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1.
Org Biomol Chem ; 18(7): 1279-1336, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32025682

RESUMO

Enantio- and diastereodivergent routes to marine-origin natural products with different sizes of cyclic ethers and lactones have been used in order to assign stereochemical features. Kainoid amino acids such as isodomoic acids have been synthesized using diastereodivergent routes. The bis(indole) alkaloid dragmacidin F has been prepared by enantiodivergent strategies as well as furanoterpenes and the tetracyclic agelastatin A. Natural products containing five-membered lactones like quercus lactones, muricatacins, goniofufuranones, methylenolactocins and frenolicin B have been synthesized using stereodivergent routes. Macrolides are very abundant lactones and have been mainly prepared from the corresponding seco-acids by lactonization, such as lasiodiplodin, zaeralanes, macrosphelides and haloprins, or by ring-closing metathesis, such as aspercyclides, microcarpalides, macrolides FD-891 and 892, and tetradic-5-en-9-olides. Other natural products including cyclic ethers (such as sesamin, asarinin, acetogenins, centrolobines and nabilones), alcohols (such as sulcatol), esters (such as methyl jasmonates), polycyclic precursors of fredericamycin, amino alcohols (such as ambroxol and sphingosines), isoprostanes, isofurans, polyketide precursors of anachelins, brevicomins, gummiferol, shikimic acid and the related compounds, and the pheromone disparlure have been synthesized stereodivergently. Heterocyclic systems such as epoxides, theobroxides and bromoxones, oxetan-3-ones, 5- to 8-membered cyclic ethers, azetidones, γ-lactams, oxazolidinones, bis(oxazolines), dihydropyridoisoindolines and octahydroisoquinolines have been prepared following stereodivergent routes. Stereodivergent routes to unnatural compounds such as alkenes, dienes, allenes, cyclopropanes, alcohols, aldols, amines, amino alcohols, ß-amino acids, carboxylic acids, lactones, nitriles and α-amino nitriles have been considered as well.


Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos/síntese química , Lactonas/síntese química , Álcoois/síntese química , Álcoois/química , Alcenos/síntese química , Alcenos/química , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Produtos Biológicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Compostos Heterocíclicos/química , Lactonas/química , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Estereoisomerismo
3.
J Enzyme Inhib Med Chem ; 35(1): 165-171, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752557

RESUMO

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (bCA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Nitrilos/farmacologia , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Bovinos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fluorometria , Humanos , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Relação Estrutura-Atividade
4.
Talanta ; 206: 120196, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514893

RESUMO

Nitroxyl (HNO), generated from nitric oxide (NO) in biological system, plays distinct biological roles in physiological process, but the role of endogenous HNO in biosystems still remains unclear, because of lacking of specific and sensitive detector to monitor HNO in real time. The conventional methods indicate the level of HNO through detecting the ultimate product nitrous oxide (N2O) of HNO dimerization and dehydration, which could easily result in inaccurate data. Therefore, developing an assay that can directly apply to detect HNO is of significance for understanding the function mechanism of HNO in biological system. In this study, we describe a near-infrared fluorescent probe 4-(2-(4-(dicyanomethylene)-4H-chromen-2-yl)vinyl) phenyl-2-(diphenylphosphanyl)-benzoate (CPN) that employs (2-(4-hydroxystyryl) -4H-chromen-4-ylidene) malononitrile (CP-OH) as a fluorophore and 2-(diphenylphosphino) benzoate as a recognition group. This probe, CPN, shows rapid-response to HNO which compared to other current probes. The fluorescent intensity reaches plateau in 20 min in vitro and in 2 min in vivo, respectively, which is important to monitor dynamic and transient state of HNO in biological system. In addition, CPN probe with a large Stokes' shift (150 nm) and near-infrared emission (700 nm) that is suitable for biological imaging. This probe has a potential of elucidating the biological function of HNO in biosystem.


Assuntos
Corantes Fluorescentes/química , Nitrilos/química , Óxidos de Nitrogênio/análise , Compostos Organofosforados/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nitrilos/síntese química , Nitrilos/toxicidade , Compostos Organofosforados/síntese química , Compostos Organofosforados/toxicidade
5.
Anal Chim Acta ; 1094: 70-79, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761049

RESUMO

To explore how hypochlorous acid (HClO) affects human health, a highly sensitive, selective, and trace detection method for hypochlorite (ClO-) is crucial for determining its non-negligible function in both environment and living systems. Herein, a dicyanoisophorone-phenylboronic acid-based novel ratiometric near-infrared fluorescent probe (Probe 1) was designed for the rapid and specific detection of ClO- based on the intramolecular charge transfer (ICT) mechanism. Excess addition of HClO to the Probe 1 solution, 186-times ratio (I652/I582) augment were gained. And this probe provided a colorimetric and ratiometric fluorescence response to ClO- with a high selectivity, a rapid response (within 30 s), and had an extremely low detection limit (15.7 nM). In addition, owing to the good sensing properties and low cytotoxicity of Probe 1, it can be used to expediently visualize exogenous ClO- in HepG2 cells and endogenous ClO- in RAW264.7 macrophage cells. Furthermore, the probe was successfully used for the bioimaging of zebrafish with an acute inflammation. Thus, Probe 1 is a promising vehicle to identify the level of HClO in animals with associated diseases.


Assuntos
Ácidos Borônicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Inflamação/metabolismo , Nitrilos/química , Animais , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Colorimetria/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Ácido Hipocloroso/metabolismo , Inflamação/induzido quimicamente , Limite de Detecção , Lipopolissacarídeos , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nitrilos/síntese química , Nitrilos/toxicidade , Células RAW 264.7 , Peixe-Zebra
6.
Molecules ; 24(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653123

RESUMO

The hydration of nitriles to amides in a water extract of pomelo peel ash (WEPPA) was realized with moderate to excellent yields without using external transition metals, bases or organic solvents. This reaction features a broad substrate scope, wide functional group tolerance, prominent chemoselectivity, and good reusability. Notably, a magnification experiment in this bio-based solvent at 100 mmol further demonstrated its practicability.


Assuntos
Amidas , Citrus/química , Frutas/química , Nitrilos , Elementos de Transição/química , Amidas/síntese química , Amidas/química , Nitrilos/síntese química , Nitrilos/química
7.
Talanta ; 205: 120166, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450476

RESUMO

Collecting sweat sample for onsite testing is a sophisticated process as the analysis process must be completed in a real-time with a highly absorptive and sensitive device in order to gain a useful assessment of its content. Thus, we developed a chemical probe incorporated into microfibrillated cellulose to introduce a novel, simple, robust and flexible aerogel. This chromogenic sponge-like aerogel assay demonstrated a color change from yellow to orange, red and blue depending on the sweat biochemical changes. Novel pH sensitive tricyanofuran hydrazone probe was prepared, characterized and encapsulated in-situ within microfibrillated cellulose to follow up sweat pH changes. The solvatochromic performance in several solvents of different polarities and the reversible pH correlated color change of this tricyanofuran hydrazone probe in an acetonitrile solution was explored by UV-Vis absorption spectra. The microporous and microfibrillated sponge-like cellulose substrate was fabricated by activation of wood pulp using phosphoric acid followed by freeze-drying process. Morphological characterization, thermal stability and fiber crystallinity of the prepared aerogel were explored using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). The visual color change was explored by studying the CIE LAB color space coordinates and color strength values. The cytotoxicity of the sponge-like aerogel sensor was also evaluated.


Assuntos
Celulose/química , Colorimetria/métodos , Suor/química , Linhagem Celular , Furanos/síntese química , Furanos/química , Géis , Humanos , Concentração de Íons de Hidrogênio , Nitrilos/síntese química , Nitrilos/química , Solventes/química , Temperatura , Fatores de Tempo
8.
Drug Dev Res ; 80(7): 970-980, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31348537

RESUMO

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC50 values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC50 value of 0.006 µM while the most potent MAO-B inhibitor exhibits an IC50 value of 0.058 µM. Interestingly, an N-oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC50 value of 0.011 µM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.


Assuntos
Indolquinonas/farmacologia , Indóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Nitrilos/farmacologia , Humanos , Indolquinonas/síntese química , Indóis/síntese química , Concentração Inibidora 50 , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Nitrilos/síntese química , Relação Estrutura-Atividade
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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 Fármacos , 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
15.
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
16.
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
17.
J Labelled Comp Radiopharm ; 62(8): 448-459, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-30912586

RESUMO

An O-methyltyrosine-containing azadipeptide nitrile was synthesised and investigated for its inhibitory activity towards cathepsins L, S, K, and B. Labelling with carbon-11 was accomplished by reaction of the corresponding phenolic precursor with [11 C]methyl iodide starting from cyclotron-produced [11 C]methane. Radiopharmacological evaluation of the resulting radiotracer in a mouse xenograft model derived from a mammary tumour cell line by small animal PET imaging indicates tumour targeting with complex pharmacokinetics. Radiotracer uptake in the tumour region was considerably lower under treatment with the nonradioactive reference compound and the epoxide-based irreversible cysteine cathepsin inhibitor E64. The in vivo behaviour observed for this radiotracer largely confirms that of the corresponding 18 F-fluoroethylated analogue and suggests the limited suitability of azadipeptide nitriles for the imaging of tumour-associated cysteine cathepsins despite target-mediated uptake is evidenced.


Assuntos
Radioisótopos de Carbono , Catepsinas/metabolismo , Cisteína/metabolismo , Dipeptídeos/química , Nitrilos/química , Nitrilos/síntese química , Tomografia por Emissão de Pósitrons/métodos , Animais , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Feminino , Humanos , Camundongos , Camundongos Nus , Nitrilos/metabolismo , Traçadores Radioativos
18.
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
19.
Bioorg Chem ; 85: 487-497, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30782563

RESUMO

A series of 60 nitrobenzonitrile analogues of the anti-viral agent MDL-860 were synthesized (50 of which are new) and evaluated for their activity against three types of enteroviruses (coxsackievirus B1, coxsackievirus B3 and poliovirus 1). Among them, six diaryl ethers (20e, 27e, 28e, 29e, 33e and 35e) demonstrated high in vitro activity (SI > 50) towards at least one of the tested viruses and very low cytotoxicity against human cells. Compound 27e possesses the broadest spectrum of activity towards all tested viruses in the same way as MDL-860 does. The most active derivatives (27e, 29e and 35e) against coxsackievirus B1 were tested in vivo in newborn mice experimentally infected with 20 MLD50 of coxsackievirus B1. Compound 29e showed promising in vivo activity (protection index 26% and 4 days lengthening of mean survival time). QSAR analysis of the substituent effects on the in vitro cytotoxicity (CC50) and anti-viral activity of the nitrobenzonitrile derivatives was carried out and adequate QSAR models for the anti-viral activity of the compounds against poliovirus 1 and coxsackievirus B1 were constructed.


Assuntos
Antivirais/farmacologia , Nitrilos/farmacologia , Poliovirus/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Relação Quantitativa Estrutura-Atividade
20.
Bioorg Med Chem ; 27(6): 1034-1042, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30773420

RESUMO

Selective proteinase inhibitors have demonstrated utility in the investigation of cartilage degeneration mechanisms and may have clinical use in the management of osteoarthritis. The cysteine protease cathepsin K (CatK) is an attractive target for arthritis therapy. Here we report the synthesis of two cathepsin K inhibitors (CKIs): racemic azanitrile derivatives CKI-E and CKI-F, which have better inhibition properties on CatK than the commercial inhibitor odanacatib (ODN). Their IC50 values and inhibition constants (Ki) have been determined in vitro. Inhibitors demonstrate differential selectivity for CatK over cathepsin B, L and S in vitro, with Ki amounting to 1.14 and 7.21 nM respectively. We analyzed the effect of these racemic inhibitors on viability in different cell types. The human osteoblast-like cell line MG63, MOVAS cells (a murine vascular smooth muscle cell line) or murine primary chondrocytes, were treated either with CKI-E or with CKI-F, which were not toxic at doses of up to 5 µM. Primary chondrocytes subjected to several passages were used as a model of phenotypic loss of articular chondrocytes, occurring in osteoarthritic cartilage. The efficiency of CKIs regarding CatK inhibition and their specificity over other proteases were validated in primary chondrocytes subjected to several passages. Racemic CKI-E and CKI-F at 0.1 and 1 µM significantly inhibited CatK activity in dedifferentiated chondrocytes, even better than the commercial CatK inhibitor ODN. The enzymatic activity of other proteases such as matrix metalloproteinases or aggrecanases were not affected. Taken together, these findings support the possibility to design CatK inhibitors for preventing cartilage degradation in different pathologies.


Assuntos
Catepsina K/antagonistas & inibidores , Desdiferenciação Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Nitrilos/farmacologia , Inibidores de Proteases/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Catepsina K/metabolismo , Linhagem Celular , Células Cultivadas , Condrócitos/citologia , Condrócitos/enzimologia , Desenho de Fármacos , Humanos , Camundongos , Nitrilos/síntese química , Nitrilos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química
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