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1.
Bioorg Med Chem Lett ; 30(12): 127193, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334913

RESUMO

This study aims to investigate active phytochemicals isolated from Pyrola incarnata Fisch. (P. incarnata) and their protection against neuroinflammation induced by LPS. Betulin, accompanied with other 9 compounds, were isolated from P. incarnata and elucidated by spectroscopic analysis (1H-, 13C NMR). ELISA kits and the measurement of NO production based on Griess reaction showed that betulin (5) (250 µg/mL) could suppress LPS-induced activation of microglial cell BV-2 better than others by inhibiting inflammatory cytokines (TNF-α, IL-6, IL-1ß) expression and NO production. With the guidance of computer-aided drug design and the analysis of biological experiment, we demonstrated betulin could reduce LPS-induced iNOS expression, prevent JNKs pathways, and down-regulate the phosphorylation levels of NF-κB/p65. In conclusion, betulin isolated from P. incarnata possessed outstanding anti-neuroinflammation potential, presumably related to iNOS expression, JNKs and NF-κB/p65 pathways. Therefore, Pyrola incarnata may be a valuable natural resource and betulin is a potential drug for the treatment of neurodegenerative disorders by inhibiting inflammatory mediators.

2.
Bioorg Chem ; 99: 103760, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32251946

RESUMO

Eight unexpected vibralactone homodimers, bisvibralactones A-H (1-8), and three new vibralactone monomers, hirsutumins A-C (9-11), were isolated from the culture of Stereum hirsutum. Their structures and absolute configurations were determined by detailed analyses of NMR, optical rotations, ECD, and high-resolution mass spectra as well as chemical transformation. Compounds 1-8 are unusual vibralactone dimers formed by the esterification of two vibralactone monomers. The absolute configurations of compounds 1 and 5 were determined by chemical conversions. All of the isolated compounds were evaluated for Porcine Pancreatic Lipase (PPL) inhibitory activities, and compound 10 showed significant inhibitory activity against PPL, with an IC50 value of 8.31 ± 1.04 µM.

3.
Phytochemistry ; 173: 112295, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32113065

RESUMO

Four undescribed bioxanthracene derivatives, dongtinganthracenes A-D, along with a previously reported analog, ES-242-3, were obtained from the solid culture broth of the fungus Penicillium sp. DT10, which was isolated from wetland soil obtained from Dongting Lake. Their structures and absolute configurations were elucidated based on extensive NMR analyses, mass spectroscopic analyses, and ECD calculations. Dongtinganthracene A represents the first 7',8'-seco-bioxanthracene produced via oxidation, and dongtinganthracenes A-D show a much higher degree of oxidation in aromatic rings compared with normal naturally occurring bioxanthracene derivatives. Dongtinganthracenes B and D and ES-242-3 exhibit cytotoxic activity, while dongtinganthracene A shows inhibitory activity against LPS-induced NO production.


Assuntos
Penicillium , Lagos , Estrutura Molecular , Solo , Áreas Alagadas
4.
J Nat Prod ; 82(11): 2994-3001, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31674782

RESUMO

Flavipesines A and B (1 and 2) and asperchalasines E-H (3-6), two cytochalasans with an unusual ring system and four merocytochalasans possessing a 5/6/11/5/5/6 ring system, were isolated from Aspergillus flavipes, along with three related compounds (7-9). Their structures, including absolute configurations, were determined on the basis of data from HRESIMS, NMR, ECD, molecular modeling, and single-crystal X-ray diffraction. Flavipesines A and B (1 and 2) represent the first examples of cytochalasans possessing a 5/6/7/6 ring system with a C-18-O-C-21 bridge. Compounds 3, 7, and 9 show moderate inhibitory activities against isocitrate dehydrogenase 1 (IDH1). This is the first report on the IDH1 inhibitory activities of cytochalasans.

5.
J Nat Prod ; 82(10): 2897-2906, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31573805

RESUMO

A preliminary phytochemical investigation on the EtOAc extracts of the fungus Bipolaris sp. TJ403-B1 resulted in the identification of 12 ophiobolin-type phytotoxins (1-12), including nine new ones, termed bipolaricins A-I (1-9). The structures of 1-9 were elucidated via spectroscopic data (including HRESIMS and 1D and 2D NMR) and single-crystal X-ray diffraction (Cu Kα) analyses. All of the isolated compounds were tested in terms of HMG-CoA reductase inhibitory, anti-inflammatory, and cytotoxic activities. Compound 10 showed HMG-CoA reductase inhibitory activity (IC50 = 8.4 ± 0.4 µM), and 2, 3, and 10-12 showed significant inhibitory potency against lipopolysaccharide (LPS)-induced nitric oxide production, with IC50 values in the range of 5.1 ± 0.3 to 20 ± 1 µM. Further experiments showed that 10 could significantly inhibit the production of IL-1ß, RANTES, MIP-1ß, and TNF-α as well as enhance the release of IL-13 in macrophages through the inhibition of HO-1 induction as well as the NF-κB pathway. These findings provide a scientific rationale for an anti-inflammatory therapeutic and a template for a new HMG-CoA reductase inhibitor to produce a potential anti-hyperlipidemia agent.

6.
Bioorg Chem ; 92: 103279, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539746

RESUMO

Seven previously undescribed metabolites, designated as tricycloalternarenes Q-W (1-7), were isolated and identified from the fermented rice substrate of fungus Alternaria brassicicola. The planar and absolute structures of all new compounds were determined on the basis of extensive NMR spectroscopic data, a modified Mosher's method, X-ray crystallographic analysis, and electronic circular dichroism (ECD) spectral analyses. All the isolates were evaluated for in vitro cytotoxicity against five human tumor MM231, MM468, HeLa, SW1990, and SW480 cell lines, and compounds 1, 2, 5, and 7 showed selective cytotoxicity against certain human tumor cell lines with IC50 values ranging from 12.83 to 32.87 µM, with no obvious cytotoxicity to the normal LO2 cell.

7.
Cell Commun Signal ; 17(1): 111, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470862

RESUMO

BACKGROUND: Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate transaminase 1 (GOT1) to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Thus, the important role of GOT1 in energy metabolism and Reactive Oxygen Species (ROS) balance demonstrates that targeting GOT1 may serve as an important therapeutic target in PDAC. METHODS: To assay the binding affinity between Aspulvinone O (AO) and GOT1 proteins, the virtual docking, microscale thermophoresis (MST), cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) methods were employed. GOT1 was silenced in several PDAC cell lines. The level of OCR and ECR were assayed by seahorse. To evaluate the in vivo anti-tumor efficacy of AO, the xenograft model was built in CB17/scid mouse. RESULTS: Screening of an in-house natural compound library identified the AO as a novel inhibitor of GOT1 and repressed glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Virtual docking analysis suggested that AO could bind to the active site of GOT1 and form obvious hydrophobic interaction with Trp141 together with hydrogen bonds with Thr110 and Ser256. Further in vitro validation, including MST, CETSA and DARTS, further demonstrated the specific combining capacity of AO. We also show that the selective inhibition of GOT1 by AO significantly reduces proliferation of PDAC in vitro and in vivo. CONCLUSIONS: Taken together, our findings identify AO as a potent bioactive inhibitor of GOT1 and a novel anti-tumour agent for PDAC therapy.

8.
Bioorg Chem ; 91: 103166, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404796

RESUMO

A new spiroaxane sesquiterpenoid talaminoid A (1) and two drimane sesquiterpenoid talaminoids B and C (2 and 3), together with four known compounds (4-7), were isolated from the solid culture broth of fungus Talaromyces minioluteum. The structures were determined by extensive 1D and 2D NMR and HRESIMS spectroscopic data analyses, and the absolute configuration of these new compounds were undoubtedly confirmed by X-ray crystal diffrations. Compound 1 is a rare spiroaxane sesquiterpenoid and the absolute configuration of spiroaxane sesquiterpenoid was determined for the first time. Compound 2 is the first drimane-type sesquiterpenoid containing both amino acid residue and butanediol group. Compounds 1, 4, and 5 showed significant suppressive effect on the production of NO on LPS induced BV-2 cells, with IC50 values ranging from 4.97 to 7.81 µM. In addition, 1, 4, and 5 exhibited significant anti-inflammatory activities against the production of TNF-α and IL-6. Further immunofluorescence experiments revealed the mechanism of action to be inhibitory the NF- κB-activated pathway.

9.
J Nat Prod ; 82(8): 2181-2188, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31390200

RESUMO

An HPLC-DAD-directed chemical investigation of the soil-derived fungus Aspergillus versicolor QC812 resulted in the isolation and identification of eight new linearly fused prenylated indole alkaloids, asperversiamides I-P (1-8), along with a congener, asperversiamide H (9). Their structures and absolute configurations were determined by spectroscopic analysis including HRESIMS and 1D and 2D NMR, electronic circular dichroism analysis, and single-crystal X-ray diffraction. Asperversiamide I (1), the first diketopiperazine derived from d-proline and l-tryptophan, possesses an unprecedented C-11-spiro-fused 6/6/5/5/6/5 hexacyclic ring system. Asperversiamide J (2) is the first linearly fused 6/6/5 tricyclic prenylated indole alkaloid to be reported. 1 and 2 showed moderate inhibitory activities against HeLa cells with IC50 values of 7.3 and 6.4 µM, respectively.

10.
Angew Chem Int Ed Engl ; 58(35): 12091-12095, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31254370

RESUMO

Bipolarolides A-G (1-7), seven novel ophiobolin-derived sesterterpenes with three new types of skeletons, were characterized from fungus Bipolaris sp. TJ403-B1. Their structures were determined via spectroscopic analyses, X-ray crystallography, and quantum chemical 13 C NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.01,6 .05,9 .18,12 ]pentadecane-bridged system. Compounds 3 and 4 featured an unprecedented 5-5-5-5-fused core skeleton, while 3 also contained an unexpected C-3-C-14 oxygen bridge to construct the caged architecture. Compounds 5-7 form a new class of highly modified pentacyclic oxaspiro[4.4]nonane-containing sesterterpene-alkaloid hybrids. Their biosynthetic pathways and potential HMG-CoA reductase inhibitory and antimicrobial activities are also discussed.

11.
Phytochemistry ; 164: 236-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31185420

RESUMO

Mangiterpenes A-C and 2',3'-seco-manginoid C, four undescribed sesquiterpene/monoterpene-shikimate-conjugated meroterpenoids with spiro ring systems, were isolated from Guignardia mangiferae. The structures and absolute configurations of these compounds were established by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Mangiterpenes A-C represent the first examples of sesquiterpene-shikimate-conjugated spirocyclic meroterpenoids, and 2',3'-seco-manginoid C features an unexpected 2',3'-seco-manginoids skeleton. Mangiterpene C strongly inhibited the production of NO inducted by LPS, with an IC50 value of 5.97 µM. It showed an anti-inflammatory effect by means of blocking in the NF-κB signaling pathway and decreasing the expression of inflammatory mediators.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Monoterpenos/farmacologia , Ácido Chiquímico/farmacologia , Compostos de Espiro/farmacologia , Terpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Ácido Chiquímico/química , Ácido Chiquímico/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação
12.
J Nat Prod ; 82(5): 1098-1106, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31012585

RESUMO

A chemical investigation of the secondary metabolites of a marine-derived Aspergillus sp. led to the isolation and characterization of 13 phenolic compounds, including 10 new compounds (1-10). Seven new compounds (1-7) are unusual phenolic C-glycosides, while the other new compounds (8-10) are structurally related aglycones. The chemical structures of these new compounds were elucidated by 1D and 2D NMR and HRESIMS spectroscopic analyses. The absolute configurations of these new C-glycosides were determined by comparison of experimental electronic circular dichroism spectra with those of calculated ones. In addition, the anti-inflammatory activities of these compounds were evaluated, and compound 9 significantly inhibited nitric oxide production with an IC50 value of 6.0 ± 0.5 µM in lipopolysaccharide-induced RAW264.7 cells. Moreover, compound 9 also showed anti-inflammatory activity by inhibiting the NF-κB-activated pathway.

13.
Biomed Res Int ; 2019: 1823149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915347

RESUMO

The study determined the chemical constituents and anti-inflammatory effects of leaf oil from Cinnamomum subavenium (CS-LO) that has been used in folk medicine to treat various symptoms including inflammation. The anti-inflammatory effects of the oil were evaluated by LPS-stimulated RAW264.7 cells and the Carr-induced hind mouse paw edema model, respectively. In vitro, nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, IL-6, and IL-1ß were significantly decreased by CS-LO, and the expression of nuclear factor-κB (NF-κB) protein was blocked as well. In in vivo, the malondialdehyde (MDA) and paw edema levels were decreased by CS-LO, and the same result came up on the NO and tumor necrosis factor (TNF-a) of serum at the 5th h after Carr injection. In addition, iNOS and COX-2 immunoreactive cells of the paw tissue were decreased significantly by CS-LO (200 mg/kg) in histological examination. The present findings indicated that CS-LO have anti-inflammatory properties, and the effects might be caused through inhibiting iNOS, COX-2, TNF-α, IL-1ß, and IL-6 expression via affecting NF-κB pathway, which will provide a power scientific basis for CS-LO to be used as the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Cinnamomum/química , Folhas de Planta/química , Óleos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/imunologia , Citocinas/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/imunologia , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Óleos Vegetais/química , Células RAW 264.7
14.
Org Lett ; 21(7): 2290-2293, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30865467

RESUMO

Niduterpenoids A (1) and B (2), two sesterterpenoids with a highly congested hexacyclic 5/5/5/5/3/5 carbon skeleton but no unsaturated functional group, were isolated from Aspergillus nidulans. Their structures were determined by a combination of spectroscopic data and single-crystal X-ray diffraction analyses. Compounds 1 and 2 present the first examples of sesterterpenoids with a hexacyclic carbon ring system. Compound 1 showed no cytotoxicity but abolished 17-estradiol-induced cell proliferation (IC50 = 11.42 ± 0.85 µM).


Assuntos
Aspergillus nidulans/química , Carbono/química , Sesterterpenos/química , Cristalografia por Raios X , Estrutura Molecular , Sesterterpenos/isolamento & purificação , Análise Espectral
15.
Ecotoxicol Environ Saf ; 170: 141-147, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30529612

RESUMO

Poisonous weeds are a global problem since they not only hinder local economic development, but also cause ecological harm. Consolida rugulosa (family Ranunculaceae) is a weed that is widespread in Northwestern China and causes severe poisoning when ingested by livestock. In the present study, we purified the toxins in this plant and investigated their mechanism of action. Five natural diterpene alkaloids (compounds 1-5)-including two new compounds (1 and 2)-were isolated, and five semi-synthetic derivatives (6-10) were synthesised based on 4 or 5 for structure-activity analysis. The toxicity of the compounds was evaluated in vitro with lactate dehydrogenase (LDH) assay. All of the compounds-especially 1-stimulated LDH release in primary cultured rat myocardial cells, an effect that was blocked by the Na+ channel blocker lidocaine. Electrocardiography revealed that rats treated with 1 had severe arrhythmia, while heart Doppler echocardiography and analysis of serum biomarkers levels revealed that administration of 1 for 15 days induced changes in cardiac structure and myocardial enzyme levels. These effects were antagonised by lidocaine treatment. Thus, diterpene alkaloids are the main compounds responsible for the cardiotoxicity of C. rugulosa, which can be mitigated by co-administration of lidocaine.


Assuntos
Cardiotoxicidade , Coração/efeitos dos fármacos , Ranunculaceae/toxicidade , Animais , Células Cultivadas , China , Alcaloides Diterpenos/toxicidade , L-Lactato Desidrogenase/metabolismo , Lidocaína/farmacologia , Miocárdio/citologia , Miocárdio/metabolismo , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/toxicidade , Plantas Daninhas/toxicidade , Ratos
16.
Org Lett ; 20(24): 7982-7986, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30525677

RESUMO

Alterbrassicicene A (1), a fusicoccane-derived diterpenoid with an unprecedented framework, together with two known biosynthetic intermediates (2 and 3), were characterized from Alternaria brassicicola. The absolute structure of 1 was assigned by extensive spectroscopic analyses and quantum chemical calculations. Compound 1 represents a newly transformed monocyclic carbon skeleton of a highly functionalized diterpenoid bearing unique dihydro-2(3 H)-furanone and 2-cyclopenten-1-one motifs. Compound 1 was the first fusicoccane-derived diterpenoid functioning as a potent PPAR-γ agonist (EC50 = 744.1 nM).


Assuntos
Alternaria/química , Diterpenos/farmacologia , PPAR gama/agonistas , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
17.
Org Biomol Chem ; 16(45): 8751-8760, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30398284

RESUMO

Altering the cultivation conditions, such as temperature, media compositions, illumination, aeration, the shape of the culturing flask, etc., is regarded as a useful strategy for the exploitation of structurally novel and bioactive secondary metabolites, which inspired us to explore the chemical and pharmacological diversities from the genetically powerful fungus Alternaria brassicicola. As a result, twelve fusicoccane-type diterpenoids, including eight new ones, termed brassicicenes Q-X (1-8), were isolated from a modified rice medium. Biosynthetically, all these compounds were derived from the mevalonic acid (MVA) pathway, and their structures incorporating absolute configurations were assigned by the interpretation of spectroscopic (HRESIMS and 1D and 2D NMR) analyses, chemical conversion, a modified Mosher's method, 13C NMR calculation, and single-crystal X-ray diffraction (Cu Kα). Structurally, compound 1 was an unusual 16-nor-dicyclopenta[a,d]cyclooctane diterpenoid bearing a fused cyclopent-2-en-1-one moiety. In addition, compound 3 was found to show significant anti-inflammatory activity against the production of NO, TNF-α, and IL-1ß at 10 µM. Further western blot and immunofluorescence experiments found the mechanism of action to be that 3 inhibited the NF-κB-activated pathway, highlighting it as a promising starting point for the development of new anti-inflammatory agents.


Assuntos
Alternaria/química , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Diterpenos/química , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Fator de Transcrição RelA/metabolismo
18.
Front Chem ; 6: 422, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271773

RESUMO

Nine novel butenolide derivatives, including four pairs of enantiomers, named (±)-asperteretones A-D (1a/1b-4a/4b), and a racemate, named asperteretone E (5), were isolated and identified from the coral-associated fungus Aspergillus terreus. All the structures were established based on extensive spectroscopic analyses, including HRESIMS and NMR data. The chiral chromatography analyses allowed the separation of (±)-asperteretones A-D, whose absolute configurations were further confirmed by experimental and calculated electronic circular dichroism (ECD) analysis. Structurally, compounds 2-5 represented the first examples of prenylated γ-butenolides bearing 2-phenyl-3-benzyl-4H-furan-1-one motifs, and their crucial biogenetically related metabolite, compound 1, was uniquely defined by an unexpected cleavage of oxygen bridge between C-1 and C-4. Importantly, (±)-asperteretal D and (4S)-4-decarboxylflavipesolide C were revised to (±)-asperteretones B (2a/2b) and D (4), respectively. Additionally, compounds 1a/1b-4a/4b and 5 were evaluated for the α-glucosidase inhibitory activity, and all these compounds exhibited potent inhibitory potency against α-glucosidase, with IC50 values ranging from 15.7 ± 1.1 to 53.1 ± 1.4 µM, which was much lower than that of the positive control acarbose (IC50 = 154.7 ± 8.1 µM), endowing them as promising leading molecules for the discovery of new α-glucosidase inhibitors for type-2 diabetes mellitus treatment.

19.
Org Biomol Chem ; 16(43): 8130-8143, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30334059

RESUMO

Fifteen new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperforatones A-O (1-15), along with 3 structurally related analogues (16-18), were isolated from the stems and leaves of Hypericum perforatum. Their structures and absolute configurations were established by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD), modified Mosher's methods, Rh2(OCOCF3)4- and [Mo2(OAc)4]-induced ECD, X-ray crystallography, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Compound 5 was found to be the first PPAP decorated by a rare 2,2,4,4,5-(pentamethyltetrahydrofuran-3-yl)methanol moiety and an oxepane ring. Furthermore, the isolates were screened for their acetylcholinesterase (AChE) and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activities. Compounds 5, 10, 11, and 15 showed desirable AChE inhibitory activities (IC50 6.9-9.2 µM) and simultaneously inhibited BACE1 (at a concentration of 5 µM) with inhibition rates of 50.3%, 34.3%, 47.2%, and 34.6%, respectively. Interestingly, compound 5 showed the most balanced inhibitory activities against both AChE and BACE1 of all the tested compounds, which means that 5 could serve as the first valuable dual-targeted PPAP for the treatment of Alzheimer's disease. Preliminary molecular docking studies of 5 with BACE1 and AChE were also performed.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Hypericum/química , Floroglucinol/química , Floroglucinol/farmacologia , Compostos Policíclicos/química , Prenilação , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Simulação de Acoplamento Molecular , Floroglucinol/metabolismo , Floroglucinol/uso terapêutico , Conformação Proteica
20.
Phytochemistry ; 156: 106-115, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30268043

RESUMO

By feeding L-tyrosine into the culture medium, nine undescribed compounds, termed as armochaetoglasins A-I, together with three known analogues, namely armochaetoglobin E, chaetoglobosin V, and chaetoglobosin J, were isolated and identified from the medicinal terrestrial arthropod-derived fungus Chaetomium globosum TW1-1. Their structures were elucidated by means of NMR spectroscopy, single-crystal X-ray crystallography, and comparison of their electronic circular dichroism (ECD) spectra. Structurally, armochaetoglasin A represented the first tyrosine-derived cytochalasan alkaloid characterized by a 13-membered carbocyclic ring system; armochaetoglasins B and C possessed a rare 19,20-seco-chaetoglobosin skeleton. Armochaetoglasin B, chaetoglobosin V, and chaetoglobosin J showed weak cytotoxic activity with IC50 values ranging from 19.5 to 34.72 µM.


Assuntos
Alcaloides/metabolismo , Chaetomium/metabolismo , Citocalasinas/metabolismo , Fermentação , Tirosina/metabolismo , Alcaloides/química , Alcaloides/isolamento & purificação , Chaetomium/química , Citocalasinas/química , Citocalasinas/isolamento & purificação , Conformação Molecular , Tirosina/química
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