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1.
Acta Crystallogr C Struct Chem ; 76(Pt 1): 1-9, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31919301

RESUMO

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α-disubstituted α-amino acid and an α-hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)-Pms-Acp-(S)-Pms-Acp-(S)-Pms-Acp-NMe2 acetonitrile solvate, C47H58N4O9·C2H3N, (3b), as well as in the related linear tetradepsipeptide amide (S)-Pms-Aib-(S)-Pms-Aib-NMe2, C28H37N3O6, (5a), the diastereoisomeric mixture (S,R)-Pms-Acp-(R,S)-Pms-Acp-NMe2/(R,S)-Pms-Acp-(R,S)-Pms-Acp-NMe2 (1:1), C32H41N3O6, (5b), and (R,S)-Mns-Acp-(S,R)-Mns-Acp-NMe2, C30H37N3O6, (5c) (Pms is phenyllactic acid, Acp is 1-aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a ß-turn conformation in the solid state, which is stabilized by intramolecular N-H...O hydrogen bonds. Whereas ß-turns of type I (or I') are formed in the cases of (3b), (5a) and (5b), which contain phenyllactic acid, the torsion angles for (5c), which incorporates mandelic acid, indicate a ß-turn in between type I and type III. Intermolecular N-H...O and O-H...O hydrogen bonds link the molecules of (3a) and (5b) into extended chains, and those of (5a) and (5c) into two-dimensional networks.


Assuntos
Aminoácidos/química , Depsipeptídeos/química , Hidroxiácidos/química , Amidas/química , Cristalografia por Raios X , Ligações de Hidrogênio , Conformação Proteica , Análise Espectral/métodos
2.
J Enzyme Inhib Med Chem ; 35(1): 498-505, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914836

RESUMO

Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.


Assuntos
Amidas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Corantes Fluorescentes/farmacologia , Amidas/síntese química , Amidas/química , Animais , Butirilcolinesterase/isolamento & purificação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular
3.
J Enzyme Inhib Med Chem ; 35(1): 59-64, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31663383

RESUMO

A primary strategy to combat antimicrobial resistance is the identification of novel therapeutic targets and anti-infectives with alternative mechanisms of action. The inhibition of the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) from pathogens (bacteria, fungi, and protozoa) was shown to produce an impairment of the microorganism growth and virulence. As phosphonamidates have been recently validated as human α-CA inhibitors (CAIs) and no phosphorus-based zinc-binding group have been assessed to date against ß-class CAs, herein we report an inhibition study with this class of compounds against ß-CAs from pathogenic bacteria, fungi, and protozoa. Our data suggest that phosphonamidates are among the CAIs with the best selectivity for ß-class over human isozymes, making them interesting leads for the development of new anti-infectives.


Assuntos
Amidas/farmacologia , Anti-Infecciosos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos Organometálicos/farmacologia , Ácidos Fosfóricos/farmacologia , Amidas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Fungos/enzimologia , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/enzimologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Ácidos Fosfóricos/química , Fósforo/química , Fósforo/farmacologia , Relação Estrutura-Atividade , Zinco/química , Zinco/farmacologia
4.
J Enzyme Inhib Med Chem ; 35(1): 85-95, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707866

RESUMO

To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Descoberta de Drogas , Quinoxalinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Células RAW 264.7 , Ratos , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade
5.
J Enzyme Inhib Med Chem ; 34(1): 1730-1739, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31822127

RESUMO

A series of readily accessible 1-(piperidin-3-yl)thymine amides was designed, synthesised and evaluated as Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors. In line with the modelling results, most inhibitors showed reasonable MtbTMPK inhibitory activity. Compounds 4b and 4i were slightly more potent than the parent compound 3. Moreover, contrary to the latter, amide analogue 4g was active against the avirulent M. tuberculosis H37Ra strain (MIC50=35 µM). This finding opens avenues for future modifications.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Timina/farmacologia , Amidas/síntese química , Amidas/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Núcleosídeo-Fosfato Quinase/metabolismo , Relação Estrutura-Atividade , Timina/síntese química , Timina/química
6.
Phys Chem Chem Phys ; 22(1): 107-113, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31807746

RESUMO

The non-enzymatic cleavage rates of amide bonds located in peptides in aqueous solution is pH-dependent and involves two distinct mechanisms: direct hydrolysis (herein termed "scission") and intramolecular aminolysis by the N-terminal amine (herein termed "backbiting"). While amide bond cleavage has been previously characterized using a variety of peptides, no systematic study has yet been reported addressing the effect of the pH on the interplay between the two amide bond cleavage pathways. In this study, the cleavage rates of the glycine dimer (GG), the glycine trimer (GGG), and the cyclic dimer (cGG), as well as the alanine trimer (AAA), were measured at pH 3, 5, 7, and 10 at 95 °C employing quantification based on 1H NMR. The distinct rate constants for scission and backbiting processes were obtained by solving the differential rate equations associated with the proposed kinetic model. Generalizations concerning the relative importance of the various amide bond cleavage pathways at pH 3, 5, 7, and 10 are presented. In particular, scission dominates at pH 10, while backbiting dominates at neutral pH. At the acidic pH of 3, both backbiting and scission are significant. The model of the reaction network, used in this work, enables the quantification of these multiple competing mechanisms and can be applied to longer peptides and to similar types of reaction networks.


Assuntos
Concentração de Íons de Hidrogênio , Peptídeos/química , Alanina/química , Amidas/química , Aminas/química , Glicina/química , Hidrólise , Cinética , Metionina/química , Estabilidade Proteica , Termodinâmica
7.
Chem Pharm Bull (Tokyo) ; 67(11): 1171-1178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685746

RESUMO

Peptides and proteins are involved in almost all biological events. In this review, three chemical biology tools, which were developed for peptide/protein sciences from a viewpoint of peptide/amide bond cleavage, are overviewed. First, study on an artificial amino acid that enables stimulus-responsive functional control of peptides/proteins is briefly described. Two N-S acyl transfer reaction-based tools, one a linker molecule for facile identification of target proteins of bioactive compounds and the other a reagent for selective labeling of proteins of interest, are then discussed.


Assuntos
Amidas/química , Peptídeos/química , Humanos , Ligantes , Estrutura Molecular
8.
Chem Pharm Bull (Tokyo) ; 67(11): 1179-1182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685747

RESUMO

Herein, the deprotonative functionalization of pyridine derivatives with aldehydes under ambient conditions has been demonstrated using an amide base generated in situ from a catalytic amount of CsF and a stoichiometric amount of tris(trimethylsilyl)amine (N(TMS)3). Pyridine substrates bearing two electron-withdrawing substituents (i.e., fluoro, chloro, bromo, and trifluoromethyl moieties) at the 3- and 5-positions efficiently react at the 4-position with various aldehydes including arylaldehydes, pivalaldehyde, and cyclohexanecarboxaldehyde.


Assuntos
Aldeídos/química , Amidas/química , Compostos de Organossilício/química , Piridinas/química , Catálise , Estrutura Molecular , Prótons
9.
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
10.
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
11.
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
12.
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
13.
Eur J Med Chem ; 183: 111684, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520926

RESUMO

This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38α/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38α/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 µM, comparable to the potency of dasatinib. Compound 2b inhibited TNF-α production in lipopolysaccharide-induced THP-1 cells with IC50 value of 58 nM. In addition, compound 2b showed low potency against hERG. It is 622.38 times less potent than E-4031 against hERG, so the risk of cardiotoxicity of the compound is very minimal. Compound 2b showed also high plasma stability in vitro in human and rat plasmas. The in vivo PK profile of compound 2b is acceptable, and its antiinflammatory effect was comparable to diclofenac with no ulcerogenic side effect on stomach.


Assuntos
Anti-Inflamatórios/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirazóis/síntese química , Amidas/química , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Descoberta de Drogas , Humanos , Masculino , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Ratos , Ureia/química
14.
Eur J Med Chem ; 183: 111671, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536892

RESUMO

The rapid emergence and spread of multi-resistant bacteria have created an urgent need for new antimicrobial agents. We report here a series of amphipathic α,α-disubstituted ß-amino amide derivatives with activity against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum ß-lactamase - carbapenemase (ESBL-CARBA) production. A variety of halogenated aromatic side-chains were investigated to improve antimicrobial potency and minimize formation of Phase I metabolites. Net positive charge and cationic character of the derivatives had an important effect on toxicity against human cell lines. The most potent and selective derivative was the diguanidine derivative 4e with 3,5-di-brominated benzylic side-chains. Derivative 4e displayed minimum inhibitory concentrations (MIC) of 0.25-8 µg/mL against Gram-positive and Gram-negative reference strains, and 2-32 µg/mL against multi-resistant clinical isolates. Derivative 4e showed also low toxicity against human red blood cells (EC50 > 200 µg/mL), human hepatocyte carcinoma cells (HepG2: EC50 > 64 µg/mL), and human lung fibroblast cells (MRC-5: EC50 > 64 µg/mL). The broad-spectrum antimicrobial activity and low toxicity of diguanylated derivatives such as 4e make them attractive as lead compounds for development of novel antimicrobial drugs.


Assuntos
Amidas/química , Anti-Infecciosos/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Amidas/síntese química , Amidas/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Halogenação , Humanos , Camundongos , Testes de Sensibilidade Microbiana
15.
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
16.
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
17.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470567

RESUMO

BACKGROUND: The development of new antifungal agents has always been a hot research topic in pesticide development. In this study, a series of derivatives of natural compound ß-pinene were prepared, and the antifungal activities of these derivatives were evaluated. The purpose of this work is to develop some novel molecules as promising new fungicides. METHODS: Through a variety of chemical reactions, ß-pinene was transformed into a series of ß-pinene-based derivatives containing amide moieties and acylthiourea moieties. The antifungal activities of these derivatives against five plant pathogens including Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikuchiana, Phomopsis sp. and Phytophthora capsici were tested; preliminary structure-activity relationship was discussed. RESULTS: Some derivatives exhibited moderate or significant antifungal activity due to the fusion of the amide moiety or the acylthiourea moiety with the pinane skeleton. The structure-activity relationship analysis showed that the fluorine atom and the strong electron withdrawing nitro group, or trifluoromethyl group on the benzene ring of the derivatives had a significant effect on the improvement of the antifungal activity against Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikuchiana and Phomopsis sp. Meanwhile, the introduction of an ethyl group at the meta-position on the benzene ring of the derivatives could improve the antifungal activity against Phytophthora capsici. Compounds 4e, 4h, 4q, 4r exhibited broad-spectrum antifungal activity against the tested strains. Compound 4o had significant antifungal activity against Phytophthora capsici (IC50 = 0.18 µmol/L). These derivatives were expected to be used as precursor molecules for novel pesticide development in further research.


Assuntos
Alternaria/efeitos dos fármacos , Colletotrichum/efeitos dos fármacos , Fungicidas Industriais/síntese química , Fusarium/efeitos dos fármacos , Phytophthora/efeitos dos fármacos , Sordariales/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Amidas/química , Colletotrichum/crescimento & desenvolvimento , Fungicidas Industriais/farmacologia , Fusarium/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Phytophthora/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Doenças das Plantas/terapia , Plantas/microbiologia , Sordariales/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tioureia/química
18.
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
19.
Org Biomol Chem ; 17(34): 7995-8000, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31408069

RESUMO

A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.


Assuntos
Furanos/química , Quinazolinas/síntese química , Sulfonamidas/química , Aldeídos/química , Amidas/química , Aminas/química , Ciclização
20.
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
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