RESUMO
Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.
Assuntos
Alcaloides , Animais Peçonhentos , Quilópodes , Animais , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Estrutura Molecular , Artrópodes/química , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Quinolinas/farmacologia , Quinolinas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , HumanosRESUMO
Four undescribed compounds including one aromatic glucoside derivative, cordyceglycoside A (1), one new isoleucine derivative inner salt, cordycepisosalt A (2), a rare four-membered lactam, cinerealactam B (3), and one sesquiterpene derivative, cordycepsetp A (4), together with six known compounds were isolated from Cordyceps militaris. The structures including absolute configurations of these new compounds, were unambiguously elucidated by spectroscopic data analysis and single crystal X-ray diffraction. Biological evaluation of compounds 1-4 showed that 3 displays anti-renal fibrotic activities in TGF-ß1 induced NRK-52e cells. Furthermore, DARTS coupled with LC-MS/MS analysis was used to identify candidate target proteins for 3. Subsequently, C1qbp knockdown using siRNA allowed us to validate the target protein of 3.
Assuntos
Cordyceps , Cordyceps/química , Cordyceps/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Análise Espectral , FibroseRESUMO
Three pairs of enantiomers and one achiral molecule that are new ethylated derivatives of sulfur and nitrogen-containing compounds named mantidisamides E-H (1-4), along with twenty known ones (5-24), were derived from the ethanol extract of Tenodera sinensis Saussure. The structures of these new compounds and their absolute configurations were assigned on the basis of spectroscopic analyses and computational methods. The assessment of activities in NRK-52e cells induced by TGF-ß1 demonstrated that the previously undescribed compounds 1 and 2 exhibited a significant capacity to inhibit the expression of proteins (fibronectin, collagen I, and α-SMA). Moreover, the biological activity of these compounds was found to increase with rising concentrations. Notably, compounds 1-4 should be artifacts; however, undescribed compounds 1 and 2, which possessed obvious biological activity, might be attractive for chemists and biologists due to the potential for more detailed exploration of their properties. It is worth mentioning that compounds 1 and 2 remain novel structures even in the absence of the ethoxy group.
Assuntos
Nitrogênio , Animais , Ratos , Nitrogênio/química , Enxofre/química , Linhagem Celular , Estrutura Molecular , FibroseRESUMO
Blapspirooxindoles A-C (1-3), three novel spirooxindole alkaloids with a unique spiro[chromane-4,3'-indoline]-2,2'-dione motif, blapcumaranons A and B (4 and 5), two new 2-cumaranon derivatives, blapoxindoles A-J (6-15), ten new oxindole alkaloid derivatives, along with one known compound (16), were isolated from the whole bodies of Blaps japanensis. Their structures including absolute configurations were determined by using spectroscopic, X-ray crystallographic, and computational methods. Compounds 1-11 and 13 exist as racemic mixtures in nature, and their (-)- and (+)-antipodes were separated by chiral HPLC. Biological evaluations of these compounds were determined with multiple assays including anti-tumor, anti-inflammatory, and renal protection activities in vitro. Several compounds displayed effective activity in one or more assays.
Assuntos
Alcaloides , Antineoplásicos , Besouros , Neoplasias , Animais , Besouros/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Alcaloides/farmacologia , Oxindóis/farmacologia , Estrutura MolecularRESUMO
Investigation on the chemical components of Valeriana jatamansi Jones (Caprifoliaceae), a new lignan with pyran-ring, dipsalignan G (1), along with eight known compounds (2-9) were isolated. Their structures were elucidated by extensive analysis of 1D, 2D NMR and HR-ESI-MS spectroscopic data. Additionally, possible biosynthetic pathway of 1 was proposed. Finally, biological evaluation results showed that 8 had significant scavenging ability to ABTS and DPPH free radicals, with IC50 values of 1.35 ± 0.01 and 2.94 ± 0.01 µg/ml, respectively.
RESUMO
[This corrects the article DOI: 10.3762/bjoc.19.59.].
RESUMO
Six new compounds, including a tetralone 1, two xanthones 2 and 3, a flavan derivative 4, and two nor-diterpenoids 7 and 8, accompanied by two known flavan derivatives 5 and 6 and a known olefine acid (9) were isolated from whole bodies of Kronopolites svenhedini (Verhoeff). The structures of the new compounds were determined by 1D and 2D nuclear magnetic resonance (NMR) and other spectroscopic methods, as well as computational methods. Selected compounds were evaluated for their biological properties against a mouse pancreatic cancer cell line and inhibitory effects on iNOS and COX-2 in RAW264.7 cells.
RESUMO
Aquilarines A (1) and B (2), two unprecedented sesquiterpenoid-chromone heterohybrids, were isolated from Aquilaria sinensis agarwood. 1 is an alkaloid featuring an unusual pyridine nucleus, and 2 possesses a rare sesquiterpenoid-chromone skeleton via a C-C bond. A plausible biosynthetic pathway for 1 and 2 was proposed. Both 1 and 2 could significantly inhibit the expression of extracellular matrix components, and α-SMA at low concentrations in TGF-ß1 induced two types of kidney cells (NRK 52E and NRK 49F) featuring selective inhibition of Smad3 instead of Smad2 phosphorylation, showing their potential in renal fibrosis.
Assuntos
Sesquiterpenos , Thymelaeaceae , Cromonas , Fibrose , Humanos , Fosforilação , Sesquiterpenos/farmacologia , Proteína Smad3 , Thymelaeaceae/químicaRESUMO
Sinkianlignans A - D (1-4), four new sesquilignans with an unusual architectures was characterized with a rarely α-γ', ß-γ', and γ-γ' linkage pattern, and sinkianlignans E - F (5 and 6), two lignans, were isolated from the Ferula sinkiangensis. Hypothetic biosynthetic pathway of compound 3 contain a newly formed six-membered C-ring by Diels-Alder cycloaddition. The structures of isolates were established by spectroscopic techniques and computational methods. Biological evaluation of all the isolated compounds revealed that compounds 2a and 2b could inhibit IL-6 and TNF-α production in lipopolysaccharide (LPS) induced RAW264.7 cells in a dose-dependent manner.
Assuntos
Ferula , Sesquiterpenos , Anti-Inflamatórios/farmacologia , Ferula/química , Estrutura Molecular , Resinas Vegetais , Sesquiterpenos/químicaRESUMO
Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1-10 µM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5-90 mg·kg-1·d-1, i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.
Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Cardiomegalia/patologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Aorta/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Fenilefrina/farmacologia , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Belamcandaoids A-N (1-14), fourteen new triterpenoids were isolated from the seeds of Belamcanda chinensis. Their structures including absolute configurations were assigned by using spectroscopic, computational, and crystallographic methods. All the compounds except 1 and 2 are 3,4-seco-triterpenoids belonging to fernane type. Biological evaluation results indicated that 3 and 13 could reduce fibronectin and collagen I expression respectively in TGF-ß1 induced kidney proximal tubular cells.
Assuntos
Células Epiteliais/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Iridaceae/química , Extratos Vegetais/farmacologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Linhagem Celular , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Matriz Extracelular/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Sementes/química , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Seven new meroterpenoids, lucidumones B-H (1 and 3-8), along with one known meroterpenoid (2), were isolated from the fruiting bodies of Ganoderma lucidum. The structures of the new compounds were assigned by spectroscopic and computational methods. All the isolated compounds were tested for their inhibition on human cancer cell migration. It was found that compounds (-)-1, (+)-2, (-)-4, (+)-6, and (+)-8 could significantly inhibit cell migration in KYSE30 cell line. Further examination disclosed that cell migration inhibition of (+)-6 and (+)-8 might be related with downregulation of N-cadherin.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ganoderma/química , Inibidores de Proteínas Quinases/farmacologia , Terpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
Chuanxiongdiolides R4-R6 (1-3), three novel phthalide dimers featuring two classes of unreported monomeric units (ligustilide/senkyunolide A and ligustilide/neocnidilide) with an unprecedented linkage style (3a,7'/7a,7'a), were isolated from the aerial parts of Ligusticum chuanxiong, together with three pairs of enantiomeric phthalide dimers [(-)/(+)-4a/4b, 5a/5b, and 6a/6b]. The bioassays revealed that compounds 1, 3, 4, 5, and 6 showed significant vasodilation effects, and the mechanism may be attributed to Cav1.2 activation blockade. Based on the established compounds library, the structure activity relationship of the phthalides was proposed. Our findings afford possible leads for developing new vasodilator against cardiovascular and cerebrovascular diseases such as hypertension and ischemic stroke.
Assuntos
Benzofuranos/farmacologia , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Ligusticum/química , Vasodilatadores/farmacologia , Animais , Benzofuranos/química , Benzofuranos/isolamento & purificação , Benzofuranos/metabolismo , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Células HEK293 , Compostos Heterocíclicos de Anel em Ponte/síntese química , Compostos Heterocíclicos de Anel em Ponte/isolamento & purificação , Compostos Heterocíclicos de Anel em Ponte/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Componentes Aéreos da Planta/química , Ligação Proteica , Coelhos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Vasodilatadores/química , Vasodilatadores/isolamento & purificação , Vasodilatadores/metabolismoRESUMO
Meyeniines A-C (1-3), three new lignans, two known neolignans (4-5), and three known lignans (6-8) were isolated from the rhizomes of Lepidium meyenii. Their structures were identified by comprehensive spectroscopic analyses and computational methods. Compound 1 represents a unique lignan featuring an aromatic ring migration. Compoundsâ 2 and 4-6 were analyzed by chiral HPLC column as enantiomers. Biological evaluation revealed that compoundâ 8 could inhibit IL-6 production in lipopolysaccharide (LPS) induced RAW264.7 cells in a dose-dependent manner.
Assuntos
Anti-Inflamatórios/química , Lepidium/metabolismo , Lignanas/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Lignanas/isolamento & purificação , Lignanas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Extratos Vegetais/química , Células RAW 264.7RESUMO
Five new compounds including three pairs of enantiomeric xanthine analogues, parvaxanthines D-F (1-3), two new guanosine derivatives, asponguanosines C and D (6 and 7), along with two known adenine derivatives were isolated from the insect Cyclopelta parva. Racemic 1-3 were further separated by chiral HPLC. Their absolute configurations were assigned by spectroscopic and computational methods. It is interesting that all of these isolates are natural product hybrids. Antiviral, immunosuppressive, antitumor and anti-inflammatory properties of all the isolates were evaluated.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Produtos Biológicos/farmacologia , Guanosina/química , Insetos/química , Xantinas/química , Animais , Produtos Biológicos/química , Células Cultivadas , Chlorocebus aethiops , Cromatografia Líquida de Alta Pressão/métodos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , EstereoisomerismoRESUMO
Five new nitrogen-containing compounds (1-3, 5, and 6), two compounds which was firstly isolated from natural origin (7 and 10), along with six known ones, were isolated from the ethanol extract of the whole bodies of Polyphaga plancyi. The structures of the new compounds including their absolute configurations at stereogenic centers were assigned on the basis of spectroscopic analyses and computational methods. Racemic 10 was separated by chiral HPLC. Biological activities of these isolates against extracellular matrix components in rat renal proximal tubular cells, EV71, COX-2, ROCK2, JAK3, and tuberculosis were evaluated. Importantly, 8 was found to be a selective Smad3 phosphorylation inhibitor.
Assuntos
Antituberculosos/farmacologia , Produtos Biológicos/farmacologia , Besouros/química , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Janus Quinase 3/antagonistas & inibidores , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/química , Antituberculosos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Células Cultivadas , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Janus Quinase 3/metabolismo , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Two structurally novel meroterpenoids, ganodermaones A (1) and B (2), were isolated from Ganoderma fungi (G. cochlear and G. lucidum). The structures of 1 and 2 were assigned by spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 represent the first examples of meroterpenoids in Ganoderma fungal species featuring with carbon migration. The plausible biosynthetic pathway for 1 was proposed. Biological evaluation showed that both 1 and 2 could inhibit renal fibrosis in TGF-ß1-induced kidney proximal tubular cells.
Assuntos
Ganoderma/química , Terpenos/química , Animais , Carbono/química , Carbono/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Fibronectinas/metabolismo , Ganoderma/metabolismo , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ratos , Terpenos/isolamento & purificação , Terpenos/farmacologia , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
Pipajiains H-J (1-3), three new phenolic derivatives with an unusual sulfone group, pipajiamides A-C (4-6), three new amide derivatives, pipajiaine A (7), one new imidazole analogue, and pipajiaine B (8), a pair of new pyrrolidine derivatives, along with three known compounds were isolated from the insect Blaps japanensis. Their structures were identified by spectroscopic and computational methods. Chiral HPLC was used to separate the (-)- and (+)-antipodes of 4 and 8. Biological activities of all the new compounds against extracellular matrix in rat renal proximal tubular cells, human cancer cells (A549, Huh-7, and K562), COX-2, ROCK1, and JAK3 were evaluated. The results show that compounds 2, (+)-4, and (-)-4 are active against kidney fibrosis, whereas, compound 9 is active toward human cancer cells, inflammation, and JAK3 kinase.
Assuntos
Besouros/química , Compostos de Nitrogênio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Enxofre/farmacologia , Animais , Células Cultivadas , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Fibrose/tratamento farmacológico , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Estrutura Molecular , Compostos de Nitrogênio/química , Compostos de Nitrogênio/isolamento & purificação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Ratos , Relação Estrutura-Atividade , Enxofre/química , Enxofre/isolamento & purificação , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismoRESUMO
Neuroinflammation is one of the critical events in neurodegenerative diseases, whereas microglia play an important role in the pathogenesis of neuroinflammation. In this study, we investigated the effects of a natural sesquiterpene lactone, 6-O-angeloylplenolin (6-OAP), isolated from the traditional Chinese medicine Centipeda minima (L.) A.Br., on neuroinflammation and the underlying mechanisms. We showed that treatment with lipopolysaccharide (LPS) caused activation of BV2 and primary microglial cells and development of neuroinflammation in vitro, evidenced by increased production of inflammatory cytokines TNF-α and IL-1ß, the phosphorylation and nuclear translocation of NF-κB, and the transcriptional upregulation of COX-2 and iNOS, leading to increased production of proinflammatory factors NO and PGE2. Moreover, LPS treatment induced oxidative stress through increasing the expression levels of NOX2 and NOX4. Pretreatment with 6-OAP (0.5-4 µM) dose-dependently attenuated LPS-induced NF-κB activation and oxidative stress, thus suppressed neuroinflammation in the cells. In a mouse model of LPS-induced neuroinflammation, 6-OAP (5-20 mg·kg-1·d-1, ip, for 7 days before LPS injection) dose-dependently inhibited the production of inflammatory cytokines, the activation of the NF-κB signaling pathway, and the expression of inflammatory enzymes in brain tissues. 6-OAP pretreatment significantly ameliorated the activation of microglia and astrocytes in the brains. 6-OAP at a high dose caused a much stronger antineuroinflammatory effect than dexamethansone (DEX). Furthermore, we demonstrated that 6-OAP pretreatment could inhibit LPS-induced neurite and synaptic loss in vitro and in vivo. In conclusion, our results demonstrate that 6-OAP exerts antineuroinflammatory effects and can be considered a novel drug candidate for the treatment of neuroinflammatory diseases.
Assuntos
Inflamação/tratamento farmacológico , Lactonas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Animais , Asteraceae/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lactonas/química , Lactonas/isolamento & purificação , Lipopolissacarídeos/farmacologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Oxirredução , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificaçãoRESUMO
Four new aromatic meroterpenoids, ganocapenoids A-D (1-4), together with twelve known analogues (5-16) were isolated from the fruiting bodies of Ganoderma capense. The structures of new compounds were determined through spectroscopic methods including 1D and 2D NMR and MS analyses. Their absolute configurations were assigned by ECD calculations and specific rotation comparison. The biological activities of these substances toward regulation of lipid metabolism, neurite outgrowth-promoting activity, and AchE inhibition were assessed. Compound 15 was found to be able to block lipid accumulation at a concentration of 20⯵M, and compounds 4a, 4b, and 11 show moderate neurite outgrowth-promoting activity at 10⯵M, while compounds 3, 6, 11, and 13 exhibit potent AchE inhibition with the IC50 values of 28.6⯱â¯1.9, 18.7⯱â¯1.6, 8.2⯱â¯0.2, 26.0⯱â¯2.9⯵M, respectively.