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1.
Chem Soc Rev ; 49(3): 908-950, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31958107

RESUMO

Donor and donor-donor carbenes are two important kinds of carbenes, which have experienced tremendous growth in the past two decades. This review provides a comprehensive overview of the recent development of donor and donor-donor carbene chemistry. The development of this chemistry offers efficient protocols to construct a wide variety of C-C and C-X bonds in organic synthesis. This review is organized based on the different types of carbene precursors, including diazo compounds, hydrazones, enynones, cycloheptatrienes and cyclopropenes. The typical transformations, the reaction mechanisms, as well as their subsequent applications in the synthesis of complex natural products and bioactive molecules are discussed. Due to the rapidly increasing interest in this area, we believe that this review will provide a timely and comprehensive discussion of recent progress in donor and donor-donor carbene chemistry.


Assuntos
Metano/análogos & derivados , Compostos Azo/química , Catálise , Ciclopropanos/química , Hidrazonas/química , Metais/química , Metano/síntese química , Estrutura Molecular , Estereoisomerismo
2.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480796

RESUMO

Diazo compounds have proven to be a useful class of carbenes or metal carbenoids sources under thermal, photochemical, or metal-catalyzed conditions, which can subsequently undergo a wide range of synthetically important transformations. Recently, asymmetric photocatalysis has provoked increasing research interests, and great advances have been made in this discipline towards the synthesis of optically enriched compounds. In this context, the past two decades have been the most productive period in the developments of enantioselective photochemical reactions of diazo compounds due to a better understanding of the reactivities of diazo compounds and the emergence of new catalytic modes, as well as easier access to and treatment of stabilized diazo compounds. This review highlights these impressive achievements according to the reaction type, and the general mechanisms and stereochemical inductions are briefly discussed as well.


Assuntos
Compostos Azo/química , Processos Fotoquímicos , Catálise , Reação de Cicloadição , Ciclopropanos/síntese química , Ciclopropanos/química , Estereoisomerismo
3.
J Agric Food Chem ; 67(42): 11591-11597, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31557017

RESUMO

A simple and eco-friendly dispersive solid-phase extraction method coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the determination of the chiral pesticide tefluthrin in food and environmental samples. The response surface methodology was applied to optimize separation conditions. The elution order of tefluthrin enantiomers was Z-cis-(1S,3S)-(-)-tefluthrin and Z-cis-(1R,3R)-(+)-tefluthrin on a Lux Cellulose-1 chiral column was identified via a polarimeter and vibrating circular dichroism. The average recoveries in five matrices ranged from 76.9 to 107.6%, with intraday relative standard deviations (RSDs) less than 15.6% and interday RSDs less than 12.5% for two enantiomers. The enantioselective degradation was investigated via laboratory incubation experiments. Slightly enantioselective degradation was observed under aerobic conditions; (1S,3S)-tefluthrin degraded preferentially with the enantiomer fraction value of 0.57 at 120 days of incubation. No remarkable enantioselective degradation was observed under anaerobic and sterile conditions. It was the first time that pyrethroid pesticides were determined at the enantiomer levels via UPLC-MS/MS. This novel method was successfully applied for the enantioselective analysis of tefluthrin enantiomers in authentic samples, indicating its efficacy in investigating the environmental stereochemistry of tefluthrin in the food web and environment. It is of crucial importance to improve risk assessment and regulation of chiral pesticides in an agricultural system.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos/química , Hidrocarbonetos Fluorados/química , Praguicidas/química , Poluentes do Solo/química , Solo/química , Espectrometria de Massas em Tandem/métodos , Estereoisomerismo
4.
Eur J Med Chem ; 182: 111626, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445232

RESUMO

A new series of fluorinated 5-HT2C agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT2 receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT2B agonism and displayed reasonable selectivity against 5-HT2A. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT2C receptor.


Assuntos
Ciclopropanos/farmacologia , Desenho de Drogas , Metilaminas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Halogenação , Humanos , Metilaminas/síntese química , Metilaminas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor 5-HT2B de Serotonina/metabolismo , Relação Estrutura-Atividade
5.
J Appl Biomater Funct Mater ; 17(2): 2280800019844746, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223071

RESUMO

BACKGROUND: Since its introduction in the field of biological imaging, the use of copper-free click chemistry has been extended to produce improved materials for vascular surgery, ophthalmology, environmental, and automotive applications. This wide applicability suggests that larger quantities of the chemical reagents for copper-free click chemistry will be required in the future. However, the large-scale synthesis of such chemicals has been barely investigated. A possible reason is the shortage of reliable synthetic protocols to obtain large quantities of these building blocks. We therefore present in this paper an improved synthetic protocol to obtain a cyclopropene-based carbonate, a key building block for the well-known copper-free click chemistry. METHOD: Our protocol builds upon an already available method to obtain a cyclopropene-based carbonate. When scaled up, several parameters of this method were changed in order to obtain an improved yield. First, the use of lower temperatures and slower addition rates of the chemicals avoided the formation of detrimental hotspots in the reaction system. Second, the use of less hygroscopic solvents minimized the decomposition of the cyclopropene carbonate. Finally, chromatographic purifications were minimized and improved by using deactivated silica. RESULTS: We obtained the compound (2-methylcycloprop-2-en-1-yl)methyl (4-nitrophenyl) carbonate, a key building block for copper-free click chemistry, in an unprecedented 60% overall yield on a six-gram scale. CONCLUSIONS: Our improved synthetic protocol demonstrates the potential of large-scale production of improved materials using click chemistry, with potential future applications in the fields of molecular imaging, vascular surgery, ophthalmology, and theranostics.


Assuntos
Materiais Biocompatíveis/química , Ciclopropanos/química , Engenharia Tecidual , Materiais Biocompatíveis/síntese química , Química Click , Meios de Contraste/síntese química , Meios de Contraste/química
6.
Methods Enzymol ; 622: 153-182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155051

RESUMO

The bioorthogonal reaction toolbox contains approximately two-dozen unique chemistries that permit selective tagging and probing of biomolecules. Over the past two decades, significant effort has been devoted to optimizing and discovering bioorthogonal reagents that are faster, fluorogenic, and orthogonal to the already existing bioorthogonal repertoire. Conversely, efforts to explore bioorthogonal reagents whose reactivity can be controlled in space and/or time are limited. The "activatable" bioorthogonal reagents that do exist are often unimodal, meaning that their reagent's activation method cannot be easily modified to enable activation with red-shifted wavelengths, enzymes, or metabolic-byproducts and ions like H2O2 or Fe3+. Here, we summarize the available activatable bioorthogonal reagents with a focus on our recent addition: modular caged cyclopropenes. We designed caged cyclopropenes to be unreactive to their bioorthogonal partner until they are activated through the removal of the cage by light, an enzyme, or another reaction partner. To accomplish this, their structure includes a nitrogen atom at the cyclopropene C3 position that is decorated with the desired caging group through a carbamate linkage. This 3-N cyclopropene system can allow control of cyclopropene reactivity using a multitude of already available photo- and enzyme-caging groups. Additionally, this cyclopropene scaffold can enable metabolic-byproduct or ion activation of bioorthogonal reactions.


Assuntos
Ciclopropanos/química , Animais , Biocatálise , Carbamatos/síntese química , Carbamatos/química , Técnicas de Química Sintética/métodos , Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos/síntese química , Humanos , Peróxido de Hidrogênio/química , Indicadores e Reagentes , Luz , Nitrogênio/química
7.
Molecules ; 24(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875844

RESUMO

2-Methylcyclopropane pyrethroid insecticides bearing chiral cyanohydrin esters or chiral ethers and two asymmetric centers on the cyclopropane ring, were synthesized. These compounds were designed using a "reverse connection approach" between the isopropyl group in Fenvalerate, and between two dimethyl groups in an Etofenprox analogue (the methyl, ethyl form), respectively. These syntheses were achieved by accessible ring opening reactions of commercially available (±)-, (R)-, and (S)-propylene oxides using 4-chlorobenzyl cyanide anion as the crucial step, giving good overall yield of the product with >98% ee. The insecticidal activity against the common mosquito (Culex pipiens pallens) was assessed for pairs of achiral diastereomeric (1R*,2S*)-, (1R*,2R*)-cyanohydrin esters, and (1R*,2S*)-, (1R*,2R*)-ethers; only the (1R*,2R*)-ether was significantly effective. For the enantiomeric (1S,2S)-ether and (1R,2R)-ether, the activity was clearly centered on the (1R,2R)-ether. The present stereostructure‒activity relationship revealed that (i) cyanohydrin esters derived from fenvalerate were unexpectedly inactive, whereas ethers derived from etofenprox were active, and (ii) apparent chiral discrimination between the (1S,2S)-ether and the (1R,2R)-ether was observed. During the present synthetic study, we performed alternative convergent syntheses of Etofenprox and novel 4-EtO-type (1S,2S)- and (1R,2R)-pyrethroids from the corresponding parent 4-Cl-type pyrethroids, by utilizing a recently-developed hydroxylation cross-coupling reaction.


Assuntos
Ciclopropanos/química , Inseticidas/química , Nitrilos/química , Piretrinas/química , Animais , Culicidae/efeitos dos fármacos , Inseticidas/síntese química , Inseticidas/farmacologia , Estrutura Molecular , Piretrinas/síntese química , Piretrinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
8.
Food Chem ; 288: 201-207, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902282

RESUMO

The objective of the present study was to investigate the effectiveness of lysozyme coatings and 1-MCP on storage and preservation of kiwifruit stored at 4 ±â€¯1 °C and 90-95% RH for 20 d. Ethylene production, respiratory rate, decay incidence, weight loss, firmness, chlorophyll, soluble solid, titratable acid, ascorbic acid, total bacterial count, ascorbate peroxidase (APX), superoxide dismutase (SOD) and catalase (CAT) activity of treated kiwifruit were examined. The results showed that lysozyme coatings or 1-MCP treatment inhibited ethylene production and respiratory rate, delayed the increase of decay incidence, weight loss, soluble solid and total bacterial count, improved firmness, chlorophyll, titratable acid, ascorbic acid content, APX, SOD and CAT activity during the storage compared with the untreated kiwifruit in different degree. Moreover, the combined effect of lysozyme coatings and 1-MCP was more excellent than that of lysozyme coatings or 1-MCP alone. In conclusion, our present results indicated that the combined treatment of lysozyme coatings and 1-MCP may be an efficient way to improve the postharvest quality and prolong the shelf life of kiwifruit.


Assuntos
Actinidia/química , Ciclopropanos/química , Conservação de Alimentos/métodos , Muramidase/química , Ascorbato Peroxidases/metabolismo , Ácido Ascórbico/metabolismo , Catalase/metabolismo , Clorofila/metabolismo , Etilenos/biossíntese , Superóxido Dismutase/metabolismo
9.
Z Naturforsch C J Biosci ; 74(7-8): 175-182, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30903762

RESUMO

Three new limonoids, designated as rubescins F (1), G (2), and H (3), together with two known compounds of this type, TS1 (4) and trichirubine A (5), were isolated from methylene chloride/methanol extracts of Trichilia rubescens leaves. The structures of these compounds were elucidated based on 1D and 2D nuclear magnetic resonance (NMR) analysis and complemented by electrospray ionization high-resolution mass spectrometry results and by comparison to data of related compounds described in the literature and ab initio calculations. Rubescin F (1) is the first limonoid from Trichilia spp. with an oxetane ring between C-7 and C-14, which seems to be formed by the isomerization of TS1 (4). The γ-hydroxybutenolide rubescin G (2) is a potential precursor of trichirubine A (5), whereas rubescin H (3) is the first example of a triterpenoid with a single bond between C-7/C-14, forming a cyclopropane ring. The absolute configuration of these limonoids was derived from biosynthetic considerations and ab initio calculations of NMR and optical rotation dispersion data.


Assuntos
Limoninas/análise , Meliaceae/química , Ciclopropanos/química , Limoninas/química , Folhas de Planta/química
10.
J Biochem ; 165(6): 517-522, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715374

RESUMO

Diacylglycerol kinase (DGK) is a lipid kinase that converts diacylglycerol (DG) into phosphatidic acid (PA). DG and PA function as lipid messengers contributing to various signalling pathways. Thus, DGK plays a pivotal role in the signalling pathways by maintaining DG and PA levels. For example, DGKδ is involved in diabetes and DGKß is important for higher brain function including memory and emotion. Recently, we also revealed that the activation of DGKα ameliorated diabetic nephropathy (DN) in mice, suggesting that DGK can be therapeutic target. However, there is no commercially available DGK subtype-specific inhibitors or activators. Therefore, in a series of experiment to find DGK subtype-specific inhibitors or activators, we tried to screen novel DGKα activators from 9,600 randomly selected compounds by using high-throughput screening we had recently developed. Finally, we obtained two lead compounds for DGKα activators, KU-8 and KU-10. Focusing KU-8, we assessed the effect of KU-8 on all mammalian DGKs activities. Thus, KU-8 activates not only DGKα but also DGKθ by approximately 20%, and strongly inhibited DGKκ. In conclusion, KU-8 would be a good lead compound for DGKα and DGKθ activators, and useful as a DGKκ inhibitor.


Assuntos
Ciclopropanos/farmacologia , Diacilglicerol Quinase/antagonistas & inibidores , Diacilglicerol Quinase/metabolismo , Dioxinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Xilenos/farmacologia , Animais , Células COS , Células Cultivadas , Ciclopropanos/química , Dioxinas/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Xilenos/química
11.
Science ; 363(6428)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30765538

RESUMO

Certain Escherichia coli strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin's chemical structure and the molecular mechanism underlying its genotoxic effects have remained unknown for more than a decade. Here we combine an untargeted DNA adductomics approach with chemical synthesis to identify and characterize a covalent DNA modification from human cell lines treated with colibactin-producing E. coli Our data establish that colibactin alkylates DNA with an unusual electrophilic cyclopropane. We show that this metabolite is formed in mice colonized by colibactin-producing E. coli and is likely derived from an initially formed, unstable colibactin-DNA adduct. Our findings reveal a potential biomarker for colibactin exposure and provide mechanistic insights into how a gut microbe may contribute to colorectal carcinogenesis.


Assuntos
Carcinogênese/metabolismo , Neoplasias Colorretais/microbiologia , Ciclopropanos/metabolismo , Adutos de DNA/metabolismo , Dano ao DNA , Escherichia coli/metabolismo , Microbioma Gastrointestinal , Mutagênicos/metabolismo , Peptídeos/metabolismo , Policetídeos/metabolismo , Alquilantes , Alquilação , Animais , Carcinogênese/genética , Neoplasias Colorretais/genética , Ciclopropanos/química , Escherichia coli/patogenicidade , Vida Livre de Germes , Células HT29 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutagênicos/toxicidade , Peptídeos/química , Peptídeos/toxicidade , Policetídeos/química , Policetídeos/toxicidade
12.
Yeast ; 36(3): 143-151, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30677185

RESUMO

Cyclopropane fatty acids, which can be simply converted to methylated fatty acids, are good unusual fatty acid candidates for long-term resistance to oxidization and low-temperature fluidity useful for oleochemistry and biofuels. Cyclopropane fatty acids are present in low amounts in plants or bacteria. In order to develop a process for large-scale biolipid production, we expressed 10 cyclopropane fatty acid synthases from various organisms in the oleaginous yeast Yarrowia lipolytica, a model yeast for lipid metabolism and naturally capable of producing large amounts of lipids. The Escherichia coli cyclopropane fatty acid synthase expression in Y. lipolytica allows the production of two classes of cyclopropane fatty acids, a C17:0 cyclopropanated form and a C19:0 cyclopropanated form, whereas others produce only the C17:0 form. Expression optimization and fed-batch fermentation set-up enable us to reach a specific productivity of 0.032 g·L-1 ·hr-1 with a genetically modified strain containing cyclopropane fatty acid up to 45% of the total lipid content corresponding to a titre of 2.3 ± 0.2 g/L and a yield of 56.2 ± 4.4 mg/g.


Assuntos
Ciclopropanos/metabolismo , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/metabolismo , Engenharia Metabólica/métodos , Proteínas Recombinantes/metabolismo , Yarrowia/genética , Yarrowia/metabolismo , Ciclopropanos/química , Ácido Graxo Sintases/genética , Ácidos Graxos/química , Fermentação , Expressão Gênica , Redes e Vias Metabólicas/genética , Proteínas Recombinantes/genética , Yarrowia/crescimento & desenvolvimento
13.
Food Chem ; 271: 466-468, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30236703

RESUMO

Fresh-cut (FC) apple, avocado and tomato fruits were examined to determine if sorption dynamics previously reported for FC apple were of general occurrence for other fruits. Fresh-cut apple consumed headspace 1-MCP at high rates, fully depleting 1-MCP in 1.5 h. FC apple pretreated with ascorbate showed 80% reduction in sorption rate. Fresh-cut avocado showed moderate sorption, depleting 95% of system 1-MCP over 6 h. FC avocado was unaffected by ascorbate. FC tomato showed negligible sorption of 1-MCP. Sorption by FC apple and avocado was differentially affected by heat. High-temperature pretreatment of FC apple and avocado resulted in 80% and 20% reductions in 1-MCP sorption rates, respectively. The data indicate that 1-MCP sorption differs significantly between FC tissues of different fruits, likely reflecting differences in thermo-tolerant, physical-sorption processes versus oxidative metabolism. Possible drawbacks in the use of 1-MCP as a post-processing treatment for FC fruits are discussed.


Assuntos
Ciclopropanos/química , Lycopersicon esculentum/química , Malus/química , Persea/química , Frutas
14.
J Enzyme Inhib Med Chem ; 34(1): 31-43, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30362368

RESUMO

The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of enzymes that synthesise cysteine and belong to the reductive sulphur assimilation pathway, absent in mammals. Previous studies have provided a novel series of inhibitors for O-acetylsulfhydrylase - a key enzyme involved in cysteine biosynthesis. Despite displaying nanomolar affinity, the most active representative of the series was not able to interfere with bacterial growth, likely due to poor permeability. Therefore, we rationally modified the structure of the hit compound with the aim of promoting their passage through the outer cell membrane porins. The new series was evaluated on the recombinant enzyme from Salmonella enterica serovar Typhimurium, with several compounds able to keep nanomolar binding affinity despite the extent of chemical manipulation.


Assuntos
Antibacterianos/farmacologia , Ácidos Carboxílicos/farmacologia , Ciclopropanos/farmacologia , Cisteína Sintase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ciclopropanos/síntese química , Ciclopropanos/química , Cisteína Sintase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Salmonella typhimurium/enzimologia , Relação Estrutura-Atividade
15.
Biotechnol J ; 14(4): e1800487, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30298619

RESUMO

The unique strained ring structure in cyclopropane fatty acids (CFA) conveys oxidative stability and lubricity to lipids. These attributes are highly valuable for industrial applications such as cosmetics and specialist lubrication but there is currently no commercial source of the lipid. Here, built on recently engineered strains of Saccharomyces cerevisiae, the authors have developed an efficient strategy for CFA production. Expression of the Escherichia coli cyclopropane fatty acid synthetase (Ec.CFAS) in the engineered yeast resulted in formation of cis-9,10-methylene-hexadecanoic and octadecanoic acids in both the phospholipid (PL) and triacylglycerol (TAG) fractions. CFA concentration in TAG of engineered yeast is 12 mg CFA g-1 DCW (fourfold above the strain expressing CFAS only). The yield of CFA increases from 13.2 to 68.3 mg L-1 , the highest reported in yeast, using a two-stage bioprocess strategy that separated cell growth from the lipid modification stage. Strategies for further improvement of this valuable lipid are proposed.


Assuntos
Ácidos Graxos/biossíntese , Lipídeos/biossíntese , Fosfolipídeos/biossíntese , Ácidos Esteáricos/química , Ciclopropanos/química , Escherichia coli/genética , Ácidos Graxos/química , Regulação Bacteriana da Expressão Gênica/genética , Lipídeos/química , Ácidos Palmíticos/química , Fosfolipídeos/química , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/genética , Triglicerídeos/química , Fermento Seco/genética
16.
Biochim Biophys Acta Biomembr ; 1861(2): 441-448, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30414847

RESUMO

Mixed Langmuir films of type 1 alpha-(α-) and keto-mycolic acids (MAs) were investigated to understand the roles of α-methyl trans-cyclopropane containing keto-MA in determining the physical and chemical properties of the monolayers. Surface pressure (π) vs. mean molecular area (A) isotherms were measured at constant mole fractions defined as the ratio of the keto-MA molarity to the total molarity of α-MA and keto-MA (Xketo) at 25 °C and 37 °C. A and the elastic modulus (E) of the mixed monolayer were compared for different Xketo at fixed π values. In keto-MA rich monolayers, A values were much larger than values of the combined areas of α-MA and keto-MA, while the E values were close to those of solid keto-MA monolayers. A and E were also plotted against the mole fraction of α-methyl trans-cyclopropane containing keto-MA, which showed that the α-methyl trans-cyclopropane group stabilized the W-form conformation of mycolic acids in monolayers, and rendered them solid state. Furthermore, a comparison of the experimental results and the α-methyl trans-cyclopropane content in cell-wall MAs from various strains indicated that the ratio of trans-cyclopropane content was important in determining the nature of the mixed MA layer.


Assuntos
Ciclopropanos/química , Ácidos Micólicos/química , Elasticidade , Peso Molecular , Mycobacterium/química , Pressão , Temperatura Ambiente
17.
Org Lett ; 21(1): 100-103, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30556696

RESUMO

A procedure allowing access to unprecedented tripeptides containing a trans-2-aminocyclopropanecarboxylic acid residue in their central position has been established. The key features of the strategy are the use of a masked trans-2-aminocyclopropanecarboxylic acid monomer equivalent for C-terminal coupling and full N-Boc protection of all amide groups until the final step.


Assuntos
Ácidos Carboxílicos/química , Ciclopropanos/química , Peptídeos/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Peptídeos/química
18.
Biomed Chromatogr ; 33(3): e4431, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30412929

RESUMO

A highly sensitive, specific and rapid liquid chromatography-tandem mass spectrometry technique for the quantification of tasimelteon in human plasma has been developed and validated using tasimelteon-d5 as internal standard. Liquid-liquid extraction technique with ethyl acetate was used for extraction of tasimelteon from the plasma. The chromatographic separation was achieved on an Agilent Zorbax, Eclipse, C18 (4.6 × 50 mm, 5 µm) column using a mobile phase of acetonitrile and 0.02% formic acid buffer (85:15, v/v) with a flow rate of 0.5 mL/min. A detailed method validation was performed as per the United States Food and Drug Administration guidelines. The linear calibration curve was obtained over the concentration range 0.30-299 ng/mL. The API-4000 liquid chromatography-tandem mass spectrometry was operated under multiple reaction monitoring mode during analysis. The validated method was successfully applied to estimate plasma concentration of tasimelteon after oral administration of a single dose of a 20 mg capsule in healthy volunteers under fasting conditions. The maximum concentration of the drug achieved in the plasma was 314 ± 147 ng/mL and the time at which this concentration was attained was 0.54 ± 0.22 h.


Assuntos
Benzofuranos/sangue , Benzofuranos/farmacocinética , Cromatografia Líquida/métodos , Ciclopropanos/sangue , Ciclopropanos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adulto , Benzofuranos/química , Benzofuranos/isolamento & purificação , Ciclopropanos/química , Ciclopropanos/isolamento & purificação , Humanos , Limite de Detecção , Modelos Lineares , Extração Líquido-Líquido , Masculino , Reprodutibilidade dos Testes , Adulto Jovem
19.
Curr Comput Aided Drug Des ; 15(4): 334-366, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30394213

RESUMO

BACKGROUND: The phosphodiesterase (PDE) is a superfamily represented by four genes: PDE4A, B,C, and D which cause the hydrolysis of phosphodiester bond of cAMP to yield inactive AMP. c-AMP catalyzing enzyme is predominant in inflammatory and immunomodulatory cells. Therapy to treat Chronic Obstructive Pulmonary Disease (COPD) with the use of PDE4 inhibitors is highly envisaged. OBJECTIVE: A molecular docking experiment with large dataset of diverse scaffolds has been performed on PDE4 inhibitors to analyze the role of amino acid responsible for binding and activation of the secondary transmitters. Apart from the general docking experiment, the main focus was to discover the role of water molecules present in the ligand-binding domain. METHODS: All the compounds were docked in the PDE4B and PDE4D active cavity to produce the free binding energy scores and spatial disposition/orientation of chemical groups of inhibitors around the cavity. Under uniform condition, the experiments were carried out with and without water molecules in the LBD. The exhaustive study was carried out on the Autodock 4.2 software and explored the role of water molecules present in the binding domain. RESULTS: In presence of water molecule, Roflumilast has more binding affinity (-8.48 Kcal/mol with PDE4B enzyme and -8.91 Kcal/mol with PDE4D enzyme) and forms two hydrogen bonds with Gln443 and Glu369 and amino acid with PDE4B and PDE4D enzymes respectively. While in absence of water molecule its binding affinity has decreased (-7.3 Kcal/mol with PDE4B enzyme and -5.17 Kcal/mol with PDE4D enzyme) as well as no H-bond interactions were observed. Similar observation was made with clinically tested molecules. CONCLUSION: In protein-ligand binding interactions, appropriate selection of water molecules facilitated the ligand binding, which eventually enhances the efficiency as well as the efficacy of ligand binding.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Aminopiridinas/química , Benzamidas/química , Sítios de Ligação/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Ciclopropanos/química , Ciclopropanos/farmacologia , Desenho de Drogas , Humanos , Ligações de Hidrogênio/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 4/química , Termodinâmica , Água/química
20.
Drug Test Anal ; 11(6): 886-897, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30578615

RESUMO

With the aim of studying their in vitro and in vivo pharmacokinetics, new chromatographic methods were developed for the determination of three new roflumilast synthetic analogs (I-III) as PDE-4B inhibitors in rat liver S9 fraction, phosphate buffered saline, pH 7.4, and human and rat plasma. The developed high performance liquid chromatography-ultra violet (HPLC-UV) methods were performed on a Zorbax Eclipse C8 column and UV detection was carried out at 215 nm. The three compounds were tested for their metabolic stability and were found to be metabolically more stable than roflumilast especially the 2-mercaptobenzothiazol-6-yl analog (III) which displayed an in vitro half-life time (247.55 minutes) higher than that of roflumilast (12.29 minutes) and a low in vitro clearance of 5.67 mL/min./kg. Possible phase I metabolites were investigated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showing hydroxylation of the unsubstituted benzothiazol-2-yl (I) and benzothiazole-6-yl (II) analogs and a cleaved benzothiazole metabolite of the 2-mercaptobenzothiazol-6-yl analog (III). Plasma protein binding affinity was tested using equilibrium membrane dialysis method showing a very high percentage (more than 95%) of plasma protein binding of compounds I and II where compound III exhibited lower percentage (53.71%) demonstrating its accessibility for tissue distribution. Also, a UPLC-MS/MS method was developed using an Acquity UPLC BEH shield RP C18 column to be applied to an in vivo pharmacokinetic study in rats following a subcutaneous dose (1 mg/kg). Compounds I-III showed improved in vivo pharmacokinetic parameters especially compound III which displayed a half-life 3-fold greater than roflumilast (21 hours) and a Cmax value of 113.958 ng/mL. Accordingly, this new chemical entity should be subjected to further investigation as it can be a good drug candidate for treating chronic obstructive pulmonary disease.


Assuntos
Aminopiridinas/sangue , Aminopiridinas/metabolismo , Benzamidas/sangue , Benzamidas/metabolismo , Inibidores da Fosfodiesterase 4/sangue , Inibidores da Fosfodiesterase 4/metabolismo , Aminopiridinas/química , Animais , Benzamidas/química , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos/sangue , Ciclopropanos/química , Ciclopropanos/metabolismo , Humanos , Fígado/metabolismo , Masculino , Inibidores da Fosfodiesterase 4/química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
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