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1.
Chem Biol Interact ; 311: 108794, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421115

RESUMO

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.


Assuntos
Diterpenos/farmacologia , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Dieta Hiperlipídica , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
2.
Chem Biodivers ; 16(10): e1900398, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456316

RESUMO

Phytotoxic natural products with either unique or various structures are one of the most abundant sources for the discovery of potential allelochemicals, natural herbicides, and plant growth regulators. Phytotoxic diterpenoids, a relatively large class of natural products, play an important role in the plant-plant or plant-microorganism interactions. This article argues that the phytotoxic diterpenoids isolated from the plants and microorganisms can either inhibit the seed germination and the growth of plant seedlings or lead to some disease symptoms on the tested plant tissues and plant seedlings.


Assuntos
Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Compostos Fitoquímicos/farmacologia , Plantas/química , Plântula/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Plantas/efeitos dos fármacos , Plantas/microbiologia
3.
Chem Biodivers ; 16(10): e1900443, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468670

RESUMO

Chronic myelogenous leukemia (CML) is a disease of the blood stem cells that features the oncoprotein Bcr-Abl. Tyrosine kinase inhibitors (TKIs) are used to treat CML patients, but these have limited efficacy due to the emergence of resistance via genetic mutation. Kamebakaurin is an ent-kaurane diterpenoid that has been isolated from Rabdosia excisa (Maxim.) H.Hara. Herein, we investigate the potential of kamebakaurin as a chemotherapy reagent for the treatment of CML. We conducted in vitro and in vivo biological experiments and found that kamebakaurin potently inhibits cell proliferation, mainly by enhancing cell apoptosis and down-regulating Bcr-Abl protein levels. In addition, kamebakaurin was found to inhibit tumor growth and has no side effects on five internal organs for in vivo experiment. These results suggest that kamebakaurin is a potential anticancer agent and is a key compound for further investigations.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Isodon/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
4.
Phytochemistry ; 166: 112062, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299395

RESUMO

Tripterygium wilfordii Hook. f. is a perennial woody vine member of the Celastraceae family. As a traditional Chinese medicine, it contains complex chemical components and exerts various pharmacological activities. In the present study, we identified a glucosyltransferase, TwUGT1, that can catalyze the synthesis of an abietane-type diterpene glucoside, namely, triptophenolide14-O-beta-D-glucopyranoside, and investigated the pharmacological activity of triptophenolide glucoside in diverse cancer cells. Triptophenolide glucoside exhibited significant inhibitory effects on U87-MG, U251, C6, MCF-7, HeLa, K562, and RBL-2H3 cells as determined by pharmacological analysis. The triptophenolide glucoside content of T. wilfordii was analyzed using Agilent Technologies 6490 Triple Quad LC/MS. The glucosyltransferase TwUGT1 belongs to subfamily 88 and group E in family 1. Molecular docking and site-directed mutagenesis of TwUGT1 revealed that the His30, Asp132, Phe134, Thr154, Ala370, Leu376, Gly382, His387, Glu395 and Gln412 residues play crucial roles in the catalytic activity of triptophenolide 14-O-glucosyltransferase. In addition, TwUGT1 was also capable of glucosylating phenolic hydroxyl groups, such as those in liquiritigenin, pinocembrin, 4-methylumbelliferone, phloretin, and rhapontigenin.


Assuntos
Biocatálise , Diterpenos/química , Diterpenos/metabolismo , Glucosídeos/química , Glucosiltransferases/metabolismo , Tripterygium/química , Glucosiltransferases/química , Simulação de Acoplamento Molecular , Conformação Proteica
5.
Phytochemistry ; 166: 112057, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306913

RESUMO

Rice (Oryza sativa) leaves accumulate phytoalexins in response to pathogen attack. The major phytoalexins in rice are diterpenoids such as oryzalexins, momilactones, and phytocassanes. We measured the amount of oryzalexin A in leaves irradiated by UV light, treated with jasmonic acid, or inoculated with conidia of Bipolaris oryzae in the japonica cultivar Nipponbare and the indica cultivar Kasalath. Nipponbare leaves accumulated oryzalexin A at a high concentration, but Kasalath leaves did not. The locus responsible for this difference was mapped using backcrossed inbred lines and chromosome substitution lines. A region on Chr. 12 containing the KSL10 gene was responsible for the deficiency in oryzalexin A in the Kasalath cultivar. The amount of KSL10 transcript increased in Nipponbare leaves but not in Kasalath leaves in response to UV light irradiation, indicating that the suppressed expression of KSL10 caused the deficiency of oryzalexin A in Kasalath. We analyzed oryzalexin A accumulation in UV light-irradiated leaves of cultivars in the world rice core collection. There were cultivars that accumulated oryzalexin A and those that did not, and both of these chemotypes were found in japonica and indica subspecies. Furthermore, these chemotypes were found in the wild rice species Oryza rufipogon. The phylogenetic relationship of KSL10 sequences was not correlated to oryzalexin A chemotypes. These findings suggested that the biosynthesis of oryzalexin A was acquired by a common ancestor of O. rufipogon and was lost multiple times during the evolutionary process.


Assuntos
Diterpenos/química , Diterpenos/metabolismo , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Cruzamento
6.
Phytochemistry ; 166: 112064, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325614

RESUMO

Seven previously undescribed polycyclic diterpenoids, euphonoids A-G, including four ent-abietanes, two ent-atisanes, and one ent-kaurene, along with 26 known analogues were isolated from the roots of Euphorbia fischeriana. The structures of the undescribed compounds were elucidated by spectroscopic analysis, ECD calculations, and single crystal X-ray diffraction. Besides, the structure of a previously reported ent-abietane diterpenoid, fischeriabietane A, was revised. All the isolates were screened for the cytotoxicities against five cancer cell lines. Euphonoid A, fischeriabietane A, 11-oxo-ebracteolatanolide B, caudicifolin, jolkinolide B, and methyl-8,11-3-dihydroxy-12-oxo-ent-abietadi-13,15(17)-ene-16-oate showed significant inhibitory activities against human prostate cancer C4-2B and C4-2B/ENZR cell lines, with IC50 values being less than 10 µM. The brief structure-activity relationships (SARs) of these diterpenoids were also discussed.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Euphorbia/química , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
7.
Chem Biodivers ; 16(8): e1900317, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31264344

RESUMO

Four new diterpenoids named cuceolatins A-D, including three labdane-type (1-3) and one abietane-type (4) as well as three known labdane analogs (5-7), were reported from the leaves of Cunninghamia lanceolata. Structural assignments for these compounds were conducted by analyses of spectroscopic data, and their absolute configurations were determined by time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculations. Among them, the abietane-type diterpenoid (11-hydroxy-12-methoxyabieta-8,11,13-trien-3-one (4)) showed significant cytotoxicity against human MDA-MB-231, MCF-7, and HeLa tumor cell lines with IC50 measurements of 4.3, 2.8 and 4.5 µm, respectively, while the labdane-type diterpenoids with a 4α-carboxy group (1-3 and 5) exhibited moderate antibacterial activity towards Bacillus subtilis and Staphylococcus aureus with IC50 values all below 25 µm.


Assuntos
Cunninghamia/química , Diterpenos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Cunninghamia/metabolismo , Teoria da Densidade Funcional , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Diterpenos de Abietano/química , Diterpenos de Abietano/isolamento & purificação , Diterpenos de Abietano/farmacologia , Humanos , Conformação Molecular , Folhas de Planta/química , Folhas de Planta/metabolismo , Staphylococcus aureus/efeitos dos fármacos
8.
Fitoterapia ; 137: 104190, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163199

RESUMO

The genus Tripterygium belongs to the family Celastraceae, and contains three species, i.e. Tripterygium wilfordii Hook. F, Tripterygium hypoglaucum (Levl.) Hutch. and Tripterygium regelii Sprague et Takeda. All three species are reported to have excellent medicinal properties that help to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus and widely used as a folk medicine in China. Phytochemical studies have led to discovering more than 500 secondary metabolites in this genus, including five main types: sesquiterpenoids, diterpenes, triterpenoids, flavonoids, lignans. This work provides structurally grouping statistic of 198 secondary metabolites of Tripterygium species published from 2008 to the present, as well as pharmacological knowledges in the past five years. The information will be helpful for developing the new discoveries of medicinal value related to the genus Tripterygium.


Assuntos
Tripterygium/química , Tripterygium/classificação , Animais , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antivirais/química , Diterpenos/química , Flavonoides/química , Humanos , Imunossupressores/química , Lignanas/química , Estrutura Molecular , Fármacos Neuroprotetores/química , Compostos Fitoquímicos/química , Metabolismo Secundário , Sesquiterpenos/química , Triterpenos/química
9.
Plant Physiol Biochem ; 141: 183-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174035

RESUMO

The present study is focused on the characterization of yacon [Smallanthus sonchifolius (Poepp. et Endl.) H. Robinson] accessions from different geographic origins (Bolivia, Ecuador, and Peru) by iPBS markers and metabolomic fingerprinting. The results showed that the number of amplified polymorphic fragment levels ranged from 20 up to 27 with a level of polymorphism ranging from 80 to 100%. Five of the iPBS primers used in this study provided no specific banding pattern able to discriminate between the different yacon accessions. However, two iPBS primer pairs were able to separate Peru accessions from those of Ecuador and Bolivia. The UPLC-HRMS/MS-based metabolomic fingerprinting showed highly similar metabolomic fingerprints characterized by the accumulation of high quantities of sesquiterpene lactones and diterpenes, but no apparent geographic clustering. The present study demonstrates that yacon accessions from different geographical origins maintained ex situ (in the Czech Republic) present a rather low chemical and genetic diversity.


Assuntos
Antioxidantes/química , Asteraceae/química , Diterpenos/química , Lactonas/química , Extratos Vegetais/química , Sesquiterpenos/química , Asteraceae/genética , Bolívia , Análise por Conglomerados , República Tcheca , Equador , Variação Genética , Geografia , Glicosilação , Espectrometria de Massas , Metabolômica , Análise Multivariada , Mapeamento de Peptídeos , Peru , Raízes de Plantas/química , Retroelementos
10.
Chem Biodivers ; 16(8): e1900278, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207097

RESUMO

Using synthetic chemicals in industry and agriculture has led to several environmental problems. Thus, plant products derived from volatile oils (VOs) could be a potential green source for bioherbicides. Little is known about the VOs of Lactuca serriola. Hence, the present study aimed to characterize the VOs chemical composition from the aerial parts of L. serriola, assessment of antioxidant activity, and evaluate allelopathic potential against the noxious weed Bidens pilosa. The VOs were extracted by hydrodistillation and analyzed by GC/MS. The VOs from the Egyptian ecospecies of L. serriola were found to comprise 34 compounds mainly oxygenated sesquiterpenes and diterpenes. The major compounds were isoshyobunone (64.22 %), isocembrol (17.35 %), and alloaromadendrene oxide-1 (7.32 %). So, L. serriola can be considered as a good source for isoshyobunone, considering that it has a much higher concentration than any other plants. Also, this plant has a high content of the oxygenated diterpene compound, isocembrol, which is rarely found in the VOs of most plants. The VOs expressed strong antioxidant activity. Also, for the first time, our results showed a strong allelopathic activity of VOs from L. serriola on germination and seedling growth of the noxious weed, B. pilosa. We suppose that the activity of the VOs from L. serriola could be attributed to these previously mentioned major compounds, as they represent about 89 % of the total identified oil constituents. Nevertheless, to evaluate these compounds as new allelochemicals, further study is needed to test the allelopathic activity of authenticated standard of these compounds either singular or in combination on several weeds as well as evaluate the safety, and improve the efficacy and stability at the field scale.


Assuntos
Antioxidantes/química , Asteraceae/química , Diterpenos/química , Óleos Voláteis/química , Sesquiterpenos/química , Asteraceae/metabolismo , Bidens/crescimento & desenvolvimento , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Germinação/efeitos dos fármacos , Óleos Voláteis/farmacologia , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Extratos Vegetais/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
11.
J Chem Ecol ; 45(5-6): 490-501, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31175497

RESUMO

The development of pesticide resistance in insects and recent bans on pesticides call for the identification of natural sources of resistance in crops. Here, we used natural variation in pepper (Capsicum spp.) resistance combined with an untargeted metabolomics approach to detect secondary metabolites related to thrips (Frankliniella occidentalis) resistance. Using leaf disc choice assays, we tested 11 Capsicum accessions of C. annuum and C. chinense in both vegetative and flowering stages for thrips resistance. Metabolites in the leaves of these 11 accessions were analyzed using LC-MS based untargeted metabolomics. The choice assays showed significant differences among the accessions in thrips feeding damage. The level of resistance depended on plant developmental stage. Metabolomics analyses showed differences in metabolomes among the Capsicum species and plant developmental stages. Moreover, metabolomic profiles of resistant and susceptible accessions differed. Monomer and dimer acyclic diterpene glycosides (capsianosides) were pinpointed as metabolites that were related to thrips resistance. Sucrose and malonylated flavone glycosides were related to susceptibility. To our knowledge, this is the first time that dimer capsianosides of pepper have been linked to insect resistance. Our results show the potential of untargeted metabolomics as a tool for discovering metabolites that are important in plant - insect interactions.


Assuntos
Capsicum/química , Diterpenos/química , Glicosídeos/química , Metabolômica , Animais , Capsicum/metabolismo , Capsicum/parasitologia , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Dimerização , Análise Discriminante , Glicosídeos/farmacologia , Interações Hospedeiro-Parasita , Metaboloma , Folhas de Planta/química , Folhas de Planta/metabolismo , Folhas de Planta/parasitologia , Análise de Componente Principal , Espectrometria de Massas em Tandem , Tisanópteros/efeitos dos fármacos , Tisanópteros/fisiologia
12.
Phytochemistry ; 165: 112048, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31229789

RESUMO

For the first time, the pigment composition of basidiocarps from the Chilean mushroom Cortinarius pyromyxa was studied under various aspects like phylogeny, chemistry and antibiotic activity. A molecular biological study supports the monotypic position of C. pyromyxa in subgenus Myxacium, genus Cortinarius. Four undescribed diterpenoids, named pyromyxones A-D, were isolated from fruiting bodies of C. pyromyxa. Their chemical structures were elucidated based on comprehensive one- and two-dimensional NMR spectroscopic analysis, ESI-HRMS measurements, as well as X-ray crystallography. In addition, the absolute configurations of pyromyxones A-D were established with the aid of JH,H, NOESY spectra and quantum chemical CD calculation. The pyromyxones A-D possess the undescribed nor-guanacastane skeleton. Tested pyromyxones A, B, and D exhibit only weak activity against gram-positive Bacillus subtilis and gram-negative Aliivibrio fischeri as well as the phytopathogenic fungi Botrytis cinerea, Septoria tritici and Phytophthora infestans.


Assuntos
Antibacterianos/farmacologia , Cortinarius/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pigmentos Biológicos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Filogenia , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação , Teoria Quântica
13.
Am J Chin Med ; 47(4): 769-785, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091976

RESUMO

Tripterygium wilfordii Hook F. (TWHF), a traditional Chinese medicine, has been widely used to treat autoimmune and inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis in China. Recently, studies have demonstrated that the bioactive components of TWHF have effective therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. In this paper, we summarize the research progress of triptolide and celastrol (the two major TWHF components) as well as their analogues in the treatment of neurodegenerative diseases. In addition, we review and discuss the molecular mechanisms and structure features of those two bioactive TWHF components, highlighting their therapeutic promise in neurodegenerative diseases.


Assuntos
Diterpenos/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Fenantrenos/uso terapêutico , Fitoterapia , Tripterygium/química , Triterpenos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Compostos de Epóxi/química , Compostos de Epóxi/isolamento & purificação , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Conformação Molecular , Fármacos Neuroprotetores , Doença de Parkinson/tratamento farmacológico , Fenantrenos/química , Fenantrenos/isolamento & purificação , Fenantrenos/farmacologia , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
14.
Chem Biodivers ; 16(7): e1900141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087758

RESUMO

Bioguided fractionation of Xylopia sericea antiplasmodial dichloromethane leaves extract led to the isolation of (-)-7-oxo-ent-kaur-16-en-19-oic acid (C20 H28 O3 ) that was identified by a combination of 1D and 2D NMR experiments (COSY, HMBC, HSQC, HSQC-TOCSY, HSQC-NOESY and NOESY) and by X-ray crystallography. A feature to be pointed out is its (4R) configuration that was inferred from the NOE experiments (HSQC-NOESY and NOESY) and X-ray crystallography. In vitro evaluation of this rare diterpene acid against the chloroquine-resistant strain Plasmodium falciparum W2 by the PfLDH method showed it disclosed a low antiplasmodial activity and was not cytotoxic to HepG2 cells (CC50 862.6±6.7 µm) by the MTT assay. The unequivocal NMR signals assignments, the X-ray crystallographic structure, the assessment to the bioactivities and the occurrence this diterpene in X. sericea are reported here for the first time.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Caurano/farmacologia , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Xylopia/química , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos de Caurano/química , Diterpenos de Caurano/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
15.
Nat Chem ; 11(6): 521-532, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086302

RESUMO

The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Azulenos/farmacologia , Morte Celular/efeitos dos fármacos , Diterpenos/farmacologia , Piridazinas/farmacologia , Tiorredoxinas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azulenos/síntese química , Azulenos/química , Linhagem Celular Tumoral , Cisteína/química , Diterpenos/síntese química , Diterpenos/química , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos SCID , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Tiorredoxinas/química
16.
J Agric Food Chem ; 67(23): 6523-6531, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31117507

RESUMO

Identification of diterpene synthase-encoding genes together with synthetic biology technology offers an opportunity for the biosynthesis of cis-abienol. The methylerythritol phosphate (MEP) and the mevalonate (MVA) pathways were both engineered for cis-abienol production in Escherichia coli, which improved the cis-abienol yield by approximately 7-fold and 31-fold, respectively, compared to the yield obtained by overexpression of the MEP pathway alone or the original MEP pathway. Furthermore, systematic optimization of cis-abienol biosynthesis was performed, such as diterpene synthase screening and two-phase cultivation. The combination of bifunctional class I/II cis-abienol synthase from Abies balsamea ( AbCAS) and class II abienol synthase from Salvia sclarea ( SsTPS2) was found to be the most effective. By using isopropyl myristate as a solvent in two-phase cultivation, cis-abienol production reached 634.7 mg/L in a fed-batch bioreactor. This work shows the possibility of E. coli utilizing glucose as a carbon source for cis-abienol biosynthesis through a modified pathway.


Assuntos
Diterpenos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia Metabólica , Ácido Mevalônico/metabolismo , Naftóis/metabolismo , Abies/enzimologia , Vias Biossintéticas , Diterpenos/química , Fermentação , Glucose/metabolismo , Naftóis/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Salvia/enzimologia
17.
Eur J Med Chem ; 176: 378-392, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31121546

RESUMO

In the past decades, triptolide has attracted considerable interests in the organic and medicinal chemistry society owing to its intriguing structure features and promising multiple pharmacological activities. However, its limited water solubility and oral bioavailability, imprecise mechanism of action and sever toxicity, scares from nature and difficulty in the synthesis have greatly hindered its clinical potential. Hence, to circumvent such problems, a lot of elegant total synthesis have been developed. With the advancement of the total synthesis, various triptolide derivatives have been synthesized and tested in the search for more drug-like derivatives for potential anticancer agents, anti-inflammatory agents, immunosuppressive agents and anti-Alzheimer's agents, etc. Meanwhile, through designing and synthesizing of various of bioactive probes, some molecular targets that are responsible for the multiple pharmacology activities as well as toxicity of triptolide have been identified. It is no doubt will help the future development of new drug-like triptolide derivatives. In order to gain a comprehensive and deep understanding of the area and provides suggestions for triptolide's further studies, i) the medicinal chemistry advancement, ii) bioactive probes-based cellular target identification and iii) clinical progress of triptolide derivatives are reviewed in this article.


Assuntos
Diterpenos/química , Diterpenos/farmacologia , Fenantrenos/química , Fenantrenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Ensaios Clínicos como Assunto , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
18.
Chin J Nat Med ; 17(4): 298-302, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076133

RESUMO

Jatrogricaine A (1), a new diterpenoid possessing a 5/6/6/4 carbon ring system, together with eight known diterpenoids (2-9) were isolated from the stems of Jatropha podagrica. Their structures were elucidated by extensive spectroscopic methods and the absolute configuration of 1 was determined by single crystal X-ray diffraction analysis. All compounds were evaluated for their anti-inflammatory activities in vitro, and compound 3 showed significant inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells with an IC50 of 13.44 ± 0.28 µmol·L-1, being comparable to the positive control, quercetin (IC50 17.00 ± 2.10 µmol·L-1).


Assuntos
Anti-Inflamatórios/química , Diterpenos/química , Jatropha/química , Extratos Vegetais/química , Caules de Planta/química , Animais , Anti-Inflamatórios/farmacologia , Carbono/análise , Diterpenos/farmacologia , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Extratos Vegetais/farmacologia , Células RAW 264.7
19.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035428

RESUMO

Mulinum crassifolium Phil. (Apiaceae) is an endemic shrub from Chile commonly used as infusion in traditional medicine to treat diabetes, bronchial and intestinal disorders and stomach ailments, including ulcers. From the EtOAc extract of this plant, the new mulinane-type diterpenoids 3 and 5 were isolated along with three known diterpenoids. The gastroprotective effect of the infusion of the plant was assayed to support the traditional use and a fast HPLC analysis using high resolution techniques was performed to identify the bioactive constituents. The EtOAc extract and the edible infusion showed gastroprotective effect at 100 mg/kg in the HCl/EtOH induced gastric ulcer model in mice, reducing lesions by 33% and 74%, respectively. Finally, a metabolomic profiling based on UHPLC-ESI-MS/HRMS of the edible infusion was performed and thirty-five compounds were tentatively identified including quercetin, caffeic acid, apigenine glucoside, p-coumaric acid, chlorogenic acids, and caffeoylquinic acids, which have been associated previously with gastroprotective and antiulcer properties. This scientific evidence can support the contribution of polyphenols in the gastroprotective activity of the edible infusion of this plant, and can validate at least in part, its ethnopharmacological use.


Assuntos
Apiaceae/química , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Diterpenos/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Espectrometria de Massas , Extratos Vegetais/química , Animais , Metaboloma , Metabolômica , Camundongos , Estrutura Molecular
20.
Molecules ; 24(9)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086098

RESUMO

Natural daphnane diterpenoids, mainly distributed in plants of the Thymelaeaceae and Euphorbiaceae families, usually include a 5/7/6-tricyclic ring system with poly-hydroxyl groups located at C-3, C-4, C-5, C-9, C-13, C-14, or C-20, while some special types have a characteristic orthoester motif triaxially connectedat C-9, C-13, and C-14. The daphnane-type diterpenoids can be classified into five types: 6-epoxy daphnane diterpenoids, resiniferonoids, genkwanines, 1-alkyldaphnanes and rediocides, based on the oxygen-containing functions at rings B and C, as well as the substitution pattern of ring A. Up to now, nearly 200 daphnane-type diterpenoids have been isolated and elucidated from the Thymelaeaceae and Euphorbiaceae families. In-vitro and in-vivo experiments of these compounds have shown that they possess a wide range of biological activities, including anti-HIV, anti-cancer, anti-leukemic, neurotrophic, pesticidal and cytotoxic effects. A comprehensive account of the structural diversity is given in this review, along with the cytotoxic activities of daphnane-type diterpenoids, up to April 2019.


Assuntos
Diterpenos/química , Euphorbiaceae/química , Thymelaeaceae/química , Animais , Fármacos Anti-HIV/química , Antineoplásicos/química , Humanos , Estrutura Molecular
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