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1.
J Nat Prod ; 83(6): 1931-1938, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32520548

RESUMO

Seven new modified fusicoccane-type diterpenoids (1-7), together with two known congeners (8 and 9), were obtained from Alternaria brassicicola. Their structures were elucidated from a combination of NMR and HRESIMS data and 13C NMR calculation as well as DP4+ probability analyses, and the absolute configurations of 1-5 were determined by ECD calculation and single-crystal X-ray diffraction (Cu Kα). Compounds 1-3 belong to a rare class of 16-nor-dicyclopenta[a,d]cyclooctane diterpenoids, and compounds 2 and 4 represent the first examples of fusicoccane-type diterpenoids featuring two previously undescribed tetracyclic 5/6/6/5 ring systems, while compound 5 features a previously undescribed tetracyclic 5/8/5/3 ring system. Compound 7 was moderately anti-inflammatory, and compounds 2, 3, 5, and 7 were weakly cytotoxic.

2.
Bioorg Chem ; 100: 103887, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32371250

RESUMO

Fusicoccane-derived diterpenoids bearing a unique bridgehead double-bond-containing tricyclo[9.2.1.03,7]tetradecane (5-9-5 ring system) core skeleton represent a rarely reported class of rearranged terpenoids, which traced back to fusicoccanes with a classical dicyclopenta[a,d]cyclooctane (5-8-5 ring system) core skeleton via a crucial Wagner-Meerwein rearrangement reaction. In this research, alterbrassicenes B-D (1-3), three new rearranged fusicoccane diterpenoids bearing a rare bridgehead double-bond-containing tricyclo[9.2.1.03,7]tetradecane core skeleton, together with two known congeners, brassicicenes O and K (4 and 5), were isolated from the modified cultures of fungus Alternaria brassicicola. Their structures were elucidated by comprehensive analyses of the NMR and HRESIMS data, and the absolute configurations of 1 and 4 were further confirmed via a combination of 13C NMR and ECD calculations and single-crystal X-ray diffraction analysis (Cu Kα). Interestingly, alterbrassicene B (1) represented the second case of bridgehead C-10-C-11 double-bond-containing natural products with a bicyclo[6.2.1]undecane core skeleton, and also featured an undescribed oxygen bridge between C-6 and C-14 to construct an unprecedentedly caged tetracyclic system. Alterbrassicenes B-D showed moderate cytotoxic activity against certain human tumor cell lines with IC50 values in the range of 15.87-36.85 µM.

3.
Phytochemistry ; 175: 112374, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32315839

RESUMO

Seven undescribed alkaloids, namely fischeramides A and B, 5,6-dimethoxycircumdatin C, 6-hydroxyacetylaszonalenin, 3-methoxyglyantrypine, 9-methoxyfumitremorgin C, and spirotryprostatin M, one undescribed natural product, namely 11-deacetyl pyripyropene A, together with nine known congeners, were isolated from the solid cultures of fungus Neosartorya fischeri, which was separated from a medicinal insect Cryptotympana atrata. Their structures were elucidated by extensive spectroscopic data, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analyses. Structurally, fischeramides A and B represented a pair of rare geometric isomers of the benzodiazepinedione derivatives with a highly conjugated feature. Fischeramide A showed potential immunosuppressive activity in LPS and anti-CD3/anti-CD28 mAbs activated murine splenocytes proliferation with IC50 values of 7.08 and 6.31 µM, respectively, and also showed anti-inflammatory activity against the lipopolysaccharide-induced nitric oxide production with an IC50 value of 25 ± 1 µM. In addition, 5,6-dimethoxycircumdatin C showed remarkable antibacterial activity against ESBL-producing E. coli with an MIC value of 2.0 µg/mL.


Assuntos
Alcaloides , Neosartorya , Animais , Aspergillus , Escherichia coli , Insetos , Camundongos
4.
J Nat Prod ; 83(1): 169-173, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31920082

RESUMO

The reported fumiquinazoline-related alkaloids cottoquinazolines E-G (1-3) were reisolated from solid cultures of the fungus Neosartorya fischeri, which was isolated from the medicinal arthropod Cryptotympana atrata. The unresolved issues regarding the absolute configurations (for cottoquinazolines E and F) prompted a reinvestigation of the configurations for all three compounds, as enabled by extensive spectroscopic methods, comparisons of experimental electronic circular dichroism data, and X-ray crystallography. In addition, cottoquinazoline F (2) showed significant antibacterial activity against ESBL-producing Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecalis with MIC values of 8, 32, 32, and 16 µg/mL, respectively.

5.
Chin J Nat Med ; 17(12): 935-944, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31882049

RESUMO

Bipolarins A-H (1-8), eight new tetracyclic ophiobolin-type sesterterpenes featuring a rare oxaspiro[4.4]nonane moiety, were isolated from cultures of fungus Bipolaris sp. TJ403-B1. Their structures and absolute configurations were elucidated by comprehensive spectroscopic analyses, single-crystal X-ray diffraction experiments, electronic circular dichroism and 13C NMR calculations. Additionally, compound 5 exhibited significant selective antimicrobial activity against Enterococcus faecalis with an MIC value 8 µg·mL-1.


Assuntos
Anti-Infecciosos/química , Ascomicetos/efeitos dos fármacos , Sesterterpenos/química , Anti-Infecciosos/isolamento & purificação , China , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sesterterpenos/isolamento & purificação , Triticum/microbiologia
6.
Org Lett ; 21(20): 8469-8472, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31580084

RESUMO

Periconiastone A (1), an ergosterol with an unprecedented pentacyclo[8.7.0.01,5.02,14.010,15]heptadecane system, was isolated from Periconia sp. TJ403-rc01. Its structure was assigned by extensive spectroscopic analyses and quantum-chemical 13C NMR and ECD calculations. A vinylogous α-ketol rearrangement and an aldol condensation reaction during biosynthesis were proposed as key steps for the formation of 1. Compound 1 showed antibacterial activity against Gram-positive S. aureus and E. faecalis with MIC values of 4 and 32 µg/mL, respectively.

7.
Org Lett ; 21(20): 8353-8357, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31573213

RESUMO

Alterbrassinoids A-D (1-4), the first examples of fusicoccane-derived diterpenoid dimers furnished by forming an undescribed C-12-C-18' linkage, were isolated from modified cultures of Alternaria brassicicola. Compounds 1 and 2 represent unprecedented heterodimers, whereas 3 and 4 represent unprecedented homodimers, and 4 also features an undescribed anhydride motif. Their structures were assigned via spectroscopic methods, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Putative biosynthetic pathways and a bioactivity evaluation for 1-4 were discussed.

8.
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.

9.
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.

10.
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.

11.
J Nat Prod ; 82(7): 1923-1929, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31265296

RESUMO

Three new dolabellane-type diterpenoids (1-3) and three new atranones (4-6) were isolated and identified from a marine-derived strain of the toxigenic fungus Stachybotrys chartarum. The planar and relative structures of 1-6 were elucidated using extensive spectroscopic methods, and their absolute configurations were fully confirmed via single-crystal X-ray diffraction analysis. Structurally, compounds 2 and 3 have a 1,14-seco dolabellane-type diterpenoid skeleton; compound 4 is the first C23 atranone featuring a propan-2-one motif linked to a dolabellane-type diterpenoid by a carbon-carbon bond; compound 5 represents the first example of a C24 atranone with a 2-methyltetrahydrofuran-3-carboxylate motif fused to a dolabellane-type diterpenoid at C-5-C-6. In an in vitro antimicrobial activity assay, compound 2 was active against Acinetobacter baumannii and Enterococcus faecalis with MIC values of 16 and 32 µg/mL, respectively, while compound 4 exhibited significant inhibitory activities against Candida albicans, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 8, 16, and 32 µg/mL, respectively.

12.
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.

13.
Phytochemistry ; 165: 112041, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203103

RESUMO

Spiroterreusnoids A-F, six undescribed spiro-dioxolane-containing adducts bearing 3,5-dimethylorsellinic acid-based meroterpenoid and 2,3-butanediol moieties were isolated from the endophytic fungus Aspergillus terreus Thom from Tripterygium wilfordii Hook. f. (Celastraceae). The structures of these adducts were established by spectroscopy, single-crystal X-ray diffraction, and experimental electronic circular dichroism (ECD) measurements. Spiroterreusnoids A-F represent the first examples of adducts composed of 3,5-dimethylorsellinic acid-based meroterpenoids. It is noteworthy that spiroterreusnoids A-F possessing a spiro-dioxolane moiety exhibited potential abilities in inhibiting BACE1 (IC50 values ranging from 5.86 to 27.16 µM) and AchE (IC50 values ranging from 22.18 to 32.51 µM), while the other analogues without this fragment displayed no such activities. Taken together, spiroterreusnoids A-F represent the first multitargeted natural adducts that could inhibit BACE1 and AchE, and might provide a new template for the development of new anti-Alzheimer's disease drugs.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Dioxolanos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos de Espiro/farmacologia , Terpenos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Aspergillus/química , Celastraceae/microbiologia , Dioxolanos/química , Dioxolanos/isolamento & purificação , Enguias , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificação
14.
Org Biomol Chem ; 17(22): 5526-5532, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31041978

RESUMO

Marine-derived fungi have been regarded as an under-explored and promising reservoir of structurally novel and bioactive natural products. In this study, five new γ-pyrone-containing polyketides, fusaresters A-E (1-5), were isolated and identified from the culture extracts of a marine-derived fungus Fusarium sp. Hungcl. The structures of compounds 1-5 were elucidated on the basis of their HRESIMS and NMR spectroscopic data as well as 13C NMR calculation and electronic circular dichroism (ECD) analyses. Remarkably, the structure of fusariumin D was revised to (9S*,11S*)-3. All these isolates were tested for the cytotoxicity against seven human cancer cell lines, including SW480, HL-60, A549, MCF-7, HepG2, HeLa and SMMC-7721, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). The results revealed that only compound 2 showed a weak inhibition rate of 56% at 40 µM.


Assuntos
Cumarínicos/química , Fusarium/química , Policetídeos/isolamento & purificação , Pironas/isolamento & purificação , Estrutura Molecular , Policetídeos/química , Pironas/química
15.
Bioorg Chem ; 83: 98-104, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30343206

RESUMO

By feeding 1-methyl-l-tryptophan (1-MT) into cultures of the arthropod-associated fungus Chaetomium globosum TW1-1, three novel cytochalasan alkaloids, termed as armochaetoglosins A-C (1-3), together with five known analogues, namely prochaetoglobosin I (4), chaetoglobosin T (5), chaetoglobosin C (6), armochaetoglobin Y (7), and chaetoglobosin Vb (8), were isolated and characterized. Their structures including absolute configurations were elucidated by means of NMR spectroscopy, single-crystal X-ray crystallography, and comparison of the experimental electronic circular dichroism (ECD) spectra. Structurally, compounds 1-3 represented the first examples of 1'-N-methyl-chaetoglobosins, which were possibly biosynthesized from the additive 1-MT rather than tryptophan. Additionally, compound 3 showed the highest antibacterial activity against K. pneumoniae and ESBL-E. coli with MIC values of 4.0 µg/mL and 16.0 µg/mL, respectively, wherein the inhibitory effect of 3 against K. pneumoniae was stronger than that of the clinically used antibiotic meropenem, with an MIC value of 8 µg/mL. Our findings may provide new chemical templates for the development of new antibacterial agents against drug-resistant microbial pathogens.


Assuntos
Alcaloides/farmacologia , Antibacterianos/farmacologia , Chaetomium/química , Citocalasinas/farmacologia , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Alcaloides/química , Alcaloides/isolamento & purificação , Antibacterianos/química , Antibacterianos/isolamento & purificação , Cristalografia por Raios X , Citocalasinas/química , Citocalasinas/isolamento & purificação , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
16.
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
17.
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
18.
Org Biomol Chem ; 16(46): 9046-9052, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30430177

RESUMO

Chemical investigation of the extracts of Aspergillus terreus resulted in the identification of terreusterpenes A-D (1-4), four new 3,5-dimethylorsellinic acid-based meroterpenoids. The structures and absolute configurations of 1-4 were elucidated by spectroscopic analyses including HRESIMS and 1D- and 2D-NMR, chemical conversion, and single crystal X-ray diffraction. Terreusterpenes A (1) and B (2) featured 2,3,5-trimethyl-4-oxo-5-carboxy tetrahydrofuran moieties. Terreusterpene D (4) was characterized by a 4-hydroxy-3-methyl gamma lactone fragment that was generated by accident from the rearrangement of 3 in a mixed tetrahydrofuran-H2O-MeOH solvent. All these compounds were evaluated for the ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and acetylcholinesterase (AchE) inhibitory activities. Among them, compounds 1 and 2 showed potentially significant BACE1 inhibitory activity, with IC50 values of 5.98 and 11.42 µM, respectively. Interestingly, compound 4 exhibited promising BACE1 and AchE inhibitory activities, with IC50 values of 1.91 and 8.86 µM, respectively, while 3 showed no such activity. Taken together, terreusterpenes A and B could be of great importance for the development of new BACE1 inhibitors, while terreusterpene D could serve as the first dual-targeted 3,5-dimethylorsellinic acid-based meroterpenoid for the treatment of Alzheimer's disease.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Aspergillus/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Resorcinóis/química , Resorcinóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Inibidores da Colinesterase/síntese química , Cristalografia por Raios X , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Resorcinóis/síntese química
19.
Bioorg Med Chem ; 26(22): 5903-5910, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30392953

RESUMO

Chemical study on the extract of a marine-derived fungus Aspergillus terreus yielded twelve butenolide derivatives, including three new compounds, namely asperlides A-C (1-3) and nine known butenolides (4-12). The structures of 1-3 were confirmed by comprehensive spectroscopic analysis, including HRESIMS, NMR spectroscopy, and calculated electronic circular dichroism (ECD). The cytotoxicity of the compounds was evaluated using PANC-1, HCC1806, HepG2, BEAS-2B and HT-29 cancer cells. The results showed that (+)-3',3'-di-(dimethylallyl)-butyrolactone II (4) and versicolactone B (6) exhibited the most potent cytotoxin of PANC-1 cell line, with the IC50 values of 5.3 and 9.4 µM, respectively. Morphological features of apoptosis were observed in 4 and 6-treated PANC-1 cells, including apoptotic body formation, membrane blebbing, cell shrinkage and nuclear condensation. Cell cycle analysis with propidium iodide staining exhibited that 4 inhibits proliferation of PANC-1 cells via the induction of G2/M and S phase arrest, while 6 could retard the PANC-1 cells via the induction of S phase arrest. Flow cytometric analysis suggested that treatment with 4 and 6 significantly induced PANC-1 cells apoptosis. These findings indicated that 4 and 6 might serve as a starting point for the development of an anticancer drug for the treatment of pancreatic ductal adenocarcinoma.


Assuntos
4-Butirolactona/análogos & derivados , Antineoplásicos/farmacologia , Aspergillus/química , Carcinoma Ductal Pancreático/tratamento farmacológico , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas , Relação Estrutura-Atividade
20.
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
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