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1.
Phys Chem Chem Phys ; 21(44): 24601-24619, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31670335

RESUMO

Natural bond orbital (NBO) analysis of electron delocalization in a series of capped isolated peptides is used to diagnose amide-amide H-bonding and backbone-induced hyperconjugative interactions, and to rationalize their spectral effects. The sum of the stabilization energies corresponding to the interactions between NBOs that are involved in the H-bonding is demonstrated as an insightful indicator for the H-bond strength. It is then used to decouple the effect of the H-bond distance from that, intrinsic, of the donor/acceptor relative orientation, i.e., the geometrical approach. The diversity of the approaches given by the series of peptides studied enables us to illustrate the crucial importance of the approach when the acceptor is a carbonyl group, and emphasizes that efficient approaches can be achieved despite not matching the usual picture of a proton donor directly facing a lone pair of the proton acceptor, i.e., that encountered in intermolecular H-bonds. The study also illustrates the role of backbone flexibility, partly controlled by backbone-amide hyperconjugative interactions, in influencing the equilibrium structures, in particular by frustrating or enhancing the HB for a given geometrical approach. Finally, the presently used NBO-based HB strength indicator enables a fair prediction of the frequency of the proton donor amide NH stretching mode, but this simple picture is blurred by ubiquitous hyperconjugative effects between the backbone and amide groups, whose magnitude can be comparable to that of the weakest H-bonds.


Assuntos
Amidas/química , Peptídeos/química , Dimerização , Ligações de Hidrogênio , Modelos Moleculares , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Teoria Quântica
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 812-816, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750823

RESUMO

Objective To investigate the effect of aldosterone (ALD) on the migration of rat hepatic stellate cells (HSC-T6) and its mechanism. Methods HSC-T6 cells were cultured and divided into control group (treated with medium only), ALD group (only 1 nmol/L ALD, 24 hours), spironolactone pre-treated group (a specific inhibitor of ALD receptor 10 nmol/L spironolactone at 1 hours before ALD treatment), Y27632 pre-treated group (a RhoA kinase inhibitor 10 nmol/L Y27632 at 1 hours before ALD treatment). A TranswellTM chamber system was used to observe the change of migration in the different groups. Changes in actin cytoskeletal organization were visualized by fluorescence staining using rhadamin-labeled phalloidin and fluorescence images were recorded using confocal microscopy. The levels of phosphorylated myosinlight chain (p-MLC) and phosphorylated moesin (p-moesin) in the RhoA/ROCK signaling pathway were evaluated by Western blotting in HSC-T6 cells. Results ALD treatment of HSC-T6 resulted in the enhancement of migration, but the effect of ALD-induced migration could be inhibited by spironolactone and Y27632. Stimulation of HSC-T6 with ALD induced a rapid morphological change conconmitant with a robust reorganization of actin cytoskeleton, while the morphological change was suppressed by spironolactone and Y27632. The effect of aldosterone on the activation of HSC migration was mediated by p-MLC and p-moesin protein expressions through the RhoA/ROCK signaling pathway. Spironolactone and Y27632 had the ability to block aldosterone-induced protein expressions in HSC-T6 cells. Conclusion ALD can induce the migration of activated HSC-T6 cells through the activation of the RhoA/ROCK signaling pathway.


Assuntos
Aldosterona/farmacologia , Movimento Celular , Células Estreladas do Fígado/efeitos dos fármacos , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo , Amidas , Animais , Células Cultivadas , Células Estreladas do Fígado/citologia , Piridinas , Ratos , Espironolactona
3.
Inorg Chem ; 58(21): 14294-14298, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31599154

RESUMO

Metal complexes to promote oxidative DNA cleavage by H2O2 are desirable as anticancer drugs. A dicopper(II) complex of known p-cresol-derived methylene-tether ligand Hbcc [Cu2(bcc)]3+ did not promote DNA cleavage by H2O2. Here, we synthesized a new p-cresol-derived amide-tether one, 2,6-bis(1,4,7,10-tetrazacyclododecyl-1-carboxyamide)-p-cresol (Hbcamide). A dicopper(II) complex of the new ligand [Cu2(µ-OH)(bcamide)]2+ was structurally characterized. This complex promoted the oxidative cleavage of supercoiled plasmid pUC19 DNA (Form I) with H2O2 at pH 6.0-8.2 to give Forms II and III. The reaction was largely accelerated in a high pH region. A µ-1,1-hydroperoxo species was formed as the active species and spectroscopically identified. The amide-tether complex is more effective in cytotoxicity against HeLa cells than the methylene-tether one.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Cresóis/farmacologia , Peróxido de Hidrogênio/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cresóis/química , Clivagem do DNA , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Peróxido de Hidrogênio/síntese química , Peróxido de Hidrogênio/química , Ligantes , Estrutura Molecular , Oxirredução
4.
Chem Commun (Camb) ; 55(86): 12904-12907, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31584577

RESUMO

A novel type of hydrogen peroxide (H2O2)-activated diazeniumdiolate based on an α-ketoamide moietey was developed as a nitric oxide (NO) donor. KA-NO-4 inhibited lung cancer cells with submicromolar activity. The H2O2-responsive behaviour of KA-NO-4 was thoroughly investigated. The NO-centered mechanism of action of KA-NO-4 was intracellularly studied.


Assuntos
Amidas/química , Antineoplásicos/química , Compostos Azo/química , Peróxido de Hidrogênio/química , Doadores de Óxido Nítrico/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Azo/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia
5.
J Agric Food Chem ; 67(44): 12182-12190, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31609606

RESUMO

In continuation of our program to develop natural-product-based pesticidal candidates, matrinic/oxymatrinic amides were obtained through structural optimization of matrine. N'-(4-Fluoro)phenyl-N-(4-bromo)phenylsulfonyloxymatrinic amide (IIm) showed potent insecticidal activity against Mythimna separata. N-(Un)substituted phenylsulfonylmatrinic acids (3a-c) exhibited promising acaricidal activity against Tetranychus cinnabarinus. By qRT-PCR analysis of nAChR subunits and AChE genes and determination of AChE activity of (un)treated T. cinnabarinus, it suggested that the open lactam ring of matrine and carboxyl group and (4-methyl)phenylsulfonyl of N-(4-methyl)phenylsulfonylmatrinic acid (3b) were necessary for action with α2, α4, α5, and ß3 nAChR subunits; compound 3b was an inhibitor of AChE in T. cinnabarinus, and AChE was one possible target of action in T. cinnabarinus against 3b; and compound 3b may be an antagonist of nAChR and AChE in T. cinnabarinus.


Assuntos
Acaricidas/química , Alcaloides/química , Amidas/química , Inseticidas/química , Quinolizinas/química , Acaricidas/síntese química , Acaricidas/farmacologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Amidas/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Feminino , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Inseticidas/síntese química , Inseticidas/farmacologia , Estrutura Molecular , Mariposas/efeitos dos fármacos , Mariposas/genética , Mariposas/crescimento & desenvolvimento , Mariposas/metabolismo , Quinolizinas/farmacologia , Relação Estrutura-Atividade , Tetranychidae/efeitos dos fármacos , Tetranychidae/genética , Tetranychidae/crescimento & desenvolvimento , Tetranychidae/metabolismo
6.
Chem Commun (Camb) ; 55(76): 11342-11345, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31479092

RESUMO

Site-selective labelling of antibodies (Abs) can circumvent problems from heterogeneity of conventional conjugation. Here, we evaluate the industrially-applied chemoenzymatic 'Q-tag' strategy based on transglutaminase-mediated (TGase) amide-bond formation in the generation of 89Zr-radiolabelled antibody conjugates. We show that, despite previously suggested high regioselectivity of TGases, in the anti-Her2 Ab Herceptin™ more precise native MS indicates only 70-80% functionalization at the target site (Q298H), in competition with modification at other sites, such as Q3H critically close to the CDR1 region.


Assuntos
Anticorpos/química , Imunoconjugados/química , Radioisótopos/química , Zircônio/química , Amidas/química , Amidas/imunologia , Amidas/metabolismo , Anticorpos/imunologia , Imunoconjugados/imunologia , Estrutura Molecular , Transglutaminases/química , Transglutaminases/imunologia , Transglutaminases/metabolismo , Zircônio/imunologia
7.
Nature ; 573(7772): 37-38, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31485062
8.
J Chromatogr A ; 1604: 460492, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31488295

RESUMO

The aim of this research study was to provide a more thorough understanding of the underlying mechanism and to broaden the application field of the recently introduced racemization method employing the amino acid derivatization tag 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC, AccQ) for heat-induced stereoisomerization of common amino acids as well as uniformly isotopically labeled [U-13C15N]-amino acids. The influence of different buffer types such as sodium borate buffer and sodium carbonate buffer as well as their pH and molarity on the racemization and deamidation of amino acids were investigated. It was found that a 0.4 M borate buffer with a pH of 8.0 +/- 0.2 was the most suitable derivatization as well as racemization buffer to ensure degradation free racemization of deamidation prone compounds such as glutamine. Hereby essential was the in-solution pH measurement before and after derivatization with AQC as well as after heat-induced racemization. This strategy provided further insight at which pH an actual racemization event was observed and when an unwanted deamidation of glutamine to glutamic acid occurred. In addition also the influence of the presence of oxygen during racemization was studied. In this context it was possible to determine ideal oxidation and racemization conditions for the production of scalemic mixtures of chiral isotopically labeled methionine AQC-DL-[U-13C15N]-Met as well as its oxidation products, AQC-DL-[U-13C15N]-Met-O and AQC-DL-[U-13C15N]-Met-O2. All stereoselective separations were performed on the zwitterionic Chiralpak ZWIX(+) column combined with HPLC-ESI-QTOF-MS analysis in positive ionization mode.


Assuntos
Amidas/química , Aminoácidos/química , Aminoquinolinas/química , Carbamatos/química , Tampões (Química) , Cromatografia Líquida de Alta Pressão/métodos , Concentração de Íons de Hidrogênio , Marcação por Isótopo , Oxirredução , Soluções , Estereoisomerismo
9.
Acta Virol ; 63(3): 309-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507197

RESUMO

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia. Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.


Assuntos
Amidas , Antivirais , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Pirazinas , Tripsina , Amidas/farmacologia , Antivirais/farmacologia , Linhagem Celular , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Oseltamivir/farmacologia , Pirazinas/farmacologia , RNA Viral/biossíntese , Tripsina/farmacologia
10.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
11.
Phytochemistry ; 167: 112098, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31450090

RESUMO

Changes in specialized metabolites were analyzed in wheat leaves inoculated with Bipolaris sorokiniana, the causal agent of spot blotch of Poaceae species. HPLC analysis detected the accumulation of six compounds in B. sorokiniana-infected leaves. Of these, we purified two compounds by silica gel and ODS column chromatography and preparative HPLC, and identified them as cinnamic acid amides, N-cinnamoyl-9-hydroxy-8-oxotryptamine and N-cinnamoyl-8-oxotryptamine, by spectroscopic analyses. The remaining four compounds were predicted to be p-coumaric acid amides of hydroxyputrescine, hydroxyagmatine, hydroxydehydroagmatine, and agmatine by mass spectrometry. The accumulation of two cinnamic acid amides was also induced by Fusarium graminearum infection, and by treatment with CuCl2, jasmonic acid, and isopentenyladenine. Antifungal activity of these amides was shown by inhibition of conidial germination and germ tube elongation of F. graminearum and Alternaria brassicicola, indicating that they act as phytoalexins. The accumulation of these amides also detected in barley leaves treated with CuCl2. We examined the accumulation of 25 phenylamides in B. sorokiniana-infected wheat leaves using LC-MS/MS. Hydroxycinnamic acid amides of tryptamine, serotonin, putrescine, and agmatine, were induced after infection with B. sorokiniana. Thus, the induced accumulation of two groups of phenylamides, cinnamic acid amides with indole amines, and p-coumaric acid amides with putrescine and agmatine related amines, represents a major metabolic response of wheat to pathogen infection.


Assuntos
Amidas/química , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Triticum/metabolismo , Cobre/farmacologia , Triticum/efeitos dos fármacos
12.
J Phys Chem Lett ; 10(16): 4720-4724, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369281

RESUMO

Probing the atomic details of intrinsically disordered proteins is crucial to understanding their biological function and relation to pathogenesis. Although amide-detected NMR experiments are widely employed in protein studies, 3JHNHα couplings between amide (1HN) and alpha (1Hα) protons impose an intrinsic limit on the achievable 1HN linewidth. Here, we present a homonuclear decoupling method that narrows the α-synuclein 1HN linewidths to 3-5 Hz. Tightly distributed 1JCαHα coupling values were employed to generate homogeneous antiphase coherences of 2HαzHNy and 4Hα(2)zHα(3)zHNy for nonglycine and glycine residues, respectively, which were combined with their in-phase HNy counterparts to achieve homonuclear decoupling. By reducing the multiplet structure to a singlet, the width of the 1HN cross-peak was reduced by ∼3-fold in the 2D HSQC and 3D intra-HNCA spectra, and good spectral quality was achieved without the need for postprocessing.


Assuntos
Ressonância Magnética Nuclear Biomolecular , alfa-Sinucleína/química , Amidas/química , Glicina/química , Prótons , Teoria Quântica , Soluções/química
13.
Eur J Med Chem ; 181: 111564, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376563

RESUMO

The P2Y14 receptor (P2Y14R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y14R antagonists. The most potent antagonist, 16c, showed comparable activity (IC50 = 1.77 nM) to PPTN, the most potent P2Y14R antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ácido Benzoico/química , Ácido Benzoico/farmacologia , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Ácido Benzoico/síntese química , Linhagem Celular , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Antagonistas do Receptor Purinérgico P2/síntese química , Ratos , Receptores Purinérgicos P2/metabolismo
14.
Eur J Med Chem ; 181: 111580, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400708

RESUMO

A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxinas/metabolismo , Amidas/química , Antineoplásicos/química , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , Tiorredoxina Redutase 1/química , Tiorredoxina Redutase 1/metabolismo
15.
Chem Commun (Camb) ; 55(71): 10567-10570, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31417998

RESUMO

Macrocyclization of linear peptide precursors using the Petasis borono-Mannich reaction affords a diverse range of macrocycles with an endocyclic amine. Analysis of the corresponding macrocyclic structures underscores that the hydrogen bond between an endocyclic amine and the adjacent amide NH is a powerful control element for conformationally homogenous peptide macrocycles.


Assuntos
Ácidos Borônicos/química , Compostos Macrocíclicos/síntese química , Peptídeos Cíclicos/síntese química , Aldeídos/química , Amidas/química , Aminas/química , Aziridinas/química , Ciclização
16.
Dent Mater J ; 38(6): 892-899, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366768

RESUMO

The purpose was to evaluate the effect of a hydrophilic amide monomer on µTBS of one-step adhesive to dentin at different application times. Clearfil Universal Bond Quick (UBQ), experimental adhesive (UBQexp; same compositions as UBQ but hydrophilic amide monomer was replaced with 2-hydroxyethyl methacrylate), Clearfil SE ONE and Clearfil SE Bond were applied to midcoronal dentin prepared with 600-grit SiC at different application time (0, 10, 20 and 40 s). Water sorption (Wsp) and the ultimate tensile strength (UTS) of polymerized adhesives were also measured. UBQ showed significantly lower Wsp and higher UTS than UBQexp. At each application time, UBQ exhibited significantly higher µTBSs than UBQexp. UBQ showed the highest µTBS at 0 s application time among all the adhesives. When the application time was prolonged from 0 s to 10 s, only UBQ showed no significant difference. The hydrophilic amide monomer increased µTBS with reduction in Wsp and increase in the UTS and may allow a shortened application time.


Assuntos
Colagem Dentária , Amidas , Resinas Compostas , Cimentos Dentários , Dentina , Adesivos Dentinários , Teste de Materiais , Cimentos de Resina , Resistência à Tração
17.
J Phys Chem Lett ; 10(18): 5463-5467, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31442055

RESUMO

Nuclear spin hyperpolarized water is utilized to obtain protein spectra not only in the folded state but also during the refolding process. Polarization transfer to Ribonuclease Sa through proton exchange and the nuclear Overhauser effect (NOE) results in NMR signal enhancements of amide protons by up to 24-fold. These enhancements enable the measurement of fast two-dimensional NMR spectra on the same time scale as the folding. Resolved amide proton signals corresponding to the folded protein are observed both under folded and refolding conditions, whereby the refolding protein shows smaller transferred signals. Residue-specific evaluation of contributions to the polarization transfer indicates that signals attributed to a relayed intramolecular NOE are not observable in the refolding experiment. These differences are explained by the absence of long-range contacts and faster molecular motions in the unfolded protein. Applications of this method include accessing residue-specific information on structure and dynamics during multistate protein folding.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Dobramento de Proteína , Proteínas/química , Amidas/química , Sequência de Aminoácidos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Modelos Moleculares , Conformação Proteica , Prótons , Ribonucleases/química , Água
18.
Fitoterapia ; 138: 104273, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344395

RESUMO

Endophytic fungi have been considered a rich source for bioactive secondary metabolites with novel chemical structures. A high diverse group of endophytes, isolated from different medicinal plants, belongs to the genus Diaporthe. In a previously study performed by our group the crude extract of strain LGMF1583 showed considerable antibacterial activity mainly against Gram-negative bacteria. Based on ITS phylogeny analysis, strain LGMF1583 was identified as belonging to Diaporthe genus and may represent a new species. In the present study, we described the new species Diporthe vochysiae based on multilocus phylogeny analysis and morphological characteristics. The species name refers to the host, from which strain LGMF1583 was isolated, the medicinal plant Vochysia divergens. In view of the biotechnological potential of strain LGMF1583, we have also characterized the secondary metabolites produced by D. vochysiae. Chemical assessment of the D. vochysiae LGMF1583 revealed two new carboxamides, vochysiamides A (1) and B (2), in addition to the known metabolite, 2,5-dihydroxybenzyl alcohol (3). In the biological activity analysis, vochysiamide B (2) displayed considerable antibacterial activity against the Gram-negative bacterium Klebsiella pneumoniae (KPC), a producer of carbapenemases, MIC of 80 µg/mL. Carbapenemases are considered a major antimicrobial resistance threat, and infections caused by KPC have been considered a public health problem worldwide, and new compounds with activity against this bacterium are nowadays even more required.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Ascomicetos/química , Myrtales/microbiologia , Plantas Medicinais/microbiologia , Amidas/isolamento & purificação , Antibacterianos/isolamento & purificação , Ascomicetos/classificação , Brasil , Linhagem Celular Tumoral , Endófitos/química , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Estrutura Molecular , Filogenia
19.
Anticancer Res ; 39(7): 3507-3518, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262875

RESUMO

BACKGROUND/AIM: Very few studies of anticancer activity of azulene amides led us to investigate the cytotoxicity of 21 N-alkylazulene-1-carboxamides introduced either with 3-methyl [1-7], 7-isopropyl-3-methyl [8-14] or 2-methoxy group [15-21] Materials and Methods: Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against three normal human oral mesenchymal cells to that against four human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50 value against OSCC cell lines. Apoptosis-inducing activity was evaluated by caspase-3 activation and appearance of subG1 cell population. RESULTS: [8-14] showed higher TS and PSE values, than [1-7] and [15-21] The most active compound [8-14] induced apoptosis in C9-22 OSCC cells at 4-times higher CC50 Quantitative structure-activity relationship analysis of [1-14] demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the molecular shape and hydrophobicity. CONCLUSION: 7-Isopropyl-3-methyl-N-propylazulene-1-carboxamide [8] can be a potential candidate of lead compound for manufacturing new anticancer drug.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Azulenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Amidas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azulenos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Relação Quantitativa Estrutura-Atividade
20.
Acta Pharm ; 69(2): 233-248, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259728

RESUMO

The paper is focused on the synthesis and screening of the antiplasmodial activity of novel fumardiamides 5-10 with the mefloquine pharmacophore and a Michael acceptor motif. Multi-step reactions leading to the title compounds included two amide bond formations. The first amide bond was achieved by the reaction of (E)-ethyl 4-chloro-4-oxobut-2-enoate (1) and N1-(2,8-bis(trifluoromethyl)quinolin-4-yl) butane-1,4-diamine (2). The obtained ester 3 was hydrolyzed and gave acid 4, which then reacted with the selected halogenanilines in the presence of HATU/DIEA and formed products 5-10. Title compounds showed marked, dose dependent activity in vitro against hepatic stages of Plasmodium berghei. IC50 values of the most active compounds 5, 7 and 9 bearing 3-fluoro, 3-chloro and 3-trifluoromethyl substituents were 3.04-4.16 µmol L-1, respectively. On the other hand, the compounds exerted only weak activity against the erythrocytic stages of two P. falciparum strains (Pf3D7 and PfDd2) in vitro, with the exception of compound 5 (IC50 = 2.9 µmol L-1).


Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Mefloquina/farmacologia , Amidas/síntese química , Amidas/química , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Mefloquina/síntese química , Mefloquina/química , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
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