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1.
Nature ; 571(7766): 546-549, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292542

RESUMO

Amide bond formation is one of the most important reactions in both chemistry and biology1-4, but there is currently no chemical method of achieving α-peptide ligation in water that tolerates all of the 20 proteinogenic amino acids at the peptide ligation site. The universal genetic code establishes that the biological role of peptides predates life's last universal common ancestor and that peptides played an essential part in the origins of life5-9. The essential role of sulfur in the citric acid cycle, non-ribosomal peptide synthesis and polyketide biosynthesis point towards thioester-dependent peptide ligations preceding RNA-dependent protein synthesis during the evolution of life5,9-13. However, a robust mechanism for aminoacyl thioester formation has not been demonstrated13. Here we report a chemoselective, high-yielding α-aminonitrile ligation that exploits only prebiotically plausible molecules-hydrogen sulfide, thioacetate12,14 and ferricyanide12,14-17 or cyanoacetylene8,14-to yield α-peptides in water. The ligation is extremely selective for α-aminonitrile coupling and tolerates all of the 20 proteinogenic amino acid residues. Two essential features enable peptide ligation in water: the reactivity and pKaH of α-aminonitriles makes them compatible with ligation at neutral pH and N-acylation stabilizes the peptide product and activates the peptide precursor to (biomimetic) N-to-C peptide ligation. Our model unites prebiotic aminonitrile synthesis and biological α-peptides, suggesting that short N-acyl peptide nitriles were plausible substrates during early evolution.


Assuntos
Evolução Química , Nitrilos/química , Nitrilos/síntese química , Origem da Vida , Peptídeos/química , Peptídeos/síntese química , Água/química , Acetileno/análogos & derivados , Acetileno/química , Dipeptídeos/síntese química , Dipeptídeos/química , Ferricianetos/química , Sulfeto de Hidrogênio/química , Concentração de Íons de Hidrogênio , Oxirredução , Compostos de Sulfidrila/química , Sulfetos/química
2.
Eur J Med Chem ; 180: 1-14, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31288149

RESUMO

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF5 enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Nitrilos/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/farmacologia , Anilidas/síntese química , Anilidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nitrilos/síntese química , Nitrilos/química , Feniltioidantoína/síntese química , Feniltioidantoína/química , Feniltioidantoína/farmacologia , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Compostos de Tosil/síntese química , Compostos de Tosil/química
3.
Chem Commun (Camb) ; 55(62): 9160-9163, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31304937

RESUMO

The rational design of heteroatom-doped C3N4 offers a great opportunity to optimize C3N4 performance. In this communication, we propose a facile method to fabricate layered-stacked B-doped C3N4 (BCN-800) ultrathin nanosheets via a one-step calcination route. The distinctive layered-stacked structure and the presence of B atoms provide an active attachment point for antibodies and antigens. In addition, the presence of C and N might aid stability and increase conductivity. When used for vomitoxin detection, the BCN-800-based electrochemical biosensor exhibits high sensitivity with a detection limit of 0.32 pg mL-1 and superior selectivity to other interfering agents.


Assuntos
Técnicas Biossensoriais , Boro/química , Ácidos Borônicos/química , Contaminação de Alimentos/análise , Inocuidade dos Alimentos/métodos , Nitrilos/síntese química , Tricotecenos/análise , Técnicas Eletroquímicas , Nitrilos/química , Tamanho da Partícula , Propriedades de Superfície
4.
Chem Pharm Bull (Tokyo) ; 67(5): 410-418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061365

RESUMO

2,4,5-Trichloro-6-((2,4,6-trichlorophenyl)amino)isophthalonitrile (SYD007) is a small molecule compound that was synthesized according to the structure of diarylamine. In this study, we evaluated the anti-bladder activities of SYD007, and determined its cytotoxic mechanism. We found that SYD007 exerted cytotoxicity to bladder cancer cells. Furthermore, SYD007 induced bladder cancer cell early apoptosis and arrested cell cycle. Mechanistically, SYD007 suppressed phosphorylated signal transducer and activator of transcription 3 (p-STAT3) (Tyr705) level in parallel with increases of p-extracellular signal-regulated kinase (ERK) and p-AKT. SYD007 significantly inhibited insulin-like growth factor 1 (IGF-1)-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in SYD007-treated cells, suggesting that SYD007 acted primarily at a posttranscriptional level. Using molecular docking analysis, SYD007 was identified as an IGF-1R inhibitor. In summary, we reported that SYD007 exerted anti-bladder activities, and these effects were partially due to inhibition of IGF-1R/STAT3 signaling.


Assuntos
Antineoplásicos/farmacologia , Nitrilos/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Nitrilos/síntese química , Nitrilos/química , Receptor IGF Tipo 1/metabolismo , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/metabolismo
5.
Chem Pharm Bull (Tokyo) ; 67(5): 397-403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061363

RESUMO

Cyano (CN) groups are equivalent to carbonyl as well as amino- and hydroxymethyl groups. Therefore, their catalytic introduction under metal catalysis is an important issue in synthetic organic chemistry. Ni-catalyzed hydrocyanation is one of the most well-investigated, powerful tools for installing a CN group. However, it is still difficult to control chemo- and regioselectivity. In this review, the author uses allenes to enable regio-, stereo-, and face-selective transformations to natural product synthesis and axial chirality transfer.


Assuntos
Alcadienos/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Níquel/química , Nitrilos/síntese química , Alcadienos/química , Produtos Biológicos/química , Catálise , Modelos Moleculares , Nitrilos/química , Estereoisomerismo
6.
Analyst ; 144(10): 3260-3266, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-30982838

RESUMO

We synthesized six 1-oxo-1H-phenalene-2,3-dicarbonitrile (OPD)-based probes with various leaving groups using an arylthioether linker and for the first time identified the probe O-NH2 capable of highly selective detection of glutathione over cysteine/homocysteine in vitro and in vivo based on an aromatic nuclear substitution reaction (SNAr) mechanism. The fluorescence of the probe O-NH2 was quenched because of the photoinduced electron transfer (PET) process, but switched on by a glutathione-triggered specific recognition reaction between the probe O-NH2 and glutathione. The recognition mechanism for glutathione was explored and verified by theoretical calculations and ESI-MS analysis. Using O-NH2 as the probe, the GSH fluorescence images were demonstrated in HeLa cells and the intracellular GSH levels in different imatinib-resistant K562 tumor cells were firstly determined. Further, O-NH2 was utilized to detect glutathione in D. magna and zebrafish embryos. The combined results indicate that O-NH2 can be applied as an effective tool for detecting glutathione in biological investigations.


Assuntos
Corantes Fluorescentes/química , Glutationa/análise , Nitrilos/química , Fenalenos/química , Animais , Linhagem Celular Tumoral , Daphnia , Desenho de Drogas , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Modelos Químicos , Nitrilos/síntese química , Nitrilos/toxicidade , Fenalenos/síntese química , Fenalenos/toxicidade , Espectrometria de Fluorescência/métodos , Peixe-Zebra
7.
Mater Sci Eng C Mater Biol Appl ; 101: 138-147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029306

RESUMO

Nanocomposites composed of Ag and γ-Fe2O3 nanoparticles within poly-γ-glutamic acid (γ-PGA) derived amorphous carbon nitride (a-CN) films (Ag + γ-Fe2O3@a-CN) were synthesized by a one-step facile pyrolysis strategy. Transmission electron microscopy analysis shows that Ag and γ-Fe2O3 nanoparticles were obtained in situ and homogeneously dispersed on the a-CN matrix. The average size of nanoparticles was 8.1 nm. The presence of γ-Fe2O3, Ag, and a-CN in the nanocomposite was confirmed by X-ray diffraction analysis, UV-visible absorption spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. Ag + γ-Fe2O3@a-CN catalyzed the degradation of methyl orange. This catalyst was also recycled ten times by magnetic separation without any loss in efficiency. Ag + γ-Fe2O3@a-CN exhibited strong antibacterial activity against E. coli and S. aureus. It also exhibited excellent antibacterial activity even after 20 times magnetic recycling. This indicates that this is a promising recyclable antibacterial and catalyst for environmental applications.


Assuntos
Antibacterianos/farmacologia , Compostos Férricos/farmacologia , Nanocompostos/química , Nitrilos/síntese química , Ácido Poliglutâmico/análogos & derivados , Pirólise , Prata/farmacologia , Animais , Compostos Azo/química , Células CHO , Catálise , Cricetinae , Cricetulus , Testes de Sensibilidade Microbiana , Nanocompostos/toxicidade , Nanocompostos/ultraestrutura , Nitrilos/toxicidade , Espectroscopia Fotoeletrônica , Ácido Poliglutâmico/química , Espectrofotometria Ultravioleta , Análise Espectral Raman , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X
8.
Nat Chem ; 11(5): 478-487, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936524

RESUMO

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologically active compounds.


Assuntos
Alcenos/síntese química , Técnicas de Química Sintética/métodos , Nitrilos/síntese química , Catálise , Complexos de Coordenação/química , Molibdênio/química , Estereoisomerismo
9.
Eur J Med Chem ; 167: 49-60, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30743097

RESUMO

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC50 = 2.67-13.19 µM) compared to bicalutamide (IC50 = 20.44 µM) in LNCaP. Remarkably, novel double branched bicalutamide analogues (27 and 28) were isolated as major by-products and found to have the best activity across three human prostate cancer cell lines (LNCaP, VCaP and PC3). The most active compound 28 shows sub-micromolar activity (IC50 = 0.43 µM in LNCaP), which represents more than 40-fold improvement over the clinical anti-androgen bicalutamide (IC50 = 20.44 µM) and a more than 3 fold improvement over enzalutamide (IC50 = 1.36 µM). Moreover, strong reduction of PSA expression in LNCaP cells upon treatment with compounds 27, 28 and 33 was observed during qPCR analysis, confirming their AR antagonist activity. Molecular modelling studies revealed a novel binding mode of these structurally distinct double branched analogues within the ligand binding domain (LBD) of the androgen receptor.


Assuntos
Antagonistas de Androgênios/síntese química , Anilidas/farmacologia , Descoberta de Drogas , Nitrilos/farmacologia , Compostos de Tosil/farmacologia , Antagonistas de Androgênios/farmacologia , Anilidas/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Modelos Moleculares , Nitrilos/síntese química , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/síntese química
10.
Artigo em Inglês | MEDLINE | ID: mdl-30781576

RESUMO

Carbon nitride (CN) with improved adsorption⁻degradation capacity was synthesized using B2O3 and CN via calcination. The pollutant removal capacity of this B2O3/CN (B-CN) was studied by a powder suspension experiment and added into concrete to evaluate the adsorption and degradation of methylene blue (MB). The characterizations of all samples indicate that B2O3 significantly affects CN, e.g., by increasing the CN specific surface area to 3.6 times the original value, extending visible light adsorption, and narrowing the band gap from 2.56 eV to 2.42 eV. Furthermore, the results show that B-CN composite materials have a higher MB-removal efficiency, with the adsorption capacity reaching 43.11 mg/g, which is about 3.3 times that of pristine CN. The MB adsorption process on B2-CN is mainly via electrostatic attraction and π⁻π interactions. In addition, B-CN added into concrete also has good performance. After five adsorption⁻degradation cycles, B-CN and photocatalytic concrete still exhibit a good regenerate ability and excellent stability, which are very important for practical applications.


Assuntos
Compostos de Boro/química , Poluentes Ambientais/isolamento & purificação , Nitrilos/química , Adsorção , Luz , Azul de Metileno/isolamento & purificação , Nitrilos/síntese química , Fotólise , Porosidade , Propriedades de Superfície
11.
Arch Pharm (Weinheim) ; 352(2): e1800317, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30600532

RESUMO

In the presence of chiral organic catalysts, the optically active 4H-chromine was synthesized from the multicomponent condensation of 5,5-dimethylcyclohexane-1,3-dione with malononitrile and methylene-active compound, and the specific angle of rotation of the compounds was determined in the AUTOPOL-III polarimeter and their structures were confirmed by the X-ray spectroscopic analysis method. These optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles were effective inhibitors of α-glycosidase, the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 21.33 ± 1.11 to 40.24 ± 10.78 µM for hCA I, 28.91 ± 6.51 to 59.97 ± 15.62 µM for hCA II, 18.16 ± 3.18 to 66.57 ± 1.36 µM for α-glycosidase, and 8.68 ± 0.93 to 102.61 ± 24.96 µM for AChE.


Assuntos
Anticonvulsivantes/farmacologia , Antagonistas Colinérgicos/farmacologia , Hipoglicemiantes/farmacologia , Nitrilos/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Antagonistas Colinérgicos/síntese química , Antagonistas Colinérgicos/química , Cristalização , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Nitrilos/síntese química , Nitrilos/química , Relação Estrutura-Atividade
12.
Analyst ; 144(5): 1696-1703, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30657480

RESUMO

In this paper, we introduced a new strategy for converting aggregation-induced emission (AIE) to fluorescence emission in solution into the rational design of new fluorescent probes. Two fluorescent probes based on this strategy, namely, PDAM-Lyso and PDAM-Me, have been synthesized and tested both in vitro and in vivo. The fluorophores of the two probes are both phenothiazine molecules, which link to the diaminomaleonitrile (DAMN) moiety through imine bonds. In the presence of imine bonds, the probes emit red fluorescence in an aqueous solution caused by the AIE effect. As the imine bonds are selectively cut-off by HClO, the DAMN moiety gets removed, inducing blue fluorescence of the reaction product. In this way, the selectivity of the DAMN-based probes toward HClO against metal ions and other reactive oxygen species (ROS) was successfully improved. The imaging of endogenous and exogenous HClO with these two probes reveals that lysosome-targeting probes are of great advantage in the detection of natively generated HClO. Furthermore, the imaging of endogenous HClO in zebrafish suggests that PDAM-Lyso is capable of monitoring the generation of HClO in vivo, illustrating that this strategy is of great significance in designing new probes.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Nitrilos/química , Fenotiazinas/química , Animais , Fenômenos Químicos , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Ácido Hipocloroso/química , Limite de Detecção , Lisossomos/metabolismo , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nitrilos/síntese química , Nitrilos/toxicidade , Fenotiazinas/síntese química , Fenotiazinas/toxicidade , Células RAW 264.7 , Peixe-Zebra
13.
Molecules ; 24(1)2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577607

RESUMO

We herein describe a flexible synthesis of a small library of 68Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (1⁻3) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between the pre-labeled bifunctional chelators (BFCs) and the 1,2-aminothiol-acetazolamide derivatives (8 and 9) yielded six new 68Ga-labeled CAIX ligands with high radiochemical yields. The click reaction conditions were optimized to improve the reaction rate for applications with short half-life radionuclides. Overall, our methodology allows for a simple and efficient radiosynthetic route to produce a variety of 68Ga-labeled imaging agents for tumor hypoxia.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Anidrase Carbônica IX/química , Química Click , Radioisótopos de Gálio/química , Nitrilos/química , Nitrilos/farmacologia , Benzotiazóis/síntese química , Cromatografia Líquida de Alta Pressão , Humanos , Marcação por Isótopo , Nitrilos/síntese química , Compostos Radiofarmacêuticos , Bibliotecas de Moléculas Pequenas
14.
Future Med Chem ; 10(24): 2771-2789, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30526032

RESUMO

AIM: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. MATERIALS & METHODS: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI50 (MG-MID) value of 3.97 µM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.


Assuntos
Antineoplásicos/farmacologia , Nitrilos/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo
15.
Talanta ; 188: 35-40, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30029387

RESUMO

A hydrothermal synthetic approach is developed for the preparation of graphitic carbon nitride quantum dots (g-C3N4 QDs) from human urine. The reported synthetic method is green, simple, low-cost, less time-consuming, and can be used for the large-scale production of the g-C3N4 QDs. The as-prepared g-C3N4 QDs possess a high quantum yield of 15.7% by using quinine sulfate as a reference, and display excitation-wavelength dependent fluorescent emission. In addition, the g-C3N4 QDs exhibit high photostability, low cytotoxicity. and are successfully used as fluorescent probes for cell multicolor imaging. It is believed that the valuable nanomaterials, g-C3N4 QDs, which are transformed from the human bodily wastes, are promising in diverse chemical applications.


Assuntos
Corantes Fluorescentes/síntese química , Grafite/síntese química , Química Verde/métodos , Nitrilos/síntese química , Pontos Quânticos/química , Urina/química , Técnicas de Química Sintética/métodos , Fluorescência , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Grafite/metabolismo , Grafite/efeitos da radiação , Grafite/toxicidade , Células Hep G2 , Humanos , Microscopia de Fluorescência , Nitrilos/metabolismo , Nitrilos/efeitos da radiação , Nitrilos/toxicidade , Imagem Óptica/métodos , Pontos Quânticos/efeitos da radiação , Pontos Quânticos/toxicidade
16.
Cancer Invest ; 36(3): 199-209, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29624460

RESUMO

A series of 3-aryl/hetarylquinoxaline-2-carbonitrile-1,4-dioxides was synthesized and evaluated against breast cancer cell lines in normoxia and hypoxia. Selected compounds in this series demonstrated better cytotoxicity and comparable hypoxia selectivity than tirapazamine. In contrast to Dox, quinoxaline-1,4-dioxides showed potent cytotoxicity against different MDR cells. Compound 2g inhibits of cancer cell growth through p53-independent mechanisms. Our results showed that compound 2g sensitized MCF-7 cells to metformin in hypoxia. Treatment with 2g results in the increase of ROS accumulation in cancer cells. Compound 2g can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents.


Assuntos
Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Nitrilos/síntese química , Quinoxalinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Células K562 , Células MCF-7 , Metformina/farmacologia , Estrutura Molecular , Nitrilos/química , Nitrilos/farmacologia , Espécies Reativas de Oxigênio/metabolismo
17.
Chem Commun (Camb) ; 54(31): 3887-3890, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29610818

RESUMO

Estrogen receptor ß (ERß) has recently been identified as a pharmaceutical target in hormone replacement therapy for breast cancers. However, the biological function of ERß in disease progression remains unclear. A highly ERß-selective fluorescent probe (FPNM) was discovered exhibiting nanomolar affinity for ERß with an ERß/ERα selectivity as high as 80, which allowed specific labeling of intracellular ERß. Moreover, distinct ERß dynamics in various cellular bio-settings such as prostate cancer (DU-145) or triple-negative breast cancer (MDA-MB-231) cells were directly observed for the first time viaFPNM staining.


Assuntos
Receptor beta de Estrogênio/metabolismo , Corantes Fluorescentes/química , Naftalenos/química , Nitrilos/química , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Corantes Fluorescentes/síntese química , Humanos , Simulação de Acoplamento Molecular , Imagem Molecular , Naftalenos/síntese química , Nitrilos/síntese química
18.
Eur J Med Chem ; 150: 851-863, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29597168

RESUMO

Highly efficient poly functionalized pyrrolo[3,2-a]carbazoles via ring contraction through rearrangement and intramolecular Michael addition reaction using one pot multicomponent reaction (MCR) is reported for the first time. Free radical scavenging and anticancer activities were determined by DPPH and MTT assays respectively. Of these, compound 8d exhibited most potent activity against HCT-15 human colon cancer cell lines with an IC50 value of 9.9 µM and low toxicity toward normal human red blood cells. The morphological changes were visualized using scanning electron microscopy (SEM) technique, intracellular ROS generation measured by spectrofluorometer and gene expression levels of caspase-3, caspase-9 and Bcl-2 were determined using Semi quantitates PCR analysis for the target compound. Further, the structure activity relationships were also carried out. The results of the present study revealed that among pyrrolo[3,2-a]carbazole compounds, 7-chloro-2-oxo-3a-(2'-oxo-2',3'-dihydro-1'H-indol-3'-yl)-2,3,3a,4,5,10-hexahydro-pyrrolo[3,2-a]carbazole-1-carbonitrile could be exploited as an excellent anticancer agent against colon cancer cells.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Desenho de Drogas , Indóis/farmacologia , Nitrilos/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
19.
J Am Chem Soc ; 140(7): 2450-2454, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29383934

RESUMO

A general synthetic strategy for the construction of large, nitrogen-containing polycyclic aromatic hydrocarbons (PAHs) is reported. The strategy involves two key steps: (1) a titanocene-mediated reductive cyclization of an oligo(dinitrile) precursor to form a PAH appended with di(aza)titanacyclopentadiene functionality; (2) a divergent titanocene transfer reaction, which allows final-step installation of one or more o-quinone, diazole, or pyrazine units into the PAH framework. The new methodology enables rational, late-stage control of HOMO and LUMO energy levels and thus photophysical and electrochemical properties, as revealed by UV/vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations. More generally, this contribution presents the first productive use of di(aza)metallacyclopentadiene intermediates in organic synthesis, including the first formal [2 + 2 + 2] reaction to form a pyrazine ring.


Assuntos
Nitrilos/síntese química , Nitrogênio/química , Compostos Organometálicos/química , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Estrutura Molecular , Nitrilos/química , Hidrocarbonetos Policíclicos Aromáticos/química
20.
Eur J Med Chem ; 146: 185-193, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407949

RESUMO

A series of novel 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge to retain the cis-orientations of A-ring and B-ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines. Compounds 6a-d exhibited superior potency, with IC50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Niacina/farmacologia , Nitrilos/farmacologia , Estilbenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzopiranos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Niacina/análogos & derivados , Niacina/síntese química , Niacina/química , Nitrilos/síntese química , Nitrilos/química , Estilbenos/química , Relação Estrutura-Atividade
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