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1.
Anal Chim Acta ; 1094: 57-69, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761048

RESUMO

In this study, a combined targeted/untargeted UHPLC-ESI-QTOF-MS/MS method for the targeted quantitative analysis of the primary platelet lipid mediators thromboxane B2 (TXB2), 12S-hydroxy-5Z,8E,10E-heptadecatrienoic acid (HHT) and its oxidation product 12-keto-5Z,8E,10E-heptadecatrienoic acid (KHT) was developed, which allowed simultaneous untargeted profiling for the detection of other lipid biomarkers such as other oxylipins and fatty acids (FAs) in platelet releasates. A general procedure for the synthesis of keto-analogs from hydroxylated polyunsaturated FAs (PUFAs) using Dess-Martin periodinane oxidation reagent was proposed for the preparation of KHT standard. MS detection was performed in data independent acquisition (DIA) mode with sequential window acquisition of all theoretical fragment ion mass spectra (SWATH) in the range of 50-500 Da with variable window sizes. The LC-MS/MS assay was validated for the targeted analytes and applied for analysis of supernatants derived from resting platelets and from platelets treated with thrombin. The targeted analytes KHT, HHT and TXB2 were found at highly elevated levels in the activated platelet releasates. On average, 13 ±â€¯7, 15 ±â€¯9, and 0.6 ±â€¯0.2 attomols per platelet were released upon thrombin-activation. Furthermore, the simultaneous untargeted profiling (n = 8 in each group) revealed that these oxylipins are released with a pool of other (significantly upregulated) oxidized (12-HETE, 12-HEPE) and non-oxidized PUFAs. All these compounds can be considered additional biomarkers of platelet activation complementing the primary platelet activation marker thromboxane B2. The other lipids may support platelet activation or trigger other biological actions with some potential implications in thromboinflammation.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ácidos Graxos/sangue , Ativação Plaquetária/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Trombina/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/síntese química , Humanos , Limite de Detecção , Tromboxano B2/sangue
2.
Org Biomol Chem ; 16(48): 9319-9333, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30511071

RESUMO

Stereoselective synthesis of Z-configured double bonds is central in organic synthesis due to the presence of such motifs in polyunsaturated fatty acids and many natural products. Traditionally, reductions of internal alkynes or Wittig, Ando or Still-Gennari reactions, are often used for preparing such compounds. The substrate scope is limited for both the Ando and the Still-Gennari reactions, while the Wittig reaction often gives low Z-selectivity for the synthesis of polyunsaturated Z-configured methylene interrupted (skipped) double bonds. Reductions of internal alkynes are challenging due to diminished Z-selectivity, poor catalyst reproducibility and over-reductions. An alternative and highly attractive approach is to employ naturally occurring and commercially available polyunsaturated fatty acids as starting materials. The main advantage of this strategy is the conservation of the multiple Z-configured double bonds present in the starting material, allowing a precise incorporation of the desired double bonds into the final product. In particular, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid have been used for the stereoselective synthesis of polyunsaturated fatty acids, their derivatives and other polyunsaturated natural products. Herein, such efforts are reviewed.


Assuntos
Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Ácidos Graxos Insaturados/síntese química , Alquinos/síntese química , Alquinos/química , Ácido Araquidônico/síntese química , Ácido Araquidônico/química , Produtos Biológicos/química , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/síntese química , Ácido Eicosapentaenoico/química , Ácidos Graxos Insaturados/química , Estereoisomerismo
3.
Bioorg Med Chem Lett ; 28(20): 3315-3319, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30220607

RESUMO

A small library of (E) α,ß-unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman's assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC50 = 4.3-12.8 M with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs. Furthermore, the screening results indicate that the chain length is crucial for obtaining an inhibitory efficacy. The best results were obtained for (2E) eicosenoic acid (14) showing inhibition constants Ki = 1.51 ±â€¯0.09 M and Ki' = 7.15 ±â€¯0.55 M. All tested compounds were mixed-type inhibitors with a dominating competitive part. Molecular modelling calculations indicate a different binding mode of active/inactive compounds for the enzymes AChE and BChE.


Assuntos
Inibidores da Colinesterase/química , Ácidos Graxos Insaturados/química , Bibliotecas de Moléculas Pequenas/química , Acetilcolinesterase/química , Animais , Butirilcolinesterase/química , Domínio Catalítico , Inibidores da Colinesterase/síntese química , Electrophorus , Ácidos Graxos Insaturados/síntese química , Cavalos , Cinética , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química
4.
Chemistry ; 24(41): 10403-10408, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-29931831

RESUMO

We report successful utilization of sequential alkene isomerization and ring-closing metathesis of dec-9-enoic acid based dienes in synthesis of macrocyclic lactones that possess a strong scent of musk. This catalytic sequence was essential to trim the chain length of starting dienes to yield macrocycles of the right size. Dec-9-enoic acid is conveniently obtainable from oleic esters by Ru-catalysed ethenolysis.


Assuntos
Alcenos/química , Biomassa , Ácidos Graxos Insaturados/síntese química , Lactonas/síntese química , Compostos Macrocíclicos/síntese química , Catálise , Ciclização , Isomerismo , Estrutura Molecular , Oxirredução , Rutênio/química , Estereoisomerismo
5.
J Org Chem ; 83(7): 3906-3914, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29547275

RESUMO

The stereoselective synthesis of resolvin D4 (RvD4) was achieved using the Wittig reaction of the C1-C10 dienal with the known C11-C22 phosphonium salt. The ( S, E)-enantiomer ( S)-10, corresponding to the C1-C8 part, was synthesized in 95% ee by the asymmetric transfer hydrogenation reaction of the corresponding acetylenic ketone followed by Red-Al reduction. Sharpless epoxidation of this alcohol using Ti(O- i-Pr)4/l-(+)-DIPT as a catalyst produced anti epoxy alcohol with >99% ee as the sole product in 82% yield. A subsequent functional group manipulation, including removal of the PMB group, produced the alcohol, which upon Swern oxidation afforded anti 4-hydroxy-5-TBS-oxy enal via epoxide ring opening of the resulting aldehyde. The Horner-Wadsworth-Emmons reaction was used to add the C9-C10 enal part to this aldehyde, and the resulting dienal was subjected to the Wittig reaction with C11-C22 phosphonium salt to furnish the entire structure of RvD4. Conversion of the primary alcohol to the methyl ester and deprotection of the three TBS groups with TBAF afforded 5,17-dihydroxy-γ-lactone, which was hydrolyzed to RvD4. Additionally, anti-4,5-dihydroxydodecanoic acid, a model compound of RvD4, in CD3OD was observed to be stable at room temperature for several weeks, whereas 20% of the acid in CDCl3 was converted into the γ-lactone after 24 h at rt.


Assuntos
Ácidos Graxos Insaturados/síntese química , Cetonas/química , Compostos Organofosforados/química , Ácidos Graxos Insaturados/química , Hidrogenação , Conformação Molecular , Oxirredução , Estereoisomerismo
6.
J Med Chem ; 61(7): 3224-3230, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29533650

RESUMO

N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice.


Assuntos
Aminoácidos/síntese química , Aminoácidos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Amidoidrolases/metabolismo , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/farmacologia , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Camundongos , Consumo de Oxigênio/efeitos dos fármacos , Estimulação Química , Relação Estrutura-Atividade
7.
Nat Prod Rep ; 35(1): 54-74, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29299588

RESUMO

Covering up to February 2017The pericarps of several species from the Zanthoxylum genus, a.k.a. the "prickly ash", have long been used for culinary purposes throughout Asia, most notably in the Sichuan (previously Szechuan) cuisine of Southwestern China, due to the unique tingling and numbing orosensations arising from a collection of polyunsaturated fatty acid amide (alkamide) constituents. The past decade has experienced dramatically increased academic and industrial interest in these pungent Zanthoxylum-derived alkamides, with a concomitant explosion in studies aimed at elucidating the specific biochemical mechanisms behind several medically-relevant biological activities exhibited by the natural products. This rapid increase in interest is partially fueled by advances in organic synthesis reported within the past few years that finally have allowed for the production of diastereomerically-pure Zanthoxylum alkamides and related analogs in multigram quantities. Herein is a comprehensive review of the discovery, total synthesis, and biological evaluation of Zanthoxylum-derived polyunsaturated fatty acid amides and synthetic analogues. Critical insights into how chemical synthesis can further benefit future chemical biology efforts in the field are also provided.


Assuntos
Amidas/química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Zanthoxylum/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ácidos Graxos Insaturados/síntese química , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia , Relação Estrutura-Atividade , Paladar
8.
Artif Cells Nanomed Biotechnol ; 46(8): 1523-1529, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28889752

RESUMO

Soybean lipoxygenase, recombinant rice allene oxide synthase-1 and rice allene oxide cyclase were covalently immobilized on nanoporous rice husk silica using two types of linkers: glutardialdehyde and polyethylene glycol. The immobilization efficiency achieved using glutardialdehyde-linked rice husk silica was higher than that achieved using polyethylene glycol-linked rice husk silica (50-92% and 25-50%, respectively). Immobilization on both types of matrices significantly decreased the specific activities of the immobilized enzymes. Solid-phase reaction yields of the enzymes were determined relative to the yields observed for the solution-phase reactions. Yields of the solid-phase reactions catalyzed by immobilized soybean lipoxygenase, rice allene oxide synthase-1, and rice allene oxide cyclase ranged from 50% to 230% and were dependent on both the enzymes and linkers used. Production of cis(+)-12-oxophytodienoic acid from α-linolenic acid by consecutive reactions using all three enzymes in a co-immobilization system resulted in 83.6% and 65.1% yields on glutardialdehyde-linked and epichlorohydrin-polyethylene glycol-linked rice husk silica, respectively. Our results suggest that immobilization of biosynthetic enzymes of the octadecanoid pathway on rice husk silica may be an efficient method for the in vitro production of oxylipins. Additionally, enzyme immobilizations on rice husk silica matrices may be more broadly applicable for producing physiologically important compounds in other biosynthetic pathways.


Assuntos
Enzimas Imobilizadas/química , Ácidos Graxos Insaturados/síntese química , Lipoxigenase/química , Oryza/química , Dióxido de Silício/química , Proteínas de Soja/química , Soja/enzimologia , Ácidos Graxos Insaturados/química
9.
J Cell Physiol ; 233(7): 5293-5309, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215703

RESUMO

Histone deacetylase inhibitors (HDACi) are a small molecule chemotherapeutics that target the chromatin remodeling through the regulation of histone and non-histone proteins. These inhibitors directed against histone deacetylase (HDAC) enzymes have become an important therapeutic tool in oncology; consequently, scientific efforts have fortified the quest for newer and novel HDACi, which forces the design of structurally innovative HDACi. Various urea containing compounds exhibited admirable anticancer activity. On the basis of these observations, we design and synthesize HDAC specific blocker molecules which are specifically besieged towards class I, class II, and class IV HDAC isoforms to enhance the structural assortment for HDACi. Through docking experiments, we identified that the compounds were tightly bound to the isoforms of the HDAC enzymes at their receptor regions. These derivatives potently inhibited the different isoforms, namely, class I, II, and IV of HDACs, by hyperacetylation of lysine residues in A549 cells. The mechanism of apoptosis is evident, regulating tumor suppressor genes and proteins, thereby facilitating the activation of the death receptor pathway by the tumor necrosis factor (TNF) receptor. These derivative facilitated the induction of reactive oxygen species (ROS) generation leading to downregulation of Bcl2 , and upregulation of Bax expression, thereby dysregulating mitochondrial membrane potential (ΔΨm ) to release cytochrome c, and activation of intrinsic pathway. These compounds downregulate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway to inhibit cell growth, proliferation, and metastasis through the matrix metalloproteinases (MMPs) MMP2 and MMP9 in A549 cells. These results suggest that our designed urea based derivatives act as epigenetic targeting agents through HDAC inhibition.


Assuntos
Ácidos Carboxílicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Células A549 , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histonas/genética , Histonas/metabolismo , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Espécies Reativas de Oxigênio/química , Ureia/química , Proteína X Associada a bcl-2/genética
10.
Chem Commun (Camb) ; 54(3): 241-243, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29199310

RESUMO

A rapid synthesis of the C1-C13 fragment of biselynbyolide A and B is reported. The judicious use of catalytic transformations for C-C bond formation and stereocenter generation greatly minimizes the use of protecting groups and oxidation state changes, as compared to previously reported routes to similar fragments.


Assuntos
Ácidos Graxos Insaturados/síntese química , Macrolídeos/química , Ácidos Graxos Insaturados/química , Estrutura Molecular , Estereoisomerismo
11.
Z Naturforsch C J Biosci ; 73(1-2): 59-66, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29161234

RESUMO

(9Z)-Methyl 4-dihydrotrisporate B and (9Z)-methyl trisporate B, pheromones of Zygomycetes fungi, have been synthesized using Stille cross-coupling from previously described cyclohexenone precursors. Conducting the coupling without protection groups allowed for a short and stereospecific synthesis route of the late trisporoids. Stability studies for both the compounds revealed (9Z)-methyl trisporate B to be very unstable against UV irradiation.


Assuntos
Cicloexenos/síntese química , Ácidos Graxos Insaturados/síntese química , Fungos não Classificados/química , Fator de Acasalamento/síntese química , Fungos não Classificados/metabolismo , Fator de Acasalamento/efeitos da radiação , Raios Ultravioleta
12.
Proc Jpn Acad Ser B Phys Biol Sci ; 93(8): 648-655, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29021513

RESUMO

A mixture of (E,Z)-isomers of methyl 12-trishomofarnesoate (methyl 3,7,11-trimethyl-2,6,10-pentadecatrienoate), a juvenile hormone mimic, was synthesized in nine steps (32.6% overall yield) by starting from only four commercially available materials: 2-hexanone, vinylmagnesium bromide, methyl acetoacetate and trimethyl phosphonoacetate. The mimic is useful in increasing the yield of silk by elongating the larval period of the silkworm, Bombyx mori (L.).


Assuntos
Ácidos Graxos Insaturados/síntese química , Hormônios Juvenis/síntese química , Seda/química , Animais , Bombyx/química , Larva/química , Estereoisomerismo
13.
Lipids ; 52(12): 1019-1032, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28956235

RESUMO

In our previous study, unusual odd-numbered dienoic acids with a terminal olefin were found as minor components in ovaries of the Japanese limpet Cellana toreuma, and the synthetic interests have been focused onto their structural confirmation and the inspection into their potential biological activity. Here, we describe an efficient and stereoselective total synthesis of two new unusual dienoic acids, 19:2∆7,18 and 21:2∆7,20, through a common pathway involving the strategic combination of alkyne-zipper reaction and Lindlar hydrogenation for the construction of their unique carbon chains. In our synthetic study, 2-propyn-1-ol was at first subjected to alkylation and alkyne-zipper reaction to form the two fragments, and the subsequent carbon chain elongation was achieved by the usual coupling reaction to obtain the C-19 and C-21 products bearing an internal acetylenic group. Then, the internal acetylenic group of these products was subjected to Lindlar hydrogenation to form a Z-alkenyl moiety, and the subsequent deprotection of the products was carried out under an acidic condition without isomerization of the internal Z-alkenyl group. Total synthesis of target fatty acids, 19:2∆7,18 and 21:2∆7,20, was finally accomplished by two-step oxidation of the resulting alcohols into carboxylic acids in a highly chemoselective manner, and the structures of these unusual natural fatty acids were finally elucidated by identifying the GC-MS spectra of the methyl esters of authentic and synthetic fatty acids.


Assuntos
Ácidos Graxos Insaturados/síntese química , Gastrópodes/química , Ovário/química , Animais , Ácidos Graxos Insaturados/química , Feminino , Hidrogenação , Estrutura Molecular , Estereoisomerismo
14.
Chem Pharm Bull (Tokyo) ; 65(7): 687-696, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28674344

RESUMO

Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E was achieved from an intermediate same as that of myriocin and mycestericin D via antipodal stereoselective dihydroxylations.


Assuntos
Aminoácidos/síntese química , Aminoácidos/química , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta
15.
Cell Stress Chaperones ; 22(3): 417-428, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28397086

RESUMO

Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using normal rat kidney (NRK-52E) cells. Five amide-substituted piperine analogs were synthesized and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability, and the expression of ER chaperone GRP78, the pro-apoptotic ER stress marker CHOP, and apoptotic caspases 3 and 12 (via western blotting). Our findings indicate that exposure to tunicamycin (0.5 µg/mL) for 2 h induces the expression of GRP78 and CHOP, and apoptotic markers (caspase-3 and caspase-12) and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP and cell death. Taken together, our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stress-related renal disorders. Graphical Abstract Piperine (PIP) reduces the expression of ER stress markers (GRP78 and CHOP) induced by pathologic stimuli and consequently decreases the activation of apoptotic caspase-12 and caspase-3; all of which contributes to its chemical chaperone and cytoprotective properties to protect renal cells against ER stress and ER stress-induced cell death, and would ultimately prevent the development of chronic kidney disease.


Assuntos
Alcaloides/farmacologia , Amidas/química , Benzodioxóis/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Amidas/síntese química , Animais , Apoptose/efeitos dos fármacos , Benzodioxóis/síntese química , Benzodioxóis/química , Caspase 12/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Proteínas de Choque Térmico/metabolismo , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Ratos , Relação Estrutura-Atividade , Fator de Transcrição CHOP/metabolismo , Tunicamicina/farmacologia , Regulação para Cima/efeitos dos fármacos
16.
Chemistry ; 23(1): 149-156, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27739117

RESUMO

A one-step homologation protocol for the synthesis of natural products containing deoxypropionate motif is described by the combination of Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)-Pd-catalyzed vinylation and ZACA-oxidation reaction. In contrast to most other synthetic strategies used to date that typically require three steps per deoxypropionate unit due to the functional-group interconversions, our one-step homologation strategy promises to provide a general and more efficient synthetic route toward deoxypropionate natural products as exemplified by significant improvements in the syntheses of intermediates and/or final products of mycolipenic acid 1 and its analogue 2, (-)-rasfonin, and syn- and anti-dicarboxylic acids 5 and 6.


Assuntos
Paládio/química , Propionatos/química , Zircônio/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Ácidos Dicarboxílicos/síntese química , Ácidos Dicarboxílicos/química , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Oxirredução , Propionatos/síntese química , Pironas/síntese química , Pironas/química , Estereoisomerismo
17.
Bioorg Med Chem Lett ; 27(3): 620-625, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28025003

RESUMO

ω-Hydroxy polyunsaturated fatty acids (PUFAs), natural metabolites from arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were prepared via convergent synthesis approach using two key steps: Cu-mediated CC bond formation to construct methylene skipped poly-ynes and a partial alkyne hydrogenation where the presence of excess 2-methyl-2-butene as an additive that is proven to be critical for the success of partial reduction of the poly-ynes to the corresponding cis-alkenes without over-hydrogenation. The potential biological function of ω-hydroxy PUFAs in pain was evaluated in naive rats. Following intraplantar injection, 20-hydroxyeicosatetraenoic acid (20-HETE, ω-hydroxy ARA) generated an acute decrease in paw withdrawal thresholds in a mechanical nociceptive assay indicating pain, but no change was observed from rats which received either 20-hydroxyeicosapentaenoic acid (20-HEPE, ω-hydroxy EPA) or 22-hydroxydocosahexaenoic acid (22-HDoHE, ω-hydroxy DHA). We also found that both 20-HEPE and 22-HDoHE are more potent than 20-HETE to activate murine transient receptor potential vanilloid receptor1 (mTRPV1).


Assuntos
Analgésicos/síntese química , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/uso terapêutico , Ácidos Hidroxieicosatetraenoicos/uso terapêutico , Dor/tratamento farmacológico , Limiar da Dor , Ratos , Canais de Receptores Transientes de Potencial/agonistas , Canais de Receptores Transientes de Potencial/metabolismo
18.
J Nat Prod ; 79(10): 2693-2702, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27704804

RESUMO

Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, 5), we provide direct evidence that the four novel mediators 1-4 are all biosynthesized from the pivotal intermediate 5. The UV and LC/MS-MS results from synthetic 13R-HDPA (5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure 5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in 5. Incubation of 5 with isolated human neutrophils gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1-4.


Assuntos
Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos Insaturados/síntese química , Animais , Cromatografia Líquida , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico/síntese química , Ácido Eicosapentaenoico/química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Humanos , Inflamação/metabolismo , Mediadores da Inflamação , Macrófagos/metabolismo , Estrutura Molecular , Neutrófilos/metabolismo , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo
19.
Org Biomol Chem ; 14(45): 10667-10673, 2016 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-27786324

RESUMO

Natural 12-hydroxyheptadecatrienoic acid (12-HHT) with an S configuration was synthesised by a Suzuki-Miyaura coupling of C10-C17 iodo alcohol with C1-C9 vinylborane. The iodo alcohol was synthesised by utilising Sharpless asymmetric epoxidation of the corresponding trimethylsilyl alcohol. The method yielded more than 100 mg of 12-HHT. Similarly, syntheses of 5,6-dihydro- and 14,15-dehydro derivatives of 12-HHT, known as HHD and HHTE, respectively, were completed in a stereoselective manner.


Assuntos
Ácidos Graxos Insaturados/síntese química , Álcoois/síntese química , Álcoois/química , Boranos/síntese química , Boranos/química , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Ácidos Graxos Insaturados/química , Estereoisomerismo , Compostos de Vinila/síntese química , Compostos de Vinila/química
20.
Mol Microbiol ; 100(5): 912-21, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26915347

RESUMO

Bacterial conjugation is the main mechanism responsible for the dissemination of antibiotic resistance genes. Hence, the search for specific conjugation inhibitors is paramount in the fight against the spread of these genes. In this pursuit, unsaturated fatty acids have been found to specifically inhibit bacterial conjugation. Despite the growing interest on these compounds, their mode of action and their specific target remain unknown. Here, we identified TrwD, a Type IV secretion traffic ATPase, as the molecular target for fatty acid-mediated inhibition of conjugation. Moreover, 2-alkynoic fatty acids, which are also potent inhibitors of bacterial conjugation, are also powerful inhibitors of the ATPase activity of TrwD. Characterization of the kinetic parameters of ATPase inhibition has led us to identify the catalytic mechanism by which fatty acids exert their activity. These results open a new avenue for the rational design of inhibitors of bacterial conjugation in the fight against the dissemination of antibiotic resistance genes.


Assuntos
Adenosina Trifosfatases/metabolismo , Conjugação Genética/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Ácidos Graxos Insaturados/farmacologia , Ácido Linoleico/farmacologia , Proteínas de Bactérias/genética , Sistemas de Secreção Bacterianos/química , Ácidos Graxos Insaturados/síntese química , Cinética , Simulação de Acoplamento Molecular , Plasmídeos
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