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1.
Org Lett ; 25(1): 169-173, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36602193

RESUMO

Cyclopropane-fused lactones are highly desirable in drug and natural products synthesis. Herein, we report on a photochemical, chemoselective reaction of aryldiazoacetates with allylic alcohols that furnishes cyclopropane-fused lactone skeletons efficiently in one step. The diastereoselectivity of the protocol was precisely controlled, and chemoselective cyclopropanation of allylic alcohols via free carbene intermediate followed by transesterification constitutes a series of bicyclic lactones in high yield without the formation of ether byproducts via typical O-H insertion reactions.


Assuntos
Ciclopropanos , Propanóis , Estereoisomerismo , Propanóis/química , Ciclopropanos/química , Lactonas/química , Álcoois/química
2.
Science ; 379(6627): 94-99, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603079

RESUMO

Maize (Zea mays) is a major staple crop in Africa, where its yield and the livelihood of millions are compromised by the parasitic witchweed Striga. Germination of Striga is induced by strigolactones exuded from maize roots into the rhizosphere. In a maize germplasm collection, we identified two strigolactones, zealactol and zealactonoic acid, which stimulate less Striga germination than the major maize strigolactone, zealactone. We then showed that a single cytochrome P450, ZmCYP706C37, catalyzes a series of oxidative steps in the maize-strigolactone biosynthetic pathway. Reduction in activity of this enzyme and two others involved in the pathway, ZmMAX1b and ZmCLAMT1, can change strigolactone composition and reduce Striga germination and infection. These results offer prospects for breeding Striga-resistant maize.


Assuntos
Lactonas , Striga , Zea mays , Germinação , Lactonas/metabolismo , Melhoramento Vegetal , Striga/crescimento & desenvolvimento , Zea mays/genética , Zea mays/metabolismo
3.
Int J Mol Sci ; 24(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36674768

RESUMO

Continuing chemical investigation of the Red Sea sponge Spongia sp. led to the isolation of four new 3,4-seco-3,19-dinorspongian diterpenoid lactones, secodinorspongins A-D (1-4), along with a classical spongian diterpenoid lactone, sponginolide (5). The chemical structures, including the absolute configurations of these compounds, were elucidated using the extensive spectroscopic study composed of 1D and 2D NMR data analyses, and a comparison between calculated-electronic-circular-dichroism (ECD) and experimental-circular-dichroism (CD) spectra. A plausible biosynthetic pathway of 1-4 was also proposed. Furthermore, the cytotoxicity, antibacterial and anti-inflammatory activities of 1-5 were evaluated. Compound 1 was found to exhibit inhibitory activity against the growth of Staphylococcus aureus (S. aureus), and 4 and 5 exhibited suppression of superoxide-anion generation and elastase release in fMLF/CB-induced human neutrophils.


Assuntos
Diterpenos , Poríferos , Animais , Humanos , Lactonas , Staphylococcus aureus , Estrutura Molecular , Poríferos/química , Diterpenos/química
4.
Molecules ; 28(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36677732

RESUMO

Centaurea is a genus compromising over 250 herbaceous flowering species and is used traditionally to treat several ailments. Among the Egyptian Centaurea species, C. lipii was reported to be cytotoxic against multidrug-resistant cancer cells. In this context, we aimed to explore the metabolome of C. lipii and compare it to other members of the genus in pursuance of identifying its bioactive principles. An LC-MS/MS analysis approach synchronized with feature-based molecular networks was adopted to offer a holistic overview of the metabolome diversity of the Egyptian Centaurea species. The studied plants included C. alexandrina, C. calcitrapa, C. eryngioides, C. glomerata, C. lipii, C. pallescens, C. pumilio, and C. scoparia. Their constitutive metabolome showed diverse chemical classes such as cinnamic acids, sesquiterpene lactones, flavonoids, and lignans. Linking the recorded metabolome to the previously reported cytotoxicity identified sesquiterpene lactones as the major contributors to this activity. To confirm our findings, bioassay-guided fractionation of C. lipii was adopted and led to the isolation of the sesquiterpene lactone cynaropicrin with an IC50 of 1.817 µM against the CCRF-CEM leukemia cell line. The adopted methodology highlighted the uniqueness of the constitutive metabolome of C. lipii and determined the sesquiterpene lactones to be the responsible cytotoxic metabolites.


Assuntos
Antineoplásicos , Centaurea , Sesquiterpenos , Extratos Vegetais/química , Cromatografia Líquida , Resistência a Múltiplos Medicamentos , Egito , Resistencia a Medicamentos Antineoplásicos , Espectrometria de Massas em Tandem , Centaurea/química , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/química , Lactonas/química
5.
Bioresour Technol ; 371: 128614, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36640821

RESUMO

Anammox was proved having the quorum sensing ability, and several acylated homoserine lactones (AHLs) signal molecules were detected in the system. In this study, the impact of exogenous N-dodecanoyl homoserine lactone (C12-HSL) with different addition modes on the nitrogen removal, key enzymes' activity, and microbial revolution were investigated in Anammox system. Results showed that once-addition of C12-HSL had no obvious impact on Anammox. Daily-addition with 40 nM slightly improved the TN removal from 71.1 % to 74.5 %, while 80 and 200 nM significantly decreased it to 62.7 % and 61.8 %, respectively. The enzyme activity of ammonia monooxygenase increased from 0.015 to 0.068, nitrite reductase increased from 0.25 to 1.23, and nitrate reductase increased from 0.05 to 0.11 µg NO2--N mg-1 Protein min-1. Arenimonas abundance showed positive correlation with TN removal while Candidatus Kuenenia was continuously suppressed. C12-HSL was beneficial for partial nitrification, and it could be adopted for regulating the nitrite production.


Assuntos
Acil-Butirolactonas , Percepção de Quorum , Homosserina/metabolismo , Oxidação Anaeróbia da Amônia , 4-Butirolactona/farmacologia , Nitrogênio , Lactonas
6.
Toxins (Basel) ; 15(1)2023 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-36668873

RESUMO

Large amounts of processing tomato are grown in Xinjiang, China. Tomato black spot disease, caused by Alternaria spp., and the produced alternaria toxins in tomato products are posing risks to human health. In this study, we isolated a rhizospheric bacterium, XJ-BV2007, from tomato (Solanum lycopersicum) fields, which we identified as Bacillus amyloliquefaciens. We found that this bacterium has a strong antagonistic effect against Alternaria alternata and reduces the accumulation of alternaria toxins in tomatoes. According to the antifungal activity of the bacteria-free filtrate, we revealed that B. amyloliquefaciens XJ-BV2007 suppresses A. alternata by the production of antifungal metabolites. Combining semi-preparative high-performance liquid chromatography, we employed UPLC-QTOF-MS analysis and the Oxford cup experiment to find that fengycin plays an important role in inhibiting A. alternata. This paper firstly reported that B. amyloliquefaciens efficiently controls tomato black spot disease and mycotoxins caused by A. alternata. B. amyloliquefaciens XJ-BV2007 may provide an alternative biocontrol strain for the prevention of tomato black spot disease.


Assuntos
Bacillus amyloliquefaciens , Toxinas Biológicas , Humanos , Ácido Tenuazônico/análise , Alternaria/metabolismo , Bacillus amyloliquefaciens/metabolismo , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Lactonas/análise , Toxinas Biológicas/metabolismo
7.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674683

RESUMO

Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9' position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9'-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9' derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9'-hydroxymethyl lead compound.


Assuntos
Furanos , Lignanas , Humanos , Furanos/química , Lignanas/farmacologia , Lignanas/química , Lactonas/química
8.
PeerJ ; 11: e14669, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36650839

RESUMO

The more axillary growth (MAX) gene family is a group of key genes involved in the synthesis and signal transduction of strigolactones (SLs) in plants. Although MAX genes play vital roles in plant growth and development, characterization of the MAX gene family has been limited in solanaceous crops, especially in tobacco. In this study, 74 members of the MAX family were identified in representative Solanaceae crops and classified into four groups. The physicochemical properties, gene structure, conserved protein structural domains, cis-acting elements, and expression patterns could be clearly distinguished between the biosynthetic and signal transduction subfamilies; furthermore, MAX genes in tobacco were found to be actively involved in the regulation of meristem development by responding to hormones. MAX genes involved in SL biosynthesis were more responsive to abiotic stresses than genes involved in SL signaling. Tobacco MAX genes may play an active role in stress resistance. The results of this study provide a basis for future in-depth analysis of the molecular mechanisms of MAX genes in tobacco meristem development and stress resistance.


Assuntos
Proteínas de Plantas , Tabaco , Tabaco/genética , Proteínas de Plantas/genética , Transdução de Sinais/genética , Lactonas/metabolismo
9.
Phytochemistry ; 206: 113557, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36496006

RESUMO

An LC-HRMS/MS-based molecular networking strategy was applied to investigate the potential sesquiterpene dimers of Aucklandia lappa, leading to the isolation of three undescribed guaiane-guaiane dimers and one guaiane-eudesmane dimer together with six known sesquiterpenes. The structures were determined by analyzing their 1D, 2D NMR, and HRESIMS data as well as ECD calculations. The biogenetic pathway of the sesquiterpene dimers was postulated to involve the Diels-Alder cycloaddition as the key step. All compounds exhibited their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages with IC50 values ranging from 0.3 to 25.1 µM.


Assuntos
Saussurea , Sesquiterpenos , Estrutura Molecular , Saussurea/metabolismo , Sesquiterpenos/química , Lactonas/química , Óxido Nítrico
10.
Eur J Pharmacol ; 939: 175456, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36528070

RESUMO

Breast cancer as most often women's cancer is the second cause of mortality worldwide. Research interest increased in testing non-standard drugs to suppress breast cancer progression and become significant supplements in anticancer therapy. The anti-obesity drug Orlistat showed significant ability for modulation of cancer cell metabolism via antiproliferative, proapoptotic, antiangiogenic, antimetastatic, and hypolipidemic effects. The anticancer potential of Orlistat was evaluated by cytotoxicity (MTT assay), type of cell death (AO/EB double staining), determination of redox status parameters (superoxide, hydrogen peroxide, lipid peroxidation, reduced glutathione), and total lipid levels with colorimetric methods, as well on angiogenesis-related (VEGF, MMP-9, CXCR4/CXCL12) and fatty acid synthesis-related (ACLY, ACC, FASN) parameters on gene and protein levels (immunocytochemistry and qPCR). Based on obtained results Orlistat induces significant cytotoxic, proapoptotic, and anti-angiogenic effects in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells, without significant cytotoxic effects on normal MRC-5 cells. It decreased total lipid levels and changed redox status parameters and cancer cell metabolism via suppression of genes and proteins involved and fatty acid synthesis. Based on showed, Orlistat may be an important supplement in antiangiogenic therapy against breast cancer with no side effects on normal cells, making it a good candidate for future clinical trials.


Assuntos
Neoplasias da Mama , Lactonas , Feminino , Humanos , Orlistate/farmacologia , Orlistate/uso terapêutico , Lactonas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Lipídeos , Apoptose , Proliferação de Células
11.
J Agric Food Chem ; 71(1): 110-120, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36579964

RESUMO

Due to its strong and unique peach-like aroma, γ-decalactone is widely used in dairy products and other foods or beverages. The oleaginous yeast Yarrowia lipolytica, which is generally regarded as safe, has shown great potential in the production of this flavor compound. Recently, the development of metabolic and process engineering has enabled the application of Y. lipolytica for the production of γ-decalactone. This Review summarizes the relevant biosynthesis and degradation pathways of Y. lipolytica, after which the related metabolic engineering strategies to increase the accumulation of γ-decalactone are summarized. In addition, the factors affecting γ-decalactone accumulation in Y. lipolytica are introduced, and corresponding process optimization strategies are discussed. Finally, the current research needs are analyzed to search for remaining challenges and future directions in this field.


Assuntos
Prunus persica , Yarrowia , Yarrowia/genética , Yarrowia/metabolismo , Prunus persica/metabolismo , Odorantes , Lactonas/metabolismo , Engenharia Metabólica
12.
ACS Infect Dis ; 9(1): 79-96, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36577009

RESUMO

Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).


Assuntos
Ácido Aminossalicílico , COVID-19 , Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Pirazinamida/farmacologia , Ácido Aminossalicílico/farmacologia , Peixe-Zebra , SARS-CoV-2 , Antituberculosos/química , Tuberculose/tratamento farmacológico , Lactonas
13.
Org Lett ; 25(1): 298-303, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36583568

RESUMO

Herein, we report direct electrochemical C(sp3)-H lactonization of 2-alkylbenzoic acids toward phthalides. The reaction provides a wide substrate scope of 2-alkylbenzoic acids bearing primary to tertiary C(sp3)-H bonds by utilizing a graphite anode, dichloromethane (DCM) solvent, hexafluoroisopropanol (HFIP) cosolvent, and n-Bu4NClO4 electrolyte. Our synthetic approach offers a simple, intuitive, and atom-economical protocol to synthesize various phthalides (25 examples, up to 92% yield) and obtain other 5- and 6-membered lactones (10 examples, up to 83% yield).


Assuntos
Benzofuranos , Lactonas , Lactonas/química , Benzofuranos/química
14.
J Biol Chem ; 299(1): 102782, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36502920

RESUMO

Lactones are prevalent in biological and industrial settings, yet there is a lack of information regarding enzymes used to metabolize these compounds. One compound, γ-valerolactone (GVL), is used as a solvent to dissolve plant cell walls into sugars and aromatic molecules for subsequent microbial conversion to fuels and chemicals. Despite the promise of GVL as a renewable solvent for biomass deconstruction, residual GVL can be toxic to microbial fermentation. Here, we identified a Ca2+-dependent enzyme from Rhodopseudomonas palustris (Rpa3624) and showed that it can hydrolyze aliphatic and aromatic lactones and esters, including GVL. Maximum-likelihood phylogenetic analysis of other related lactonases with experimentally determined substrate preferences shows that Rpa3624 separates by sequence motifs into a subclade with preference for hydrophobic substrates. Additionally, we solved crystal structures of this ß-propeller enzyme separately with either phosphate, an inhibitor, or a mixture of GVL and products to define an active site where calcium-bound water and calcium-bound aspartic and glutamic acid residues make close contact with substrate and product. Our kinetic characterization of WT and mutant enzymes combined with structural insights inform a reaction mechanism that centers around activation of a calcium-bound water molecule promoted by general base catalysis and close contacts with substrate and a potential intermediate. Similarity of Rpa3624 with other ß-propeller lactonases suggests this mechanism may be relevant for other members of this emerging class of versatile catalysts.


Assuntos
Lactonas , Rodopseudomonas , Cálcio , Catálise , Lactonas/química , Filogenia , Solventes/química , Especificidade por Substrato , Água/química
15.
Pharmacol Res ; 187: 106617, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36535572

RESUMO

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-ß-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-ß1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.


Assuntos
Doenças Retinianas , Neovascularização Retiniana , Animais , Humanos , Camundongos , Ratos , Citocinas/uso terapêutico , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Lactonas/uso terapêutico , Camundongos Endogâmicos C57BL , Neovascularização Patológica/patologia , NF-kappa B , Oxigênio , Doenças Retinianas/patologia , Neovascularização Retiniana/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-36481725

RESUMO

Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) combined with multivariate statistical analysis was applied to the study of plant metabolomics to reveal the factors affecting the content of ginkgo leaf compounds. As a follow-up analysis, the terpene lactones and ginkgolic acids were quantified simultaneously using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS/MS), and subsequently total flavonol glycosides were quantified by high-performance liquid chromatography (HPLC). The results revealed that a total of 52 compounds were potentially identified by establishing a database, and 10 compounds were verified by reference standards; terpene lactones, ginkgolic acids, and flavonoids were the differential compounds; and ginkgolide A was identified as an important indicator compound for tree age. In addition, quantitative analysis showed that the contents of total flavonol glycosides and terpene lactones were highest during April and August in young ginkgo leaves, and differed based on origin. In summary, numerous compounds were rapidly detected by liquid chromatography coupled with MS, the ginkgo leaf samples were compared, and the differential metabolites were screened out. The content changing rules of the target compounds in ginkgo leaves from different regions with different tree ages and harvesting periods were clarified.


Assuntos
Ginkgo biloba , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Folhas de Planta/química , Flavonóis/análise , Glicosídeos/análise , Cromatografia Líquida de Alta Pressão/métodos , Terpenos/análise , Lactonas/química , Extratos Vegetais/química
17.
Appl Microbiol Biotechnol ; 107(2-3): 807-818, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36580089

RESUMO

Bacterial expression systems play an indispensable role in the biosynthesis of recombinant proteins. Different proteins and the tasks associated with them may require different systems. The purpose of this work is to make an expression vector that allows switching on and off the expression of the target gene during cell incubation. Several expression vectors for use in Escherichia coli cells were developed using elements of the luxR/luxI type quorum sensing system of psychrophilic bacterium Aliivibrio logei. These vectors contain A. logei luxR2 and (optionally) luxI genes and LuxR2-regulated promoter, under the control of which a target gene is intended to be inserted. The synthesis of the target protein depends directly on the temperature: gene expression starts when the temperature drops to 22 °C and stops when it rises to 37 °C, which makes it possible to fix the desired amount of the target protein in the cell. At the same time, the expression of the target gene at a low temperature depends on the concentration of the autoinducer (L-homoserine N-(3-oxohexanoyl)-lactone, AI) in the culture medium in a wide range from 1 nM to 10 µM, which makes it possible to smoothly regulate the rate of target protein synthesis. Presence of luxI in the vector provides the possibility of autoinduction. Constructed expression vectors were tested with gfp, ardA, and ardB genes. At maximum, we obtained the target protein in an amount of up to 33% of the total cellular protein. KEY POINTS: • A. logei quorum sensing system elements were applied in new expression vectors • Expression of target gene is inducible at 22 °C and it is switched off at 37 °C • Target gene expression at 22 °C is tunable by use different AI concentrations.


Assuntos
Acil-Butirolactonas , Proteínas de Escherichia coli , Acil-Butirolactonas/metabolismo , Temperatura , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Lactonas/metabolismo , Regiões Promotoras Genéticas , Escherichia coli/genética , Escherichia coli/metabolismo , Percepção de Quorum , Regulação Bacteriana da Expressão Gênica , 4-Butirolactona/metabolismo , Proteínas de Escherichia coli/genética , Proteínas Repressoras/genética
18.
Chem Commun (Camb) ; 59(4): 446-449, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36519364

RESUMO

Herein, we disclose the first report on the generation of cyanonitrone in situ from diazoacetonitrile and nitrosoarene, and its subsequent [3+2] cycloaddition with oxabicyclic alkenes to access fused tricyclic cyanoisoxazolidines. Further, this methodology could be extended to access fused tricyclic trifluoromethylated and phosphonylated isoxazolidines. Surprisingly, the reductive ring-opening of cyanoisoxazolidines was followed by a spontaneous lactonization to produce fused tricyclic amino lactones. Moreover, the N-O bond of the obtained tricyclic trifluoromethylated isoxazolidines could be cleaved to obtain 1,3-amino alcohols.


Assuntos
Alcenos , Amino Álcoois , Ciclização , Alcenos/química , Lactonas/química , Reação de Cicloadição
19.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36555498

RESUMO

The current investigation assessed the effect of the eudesmanolid, Vulgarin (VGN), obtained from Artemisia judaica (A. judaica), on the antidiabetic potential of glibenclamide (GLB) using streptozotocin (STZ) to induce diabetes. Seven groups of rats were used in the study; the first group received the vehicle and served as normal control. The diabetic rats of the second to the fifth groups were treated with the vehicle (negative control), GLB at 5 mg/kg (positive control), VGN at 10 mg/kg (VGN-10) and VGN at 20 mg/kg (VGN-20), respectively. The diabetic rats of the sixth and seventh groups were administered combinations of GLB plus VGN-10 and GLB plus VGN-20, respectively. The diabetic rats treated with GLB plus VGN-20 combination showed marked improvement in the fasting blood glucose (FBG), insulin and glycated hemoglobin (HbA1c), as well as the lipid profile, compared with those treated with GLB alone. Further, the pancreatic tissues of the diabetic rats that received the GLB+VGN-20 combination showed superior improvements in lipid peroxidation and antioxidant parameters than those of GLB monotherapy. The insulin content of the ß-cells was restored in all treatments, while the levels of glucagon and somatostatin of the α- and δ-endocrine cells were reduced in the pancreatic islets. In addition, the concurrent administration of GLB+VGN-20 was the most effective in restoring PEPCK and G6Pase mRNA expression in the liver. In conclusion, the results demonstrated that the GLB+VGN-20 combination led to greater glycemic improvement in diabetic rats compared with GLB monotherapy through its antioxidant effect and capability to modulate PEPCK and G6Pase gene expression in their livers.


Assuntos
Artemisia , Diabetes Mellitus Experimental , Sesquiterpenos , Ratos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Glibureto/farmacologia , Glibureto/uso terapêutico , Estreptozocina , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Insulina , Antioxidantes/farmacologia , Fosfoenolpiruvato Carboxilase , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Lactonas , Glicemia
20.
Molecules ; 27(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36500514

RESUMO

Using the methodology of "click" chemistry, a singular method has been developed for the synthesis of unique conjugates based on sesquiterpene lactones: dehydrocostuslactone and alantolactone with polyalkoxybenzenes. To expand the structural range of the resulting conjugates, the length of the 1,2,3-triazole spacer was varied. For all synthesized compounds, the cytotoxic profile was determined on the cell lines of tumor origin (SH-SY5Y, HeLa, Hep-2, A549) and normal Hek 293 cells. It was found that the compounds based on alantolactone 7a-d with a long spacer and substances containing dehydrocostuslactone 10a-d with a short spacer have the greatest toxic effect. The decrease in cell survival under the action of these conjugates may be due to their ability to cause dissipation of the transmembrane potential of mitochondria and inhibit the process of glycolysis, leading to cell death. The obtained results confirm the assumption that the development of conjugates based on sesquiterpene lactones and polyalkoxybenzenes can be considered as a promising strategy for the search for potential antitumor agents.


Assuntos
Antineoplásicos , Neuroblastoma , Sesquiterpenos , Humanos , Sesquiterpenos/química , Células HEK293 , Lactonas/química , Antineoplásicos/farmacologia , Compostos Fitoquímicos , Química Click
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