores Tumorais/sangue , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Humanos , Indóis/síntese química , Limite de Detecção , Níquel/química , Neoplasias Ovarianas/sangue , Poliestirenos/síntese química , Espectrometria de Fluorescência/métodos
9.
Eur J Med Chem ; 175: 357-372, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096156

RESUMO

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 µM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Furanos/química , Ensaios de Triagem em Larga Escala , Histona Desmetilases/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Concentração Inibidora 50 , Leucemia Mieloide Aguda/patologia , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
10.
Analyst ; 144(11): 3643-3648, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31073567

RESUMO

Using fluorescent probes to detect endogenous hydrogen peroxide, which is associated with many diseases in the human body, remains an essential technique. Cyanine fluorochromes are a class of dyes that have attracted much attention and are widely used in the synthesis of fluorescent probes. In this article, a novel near-infrared (NIR) fluorescence probe for the detection of hydrogen peroxide was constructed and successfully applied to imaging endogenous hydrogen peroxide in vivo. Notably, probe 1 was designed by connecting 4-(bromomethyl)benzeneboronic acid pinacol ester as the sensing unit to the IR-780 hemicyanine skeleton, which exhibits excellent properties like NIR fluorescence emission over 700 nm. Probe 1 has satisfactory sensitivity to hydrogen peroxide with a low detection limit of 0.14 µM (S/N = 3), attributed to a responding mechanism that leads to the oxidation of phenylboronic acid pinacol ester and thereby releases fluorophore 2. Moreover, probe 1 displays excellent selectivity towards hydrogen peroxide over other substances. Taking advantage of these properties, the probe proved to be cell-permeable. Based on the results of N-acetylcysteine and rotenone together, probe 1 is capable of clearly visualizing endogenously produced hydrogen peroxide in living HepG2 cells and mice. The superior performance of the probe, as a reliable chemical tool, makes it of great potential application for exploring the role played by hydrogen peroxide in biological systems.


Assuntos
Ácidos Borônicos/química , Corantes Fluorescentes/química , Peróxido de Hidrogênio/análise , Indóis/química , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Indóis/síntese química , Indóis/toxicidade , Limite de Detecção , Camundongos Endogâmicos BALB C , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Oxirredução , Rotenona/farmacologia , Temperatura Ambiente
11.
Comput Biol Chem ; 80: 374-383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31103918

RESUMO

Colony-stimulating factor 1 receptor is a type III receptor protein tyrosine kinase belonging to PDGFR family. CSF1R signaling is essential for differentiation, proliferation and survival of macrophages. Aberrant expression of CSF1R appears to be an attractive target in several cancer types. Higher expression of CSF1R ligands correlates to tumor progression. CSF1R inhibitors have been shown to suppress cancers. We have attempted an in silico fragment derived drug discovery approach by screening ˜25,000 in-house compounds as potential CSF1R inhibitors. Using FBDD approach we have identified six diverse fragments that exhibit affinity towards hinge region of CSF1R. Some of the fragments 5-nitroindole and 7-azaindole and their derivatives were synthesized for further evaluation. The in silico and in vitro enzyme activity studies reveal moderate inhibition of CSF1R kinase activity by 5-nitroindole and good inhibition by 7-azaindole fragments. Bio and chemiinformatics studies have shown that 7-azaindole compounds have better membrane permeability and enzyme inhibition properties. Molecular docking studies show that the amino acid residues 664-666 in the hinge region of the cytosolic domain of CSF1R to be the preferred region of binding for nitroindole and azaindole derivatives. Further optimization and biological analysis would identify these fragments as potential and promising leads as CSF1R inhibitors.


Assuntos
Indóis/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Biologia Computacional , Desenho de Drogas , Humanos , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
12.
Chemistry ; 25(39): 9266-9271, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31050042

RESUMO

A two-step, one-flask synthesis of central seven-membered borondifluoride-3,3-dimethyl-2-[2-(2-pyrrolyl)ethenyl] indole (BOPYIN) ligands has been developed by using the unexplored 3,3-dimethyl-2-[2-(2-pyrrolyl)ethenyl] indole. The simple synthetic approach has enabled modification of the electronic structure by changing the substituents on the indole unit. X-ray analysis indicated that conformations of the seven-membered BF2 complex including BOPYIN and diazaborepin differ from that of the five- and six-membered organoboron complexes. Interestingly, the bond angle of the N⋅⋅⋅B-N bond increases with the number of atoms in the core ring, based on Baeyer strain theory. These unsymmetric BOPYIN derivatives have excellent photophysical properties, including high fluorescence quantum yields, except for BOPYIN-4 in the solution state, large Stokes shifts, and good molar absorptivity. The dipole moment of BOPYIN-3 in the first excited singlet state and ground state was demonstrated by a linear Lippert-Mataga plot. The absorption and emission spectra were not mirror images for BOPYIN-1-3 and 5, in contradiction to Kasha's rule, as determined by TDDFT. The synthesized BOPYINs have been shown to be biocompatible fluorophores in cell bioimaging.


Assuntos
Indóis/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Células HeLa , Humanos , Indóis/síntese química , Microscopia Confocal , Conformação Molecular , Espectrometria de Fluorescência
13.
Eur J Med Chem ; 174: 45-55, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31026746

RESUMO

Human 15-lipoxygenase-1 (15-LOX-1) is a mammalian lipoxygenase which plays an important regulatory role in several CNS and inflammatory lung diseases. To further explore the role of this enzyme in drug discovery, novel potent inhibitors with favorable physicochemical properties are required. In order to identify such new inhibitors, we established a combinatorial screening method based on acylhydrazone chemistry. This represents a novel application of combinatorial chemistry focusing on the improvement of physicochemical properties, rather than on potency. This strategy allowed us to efficiently screen 44 reaction mixtures of different hydrazides and our previously reported indole aldehyde core structure, without the need for individual synthesis of all possible combinations of building blocks. Our approach afforded three new inhibitors with IC50 values in the nanomolar range and improved lipophilic ligand efficiency.


Assuntos
Hidrazonas/química , Indóis/química , Inibidores de Lipoxigenase/química , Araquidonato 15-Lipoxigenase/química , Técnicas de Química Combinatória , Descoberta de Drogas , Humanos , Hidrazonas/síntese química , Indóis/síntese química , Ligantes , Inibidores de Lipoxigenase/síntese química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 174: 56-65, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029944

RESUMO

A zinc(II) phthalocyanine substituted with three 2,4-dinitrobenzenesulfonate (DNBS) groups and a cyclic arginine-glycine-aspartic acid (cRGDfK) moiety was prepared and characterized. With three strongly electron-withdrawing DNBS groups, this compound was fully quenched in terms of fluorescence emission and singlet oxygen generation in N,N-dimethylformamide and phosphate buffered saline due to the strong photoinduced electron transfer effect. In the presence of glutathione (GSH), which is the most abundant intracellular thiol particularly in tumor cells, the DNBS moieties were cleaved, thereby restoring these photoactivities and making the conjugate as a GSH-activated photosensitizer. Being a well-known integrin antagonist, the cyclic RGD peptide sequence could enhance the localization of the conjugate in integrin-upregulated tumor cells. As shown by confocal laser scanning microscopy and flow cytometry, the intracellular fluorescence intensity of the conjugate was significantly higher in the integrin-positive A549 and MDA-MB-231 cells than in the integrin-negative MCF-7 and HEK293 cells. The photocytotoxicity of the conjugate against MDA-MB-231 cells was also higher than that toward MCF-7 cells. The results suggest that this dual-functional photosensitizer is a promising candidate for targeted photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Glutationa/metabolismo , Indóis/farmacologia , Peptídeos Cíclicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Benzenossulfonatos/síntese química , Benzenossulfonatos/metabolismo , Benzenossulfonatos/farmacologia , Benzenossulfonatos/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/efeitos da radiação , Fluorescência , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/efeitos da radiação , Integrinas/metabolismo , Luz , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Zinco/química
15.
Eur J Med Chem ; 174: 181-197, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31035239

RESUMO

The scarcity of hematopoietic stem cells (HSCs) significantly hindered their clinical potentials. Umbilical cord blood (UCB) has become the leading source of HSCs for both research and clinical applications. But the low content of HSCs in a single UCB unit limited its use only to pediatric patients. Various cytokines and small molecules have demonstrated strong abilities in promoting HSC ex vivo expansion, of which UM171 is the newest and by far the most potent HSC ex vivo expansion agent. In this study, we synthesized 37 pyrimidoindole analogs and identified 6 compounds to be potent in promoting HSC ex vivo expansion. In particular, analog 11 was found to be the most effective in stimulating ex vivo expansion of UCB CD34+ cells and CD34+CD38- cells. Initial data indicated that compound 11 promoted the absolute number of long term HSCs and inhibited their differentiation. UCB HSCs expanded with 11 retained adequate multi-lineage differentiation capacity. In addition, compound 11 is not cytotoxic at its test concentrations, suggesting that it merits further investigation for potential clinical applications.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Indóis/farmacologia , Pirimidinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/citologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/toxicidade , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 174: 198-215, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31035240

RESUMO

A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC50 = 0.39 ±â€¯0.13 µM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish.


Assuntos
Artrite/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Indóis/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Quinoxalinas/uso terapêutico , Animais , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Adjuvante de Freund , Índio , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Estrutura Molecular , Esclerose Múltipla/induzido quimicamente , Glicoproteína Oligodendrócito-Mielina , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/toxicidade , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/toxicidade , Ratos , Relação Estrutura-Atividade , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
17.
Analyst ; 144(10): 3381-3388, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-30984924

RESUMO

Hydrogen sulfide (H2S) exists in the cytosol and mitochondria of mammalian cells as a signaling molecule. Scientists have explored many important physiological functions of H2S, such as regulating vasodilator relaxation, protecting living cells and avoiding damage. The measurement of H2S is therefore necessary for exploring the biological function of cells and tissues. Herein, we report the design and synthesis of a new aggregation-induced emission luminogen (AIEgen) with greater conjugation and more positive charges, based on previous research on mitochondrial-targeted luminogens. The Indo-TPE-Indo can enter cells rapidly, as compared with an AIEgen with only one indolium (TPE-indo), and can selectively recognize HS- in mitochondria with the nucleophilic reaction of indolium and HS-. The linear range (1-100 µM) of HS- sensing can satisfy the requirement for HS- concentration in living cells and tumors.


Assuntos
Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Indóis/química , Mitocôndrias/metabolismo , Estilbenos/química , Animais , Estabilidade de Medicamentos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana , Humanos , Sulfeto de Hidrogênio/metabolismo , Indóis/síntese química , Indóis/efeitos da radiação , Luz , Células MCF-7 , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Neoplasias/metabolismo , Estilbenos/síntese química , Estilbenos/efeitos da radiação
18.
Analyst ; 144(10): 3422-3427, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31011741

RESUMO

Mitochondria as essential organelles play critical roles in cellular metabolism. Mitochondrial pH is a vital parameter that directly affects the unique function of mitochondria. Herein, we present a new ratiometric fluorescent probe M-pH for monitoring the pH within the mitochondria. M-pH consists of a stable and large π-electron conjugated merocyanine system. The lipophilic cationic benzyl group will facilitate the accumulation of M-pH in mitochondria. The phenol unit is the recognition moiety, achieving the ratiometric sensing of pH changes. The experimental results indicate that M-pH displays ratiometric fluorescence response to different pH values. Meanwhile, M-pH shows negligible response to common species, and has high stability and low cytotoxicity. In biological experiments, M-pH can solely accumulate in mitochondria and visualize the pH changes during mitophagy and cell apoptosis. We thus believe that M-pH has great potential as a practical tool for real-time monitoring of pH changes of mitochondria, contributing to revealing the pathogenesis of mitochondrial pH associated diseases.


Assuntos
Corantes Fluorescentes/química , Indóis/química , Mitocôndrias/metabolismo , Fenóis/química , Apoptose/fisiologia , Linhagem Celular Tumoral , Colorimetria/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Indóis/síntese química , Indóis/efeitos da radiação , Indóis/toxicidade , Luz , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Degradação Mitocondrial/fisiologia , Fenóis/síntese química , Fenóis/efeitos da radiação , Fenóis/toxicidade
19.
Org Lett ; 21(10): 3610-3614, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31033299

RESUMO

An expedient synthesis of tetrahydroindoles and tetrahydrocyclopenta[ b]pyrroles, highlighted by Brønsted acid catalyzed formal [2 + 2 + 1] annulation reaction, is reported. Using three readily accessible reaction components, i.e., an electrophilic species in silyloxyallyl cations and two distinct nucleophiles in silylenol ethers and amines, our chemistry enables the assembly and functionalization of these biologically important N-heterocycles in a highly modular manner.


Assuntos
Aminas/química , Éteres/química , Indóis/síntese química , Pirróis/síntese química , Catálise , Indóis/química , Estrutura Molecular , Pirróis/química
20.
Eur J Med Chem ; 170: 1-15, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878825

RESUMO

Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound 5 and SAR study, the 7-azaindole moiety in compound 5 was systematically optimized. The results showed that compound 6f, which has a difluoroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375 cell lines. In a xenograft mouse model, oral administration of compound 6f led to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that 6f could influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375 cells. More importantly, compound 6f significantly inhibited migration of A375 cells in a concentration-dependent manner. Collectively, 6f may serve as a lead compound in the development of potent PKM2 activators for cancer therapy.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Proteínas de Transporte/agonistas , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Proteínas de Membrana/agonistas , Tiocarbamatos/farmacologia , Hormônios Tireóideos/agonistas , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Humanos , Indóis/síntese química , Indóis/química , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/química , Hormônios Tireóideos/metabolismo
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