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1.
J Org Chem ; 86(15): 10224-10234, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34291942

RESUMO

α-Amino ketones are useful compounds because of their synthetic utility and bioactivities. After observing the ability of N,N'-dipyridin-2-yl aminals to form imines in situ, the synthesis of α-amino ketones using N,N'-dipyridin-2-yl aminals was proposed. Through the NHC-catalyzed aza-benzoin reaction between aromatic/aliphatic aldehydes and N,N'-dipyridin-2-yl aminals, α-amino ketones, including aromatic, heterocyclic, and aliphatic versions, were synthesized with yields up to 99%. A direct route toward N-Boc-protected α-amino ketones from N,N,N'-tris-Boc aminals was also discovered, yielding the desired N-Boc-protected α-amino ketones in yields up to 73%.


Assuntos
Aldeídos , Benzoína , Catálise , Estrutura Molecular , Estereoisomerismo
2.
Molecules ; 26(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809372

RESUMO

In this study, we examined the Aureobasidium pullulans strains DSM 14940 and DSM 14941 included in the Blossom Protect™ agent to be used in the bioreduction reaction of a symmetrical dicarbonyl compound. Both chiral 2-hydroxy-1,2-diphenylethanone antipodes were obtained with a high enantiomeric purity. Mild conditions (phosphate buffer [pH 7.0, 7.2], 30 °C) were successfully employed in the synthesis of (S)-benzoin using two different methodologies: benzyl desymmetrization and rac-benzoin deracemization. Bioreduction carried out with higher reagent concentrations, lower pH values and prolonged reaction time, and in the presence of additives, enabled enrichment of the reaction mixture with (R)-benzoin. The described procedure is a potentially useful tool in the synthesis of chiral building blocks with a defined configuration in a simple and economical process with a lower environmental impact, enabling one-pot biotransformation.


Assuntos
Aureobasidium/metabolismo , Benzoína/metabolismo , Benzoína/química , Biocatálise , Biotransformação , Concentração de Íons de Hidrogênio , Oxirredução , Fenilglioxal/análogos & derivados , Fenilglioxal/química , Fenilglioxal/metabolismo , Estereoisomerismo
3.
Org Lett ; 23(4): 1416-1421, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33538602

RESUMO

We report the shortest synthesis of glycosidase inhibitor (+)-hyacinthacine A1 using a highly chemoselective N-heterocyclic carbene-catalyzed cross-benzoin reaction as well as a furan photooxygenation-amine cyclization strategy. This is the first such cyclization on a furylic alcohol, an unprecedented reaction due to the notorious instability of the formed intermediates. The photooxygenation strategy was eventually incorporated into a three-step one-pot process that formed the requisite pyrrolizidine framework of (+)-hyacinthacine A1.


Assuntos
Aminas/química , Benzoína/química , Furanos/química , Metano/análogos & derivados , Catálise , Ciclização , Metano/química , Estrutura Molecular , Estereoisomerismo
4.
Molecules ; 25(15)2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32756525

RESUMO

Benzoin is one of the most commonly used photoinitiators to induce free radical polymerization. Here, improved benzoin properties could be accomplished by the introduction of two methoxy substituents, leading to the formation of 3',5'-dimethoxybenzoin (DMB) which has a higher photo-cleavage quantum yield (0.54) than benzoin (0.35). To elucidate the underlying reaction mechanisms of DMB and obtain direct information of the transient species involved, femtosecond transient absorption (fs-TA) and nanosecond transient absorption (ns-TA) spectroscopic experiments in conjunction with density functional theory/time-dependent density functional theory (DFT/TD-DFT) calculations were performed. It was found that the photo-induced α-cleavage (Norrish Type I reaction) of DMB occurred from the nπ* triplet state after a rapid intersystem crossing (ISC) process (7.6 ps), leading to the generation of phenyl radicals on the picosecond time scale. Compared with Benzoin, DMB possesses two methoxy groups which are able to stabilize the alcohol radical and thus result in a stronger driving force for cleavage and a higher quantum yield of photodissociation. Two stable conformations (cis-DMB and trans-DMB) at ground state were found via DFT calculations. The influence of the intramolecular hydrogen bond on the α-cleavage of DMB was elaborated.


Assuntos
Benzoína/química , Teoria da Densidade Funcional , Luz , Benzoína/análise , Cromatografia Gasosa , Radicais Livres/química , Cinética , Polimerização , Espectrofotometria
5.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671764

RESUMO

Inflammation is a key mediator in the progression of atherosclerosis (AS). Benzoinum, a resin secreted from the bark of Styrax tonkinensis, has been widely used as a form of traditional Chinese medicine in clinical settings to enhance cardiovascular function, but the active components of the resin responsible for those pharmaceutical effects remain unclear. To better clarify these components, a new phenylpropane derivative termed stybenpropol A was isolated from benzoinum and characterized via comprehensive spectra a nalysis. We further assessed how this phenylpropane derivative affected treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α). Our results revealed that stybenpropol A reduced soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß) expression by ELISA, inhibited apoptosis, and accelerated nitric oxide (NO) release in TNF-α-treated HUVECs. We further found that stybenpropol A decreased VCAM-1, ICAM-1, Bax, and caspase-9 protein levels, and increased the protein levels of Bcl-2, IKK-ß, and IκB-α. This study identified a new, natural phenylpropane derivative of benzoinum, and is the first to reveal its cytoprotective effects in the context of TNF-α-treated HUVECs via regulation of the NF-κB and caspase-9 signaling pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Benzoína/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Aterosclerose/metabolismo , Basidiomycota/química , Benzoína/química , Caspase 9/metabolismo , Molécula 1 de Adesão Celular/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8 , Inibidor de NF-kappaB alfa/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteína X Associada a bcl-2/metabolismo
6.
Molecules ; 24(22)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752140

RESUMO

We first reported the new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions. The system could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) in moderate to excellent yields. The protocol allows rapid access to the most common scaffolds found in FDA-approved pharmaceuticals.


Assuntos
Benzoína/análogos & derivados , Cobre/química , Halogênios/química , Oximas/química , Azóis/química , Benzoína/química , Carbono/química , Catálise , Nitrogênio/química , Piperidinas/química , Pirrolidinas/química
7.
Angew Chem Int Ed Engl ; 58(37): 12960-12963, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31218804

RESUMO

Pickering emulsions (PEs) are particle-stabilized multiphase systems with promising features for synthetic applications. Described here is a novel, simplified set-up employing catalytically active whole cells for simultaneous emulsion stabilization and synthetic reaction. In the stereoselective carboligation of benzaldehyde to (R)-benzoin catalyzed by a benzaldehyde lyase in E. coli, the set-up yielded maximum substrate conversion within very short time, while economizing material demand and waste. Formation and activity of freshly produced PEs were enhanced when the catalytic whole cells were covered with hydrophobic silicone prior to PE formation. Benchmarked against other easy-to-handle whole-cell biocatalysts in pure organic solvent, neat substrate, an aqueous emulsion in substrate, and a micro-aquatic system, respectively, the cell-stabilized PE outperformed all other systems by far.


Assuntos
Aldeído Liases/química , Benzaldeídos/química , Benzoína/química , Emulsões/química , Escherichia coli/enzimologia , Biocatálise , Escherichia coli/citologia , Interações Hidrofóbicas e Hidrofílicas , Silicones/química , Estereoisomerismo
8.
Langmuir ; 35(17): 5871-5877, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30955338

RESUMO

Reverse micelles (RMs) with confined water pools have been applied in many fields. However, the water insolubility of RMs seriously limits the scope of their application, especially those needed to operate in aqueous environments. Here, we report the first successful transfer of RMs from the organic phase to water phase without disturbing their confined water pools and hydrophobic alkyl region. This transfer was achieved by virtue of a mild host-guest interaction between the hydrophobic tails of interfacial cross-linked reverse micelles (ICRMs) and the hydrophobic cavity of (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD). Benefitting from the maintained confined water pools and the hydrophobic scaffold, the obtained water-soluble ICRMs served as multifunctional nanoplatforms for enzyme-mimicking catalysis and image-guided cancer therapy, which were impossible for normal RMs lacking water solubility or confined pool-buried water-soluble nanoparticles without a hydrophobic alkyl chain. This mild transfer approach thus surmounts the application obstacle of RMs and opens up new avenues for their application in aqueous environments.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Corantes Fluorescentes/química , Nanopartículas Metálicas/química , Micelas , 2-Hidroxipropil-beta-Ciclodextrina/química , Células A549 , Benzoína/química , Catálise , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Fluoruracila/análogos & derivados , Fluoruracila/farmacologia , Ouro/química , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Oxirredução , Rodaminas/química , Água/química
9.
Nanoscale ; 11(13): 5891-5895, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30874704

RESUMO

Biocatalytic self-assembly in a nanoconfined environment is widely used in nature to construct complex structures that endow special characteristics to life. There is tremendous interest in mimicking such bottom-up processes to fabricate functional materials. In this study, we have investigated a novel biomimetic scaffold based on lipidic cubic mesophases (LCMs), which provide a special nanoconfined environment for biocatalytic self-assembly and subsequent formation of organic crystals. (R)-Benzoin generated in situ from benzaldehyde in a reaction catalyzed by the enzyme benzaldehyde lyase (BAL) exhibits - when confined within LCMs - enhanced chirality compared to (R)-benzoin in solution or (R)-benzoin-doped LCMs. We infer that a metastable state is formed under kinetic control that displays enhanced supramolecular chirality. As they age, these metastable structures can further grow into thermodynamically stable crystals. The biomimetic, nanoconfined environment provided by the LCMs plays a key role in the development of supramolecular chirality and subsequent crystallization.


Assuntos
Benzoína/química , Lipídeos/química , Aldeído Liases/metabolismo , Benzaldeídos/química , Benzaldeídos/metabolismo , Benzoína/metabolismo , Biocatálise , Dicroísmo Circular , Cristalização , Espalhamento a Baixo Ângulo , Estereoisomerismo , Difração de Raios X
10.
Arch Microbiol ; 201(5): 591-601, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30714085

RESUMO

Plant endophytes play vital role in plant growth promotion as well as in abiotic and biotic stress tolerance. They also mediate biotransformation of complex organic materials to simpler and useful by-product. Therefore, the role of plant endophyte in plant growth promotion and stress tolerance has gained considerable attention in recent days. Sphingomonas sp. LK11 is an important plant endophyte that actively regulates plant growth. However, the biotransformation and stress tolerance potential of Sphingomonas sp. LK11 was yet to be elucidated. Therefore, we studied the biotransformation of benzoin by Sphingomonas sp. LK11. We found that, Sphingomonans sp. LK11 biotransformed benzoin to benzamide. Further application of benzamide to Cucumis sativus led to decrease in agronomic potential of C. sativus as benzamide acts as an abiotic stress agent. However, the application of Sphingomonas sp. LK11 inoculums with benzamide reverted back the agronomic trait of the plants, suggesting the role of Sphingomonas sp. LK11 in biotransformation and abiotic stress tolerance in plants.


Assuntos
Benzamidas/metabolismo , Benzoína/metabolismo , Cucumis sativus/crescimento & desenvolvimento , Sphingomonas/metabolismo , Estresse Fisiológico/fisiologia , Biotransformação/fisiologia , Endófitos/metabolismo , Desenvolvimento Vegetal , Reguladores de Crescimento de Plantas/metabolismo
11.
Med Chem ; 15(4): 417-429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30207238

RESUMO

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. OBJECTIVES: Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity. METHODS: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. RESULTS: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα. CONCLUSION: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoína/síntese química , Benzoína/farmacologia , Desenho de Fármacos , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzoína/química , Benzoína/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade
12.
Bioorg Chem ; 82: 385-392, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30428417

RESUMO

We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5 µg/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50 = 3.5 µM; Ki = 4.8 µM) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC50 = 2.3 µM; Ki = 0.7 µM) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity.


Assuntos
Antibacterianos/farmacologia , Benzoína/análogos & derivados , Benzoína/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Benzoína/síntese química , Domínio Catalítico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Meticilina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos
13.
J Oleo Sci ; 67(9): 1123-1129, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30111681

RESUMO

Two novel types of non-aqueous bioconversion systems using fungal spores, either adsorbed on the surface of a filter pad or entrapped in calcium alginate beads, were constructed and applied for a model reaction: reduction of benzil to benzoin by Aspergillus sojae NBRC 32074. The spores adsorbed on a filter pad catalyzed the reduction in some toxic organic solvents, such as methylcyclohexane (log P: 3.61) and din-butyl ether (3.21). For the relationship between the reduction activity and the log P value of the organic solvent, a highly positive correlation (R2: 0.815) was observed. Surprisingly, the reduction proceeded in the more hydrophilic and toxic tert-butyl acetate (log P: 1.76). Glycerol was selected as the best hydride source. The higher the glycerol content, the more the benzoin was produced. While the production of benzil by spores was lower than that by mycelia in harmless di-n-hexyl ether (log P: 5.12), mycelia could not catalyze the reduction in the toxic tert-butyl acetate. In contrast, the spores entrapped in the calcium alginate beads could catalyze the reduction. Although the reduction by alginate-entrapped spores could be stably repeated 5 times in di-n-hexyl ether without a decline in the reduction activity, it was observed that the reduction activity of the spores gradually decreased after repeated reduction in tert-butyl acetate.


Assuntos
Reatores Biológicos , Esporos Fúngicos/metabolismo , Acetatos , Adsorção , Alginatos , Aspergillus , Benzoína , Reatores Biológicos/microbiologia , Catálise , Cicloexanos , Éteres , Ácido Glucurônico , Glicerol , Ácidos Hexurônicos , Interações Hidrofóbicas e Hidrofílicas , Fenilglioxal/análogos & derivados , Fenilglioxal/metabolismo , Solventes
14.
ACS Comb Sci ; 20(7): 377-399, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29863839

RESUMO

Photolabile linkers are the subjects of intense research because they allow the release of the target molecule simply by irradiation. Photochemical release of synthesis products is often facilitated without additional reagents under mild reaction conditions, which may even be environmentally friendly and appealing in the context of greener chemistry. The mild conditions also allow for applications of released material in subsequent biological screening experiments, where contamination with cleavage reagents would be detrimental. This Review pays attention to the increasing number of photolabile linkers developed for solid-phase synthesis and release and covers: (i) o-nitrobenzyloxy linkers, (ii) o-nitrobenzylamino linkers, (iii) α-substituted o-nitrobenzyl linkers, (iv) o-nitroveratryl linkers, (v) phenacyl linkers, (vi) p-alkoxyphenacyl linkers, (vii) benzoin linkers, (viii) pivaloyl linkers, and (ix) other photolabile linkers.


Assuntos
Indicadores e Reagentes/química , Técnicas de Síntese em Fase Sólida/métodos , Aminas/química , Benzoína/análogos & derivados , Benzoína/química , Luz , Nitrobenzenos/química , Oxirredução , Fotólise
15.
Med Chem ; 14(7): 695-708, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651943

RESUMO

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. OBJECTIVES: Target compounds were designed to probe the significance of alcohol and imine moieties tailored on a benzoin scaffold to better understand the structure activity relation (SAR) and improve their biological activity as anticancer compounds. METHODS: Chemical synthesis of the targeted compounds, biological evaluation tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, as well as Glide docking studies were employed in this investigation. RESULTS: A new series of 1,2-diphenylimino ethanol was successfully synthesized and characterized by means of FT-IR, HRMS, NMR, and by elemental analysis. Biological screening revealed that the newly synthesized compounds inhibit PI3Kα activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines. Results additionally showed that these compounds exhibit selective antiproliferative activity, induce apoptosis, and suppress the VEGF production. Compounds 2b, 2d, and 2g displayed promising inhibitory activity in HCT-116 suggesting that hydrophobic and/or hydrogen bond-acceptor mediate(s) ligand-receptor interaction on o- and mpositions. Furthermore, compounds 2g, 2i, 2j, and 2h, bearing hydrophobic moiety on m- and pposition, exerted high antiproliferative activity in T47D and MCF-7 cells, whereas compound 2e showed selectivity against T47D and MCF-7. Molecular docking studies against PI3Kα and caspase-3 demonstrated a strong correlation between the predicted binding affinity (ΔGobsd) and IC50 values of prepared compounds for the caspase-3 model, implying that the cellulous inhibitory activity was caspase-3-dependent. Moreover, Glide docking against PI3Kα identified Ser774, Lys802, E849, V851, and Asp933 as key binding residues. CONCLUSION: The series exerted a potential PI3Kα inhibitory activity in human carcinoma cell lines expressing PI3Kα.


Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Bases de Schiff/síntese química , Apoptose/efeitos dos fármacos , Benzoína , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Bioorg Med Chem ; 26(8): 1653-1664, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29472126

RESUMO

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.


Assuntos
Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Supressores da Gota/farmacologia , Gota/tratamento farmacológico , Oximas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Animais , Benzoína/análogos & derivados , Benzoína/química , Benzoína/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Supressores da Gota/síntese química , Supressores da Gota/química , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Oximas/síntese química , Oximas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Úrico/sangue , Xantina Oxidase/metabolismo
17.
Angew Chem Int Ed Engl ; 56(19): 5304-5307, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28387004

RESUMO

Intramolecular benzoin reactions catalyzed by benzaldehyde lyase from Pseudomonas fluorescens biovar I (BAL) are reported. The structure of the substrates envisaged for this reaction consists of two benzaldehyde derivatives linked by an alkyl chain. The structural requirements needed to achieve the intramolecular carbon-carbon bond reaction catalyzed by BAL were established. Thus, a linker consisting of a linear alkyl chain of three carbon atoms connected through ether-type bonds to the 2 and 2' positions of two benzaldehyde moieties, which could be substituted with either Cl, Br, or OCH3 at either the 3 and 3' or 5 and 5' positions, were suitable substrates for BAL. Reactions with 61-84 % yields of the intramolecular product and ee values between 64 and 98 %, were achieved.


Assuntos
Aldeído Liases/metabolismo , Benzoína/metabolismo , Pseudomonas fluorescens/enzimologia , Benzoína/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular
18.
Chem Biodivers ; 14(7)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28374446

RESUMO

Phytochemical investigation from the tube roots of Butea superba, led to the isolation and identification of a new 2-aryl-3-benzofuranone named superbanone (1), one benzoin, 2-hydroxy-1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone (2), eight pterocarpans (3 - 10), and eleven isoflavonoids (11 - 21). Compound 2 was identified for the first time as a natural product. The structure of the isolated compounds was elucidated using spectroscopic methods, mainly 1D- and 2D-NMR. The isolated compounds and their derivatives were evaluated for α-glucosidase inhibitory and antimalarial activities. Compounds 3, 7, 8, and 11 showed promising α-glucosidase inhibitory activity (IC50  = 13.71 ± 0.54, 23.54 ± 0.75, 28.83 ± 1.02, and 12.35 ± 0.36 µm, respectively). Compounds 3 and 11 were twofold less active than the standard drug acarbose (IC50  = 6.54 ± 0.04 µm). None of the tested compounds was found to be active against Plasmodium falciparum strain 94. On the basis of biological activity results, structure-activity relationships are discussed.


Assuntos
Antimaláricos/isolamento & purificação , Benzofuranos/isolamento & purificação , Butea/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Antimaláricos/química , Antimaláricos/farmacologia , Benzofuranos/farmacologia , Benzoína/isolamento & purificação , Flavonoides/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Raízes de Plantas/química , Plasmodium falciparum/efeitos dos fármacos , Pterocarpanos/isolamento & purificação , Relação Estrutura-Atividade
19.
Trends Biotechnol ; 35(5): 379-382, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28190624

RESUMO

The experimentally determined Michaelis constant Km results from a combination of two effects: the recognition of the substrate by the enzyme and the interactions between substrate and solvent. For a solvent-independent analysis of substrate specificity, the thermodynamic activity of the substrate, rather than its concentration, must be considered.


Assuntos
Aldeído Liases/química , Benzoína/química , Ativação Enzimática , Hexanonas/imunologia , Modelos Químicos , Especificidade por Substrato , Termodinâmica , Sítios de Ligação , Simulação por Computador , Ligação Proteica
20.
Chemistry ; 22(39): 13999-14005, 2016 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-27515897

RESUMO

The catalytic asymmetric synthesis of chiral 2-hydroxy ketones by using different thiamine diphosphate dependent enzymes, namely benzaldehyde lyase from Pseudomonas fluorescens (PfBAL), a variant of benzoylformate decarboxylase from Pseudomonas putida (PpBFD-L461A), branched-chain 2-keto acid decarboxylase from Lactococcus lactis (LlKdcA) and a variant of pyruvate decarboxylase from Acetobacter pasteurianus (ApPDC-E469G), was studied. Starting with the same set of substrates, substituted benzaldehydes in combination with different aliphatic aldehydes, PfBAL and PpBFD-L461A selectively deliver the (R)- and (S)-2-hydroxy-propiophenone derivatives, respectively. The (R)- and (S)-phenylacetylcarbinol (1-hydroxy-1-phenylacetone) derivatives are accessible in a similar way using LlKdcA and ApPDC-E469G, respectively. In many cases excellent stereochemical purities (>98 % enantiomeric excess) could be achieved. Hence, the regio- and stereochemistry of the product in the asymmetric aliphatic-aromatic cross-benzoin reaction can be controlled solely by choice of the appropriate enzyme or enzyme variant.


Assuntos
Acetobacter/enzimologia , Acetona/análogos & derivados , Técnicas de Química Sintética/métodos , Hidroxipropiofenona/síntese química , Lactococcus lactis/enzimologia , Pseudomonas fluorescens/enzimologia , Pseudomonas putida/enzimologia , Acetona/síntese química , Acetona/química , Aldeído Liases/química , Aldeídos/química , Benzoína/química , Biocatálise , Carboxiliases/química , Hidroxipropiofenona/química , Estereoisomerismo , Tiamina Pirofosfato/química
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