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1.
Org Lett ; 22(6): 2162-2166, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32129633

RESUMO

The study of Aspergillus micronesiensis led to the isolation of three unprecedented cytochalasans (1-3). Dimericchalasine A (1) is the first cytochalasan homodimer fused by a C-20/C-20' single bond. Amichalasines D (2) and E (3) represent a new type of cytochalasan heterotrimer with a decacyclic 5/6/11/5/5/6/5/12/6/5 ring system. Their structures were determined by extensive spectroscopic data and single-crystal X-ray diffraction. The plausible biosynthetic pathways of 1-3 were proposed.

2.
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
3.
Phytochemistry ; 164: 41-49, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078778

RESUMO

Hyperforatins L-U, ten undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) bearing a terminal double bond, together with a known compound hypericumoxide J, were isolated from the aerial parts of Hypericum perforatum L. Their structures were elucidated by spectroscopic methods, including HRESIMS, IR, UV, and NMR (1H, 13C, DEPT, HSQC, HMBC, 1H-1H COSY, and NOESY experiments). Their absolute configurations were determined by comprehensive analyses of their experimental ECD spectra in conjunction with a modified Mosher's method. Evaluation of their neuroprotective activities highlighted hyperforatin L, which displayed mild activity at a concentration of 10 µM.


Assuntos
Inibidores da Colinesterase/farmacologia , Hypericum/química , Fármacos Neuroprotetores/farmacologia , Floroglucinol/farmacologia , Acetilcolinesterase/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Corticosterona , Relação Dose-Resposta a Droga , Conformação Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Floroglucinol/análogos & derivados , Floroglucinol/química , Ratos , Relação Estrutura-Atividade
4.
J Org Chem ; 84(9): 5483-5491, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30997804

RESUMO

Amiaspochalasins A-H (1-8), eight undescribed aspochalasins, and trichalasin D (9), a known analogue, were isolated from the solid culture of Aspergillus micronesiensis. Compounds 1-9 are aspochalasins with a C-21 ester carbonyl, and their structures were determined by spectroscopic data, X-ray crystallographic analyses, electronic circular dichroism calculations, and chemical methods. The CH3-25 in compound 1 is located at C-16 rather than C-14 in the previously reported aspochalasins, endowing 1 with an unexpected carbon skeleton. Compounds 2 and 3 are the first examples of aspochalasins with an unprecedented 5/6/6/8 tetracyclic ring system. Compounds 4 and 5 are diastereomers of aspochalasins I and J, respectively. Compounds 6 and 7 are the first aspochalasins featuring a long open-chain system, and their absolute configurations were discussed by comparing the NMR data of the hydrolysis and methyl esterification products of 4 and 5. Compound 8 is an isomeride of 9. The cytotoxic and antimicrobial effects of 1-9 were tested.

5.
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.

6.
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
7.
Front Chem ; 6: 605, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581815

RESUMO

(±)-Peniorthoesters A and B (±1 and ±2), two pairs of unprecedented spiro-orthoester enantiomers with a 1,4,6-trioxaspiro[4. 5]decane-7-one unit, were obtained from Penicillium minioluteum. Their structures were determined by spectroscopic methods, X-ray diffraction analyses, and ECD calculations. (±)-Peniorthoesters A and B are the first examples of spiro-orthoester enantiomers, and they represent the first spiro-orthoesters originating from fungi. All compounds showed potential inhibitory activities comparable to dexamethasone against NO production with IC50 values ranging from 14.2 to 34.5 µM.

9.
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
10.
Curr Med Sci ; 38(1): 11-18, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30074146

RESUMO

Kinsenoside is a main active component isolated from plants of the genus Anoectochilus, and exhibits many biological activities and pharmacological effects, including hepatoprotective, anti-hyperglycemic, anti-hyperliposis, anti-inflammatory, vascular protective and anti-osteoporosis effects and so on, which is contributing to its promising potency in disease treatments. This review aims to recapitulate the pharmacological functions of kinsenoside, as well as its source, extraction, identification, quantitative analysis, pharmacokinetics, synthesis and patent information. The data reported in this work can confirm the therapeutic potential of kinsenoside and provide useful information for further new drug development.


Assuntos
4-Butirolactona/análogos & derivados , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/farmacocinética , Hipoglicemiantes/farmacologia , Monossacarídeos/farmacologia , Orchidaceae/química , 4-Butirolactona/química , 4-Butirolactona/farmacocinética , 4-Butirolactona/farmacologia , Animais , Conservadores da Densidade Óssea/química , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Fígado/efeitos dos fármacos , Monossacarídeos/química , Monossacarídeos/farmacocinética
11.
Org Lett ; 20(17): 5198-5202, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30095270

RESUMO

The structure-stability relationships of 1-6 were investigated to show that 1 converted to 5 via a kinetic, solution-mediated autoxidation. In addition, alterbrassicene A (7), a fusicoccane-derived diterpenoid bearing an unprecedented 5/9/4-fused carbocyclic skeleton with a rare fused 2-cyclobuten-1-one motif, was characterized from Alternaria brassicicola. Its absolute structure was elucidated by spectroscopic analyses and quantum chemical calculations. Compound 7 was the first fusicoccane derivative acting as a potent IKKß inhibitor in the NF-κB signaling pathway.


Assuntos
Alternaria/química , Diterpenos/química , Diterpenos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Animais , Desenho de Fármacos , Estabilidade de Medicamentos , Quinase I-kappa B/química , Camundongos , Modelos Moleculares , Conformação Proteica , Células RAW 264.7 , Relação Estrutura-Atividade
12.
J Org Chem ; 83(15): 8483-8492, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30016097

RESUMO

Asperversiamides A-H (1-8), eight linearly fused prenylated indole alkaloids featuring an unusual pyrano[3,2- f]indole unit, were isolated from the marine-derived fungus Aspergillus versicolor. The structures and absolute configurations of these compounds were elucidated by extensive spectroscopic analyses, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, and optical rotation (OR) calculations. The relative configuration of C-21 of iso-notoamide B was herein revised, and a new methodology for preliminarily determining if the relative configuration of the bicyclo[2.2.2]diazaoctane moiety of a spiro-bicyclo[2.2.2]diazaoctane-type indole alkaloid is syn or anti was developed. The anti-inflammatory activities of the isolated compounds were all tested, and of these compounds, 7 exhibited a potent inhibitory effect against iNOS with an IC50 value of 5.39 µM.


Assuntos
Organismos Aquáticos/microbiologia , Aspergillus/química , Alcaloides Indólicos/química , Prenilação , Modelos Moleculares , Conformação Molecular
13.
J Nat Prod ; 81(7): 1578-1587, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-29969028

RESUMO

The cocultivation of Aspergillus flavipes and Chaetomium globosum, rich sources of cytochalasans, on solid rice medium, resulted in the production of 13 new, highly oxygenated cytochalasans, aspochalasinols A-D (1-4) and oxichaetoglobosins A-I (5-13), as well as seven known compounds (14-20). Of these compounds, 13 is a novel cytochalasan with an unexpected 2-norindole group. The isolated compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD experiments. Compounds 1-4 represent the first examples of Asp-type cytochalasans with C-12 hydroxy groups, which may be a result of the coculture, as hydroxylated Me-12 groups are frequently found in Chae-type cytochalasans from C. globosum. In addition, 5-10 are unusual cytochalasans with an oxygenated C-10. Interestingly, 13 is the first example of a naturally occurring cytochalasan possessing a uniquely degraded indole ring that is derived from chaetoglobosin W, with 11 and 12 both serving as its biosynthetic intermediates. In the coculture of A. flavipes and C. globosum, most of these cytochalasans are more functionalized than normal cytochalasans, and the underlying causes may attract substantial attention from synthetic biologists. The cytotoxicities against five human cancer cell lines (SW480, HL-60, A549, MCF-7, and SMMC-7721) and the immunomodulatory activities of these new compounds were evaluated in vitro.


Assuntos
Aspergillus/metabolismo , Chaetomium/metabolismo , Citocalasinas/biossíntese , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Técnicas de Cocultura , Cristalografia por Raios X , Citocalasinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Estrutura Molecular
14.
Mar Drugs ; 16(6)2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29882867

RESUMO

Asperversins A (1) and B (2), two novel meroterpenoids featuring an uncommon 5/6/6/6 ring system, along with five new analogues (3⁻7) and a known compound asperdemin (8), were obtained from the marine-derived fungus Aspergillus versicolor. Their structures and absolute configurations were confirmed by extensive spectroscopic analyses, single-crystal X-ray diffraction studies, and electronic circular dichroism (ECD) calculation. All new compounds were tested for their acetylcholinesterase enzyme (AChE) inhibitory activities and cytotoxic activities, of which compound 7 displayed moderate inhibitory activity against the AChE with an IC50 value of 13.6 μM.


Assuntos
Organismos Aquáticos/metabolismo , Aspergillus/metabolismo , Inibidores da Colinesterase/química , Terpenos/química , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Dicroísmo Circular , Cristalografia por Raios X , Concentração Inibidora 50 , Estrutura Molecular , Análise Espectral , Terpenos/isolamento & purificação , Terpenos/farmacologia
15.
Fitoterapia ; 128: 79-85, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29778571

RESUMO

Three new cleistanthane diterpenoids, phyllanglins A-C (1-3), a new natural product, 4-acetyl-bergenin (4), and three known compounds (5-7) were isolated from the roots of Phyllanthus glaucus. Their structures were elucidated by extensive spectroscopic data analyses and single-crystal X-ray diffraction. Phyllanglins A-C were unusual cleistanthane diterpenoids with phenylacetylene moieties, and a plausible biogenetic pathway was proposed to discuss the origins of them. All of the isolates were evaluated for their anti-inflammatory activities.


Assuntos
Acetileno/análogos & derivados , Diterpenos/isolamento & purificação , Phyllanthus/química , Raízes de Plantas/química , Acetileno/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Diterpenos/farmacologia , Camundongos , Estrutura Molecular , Células RAW 264.7
16.
J Nat Prod ; 81(6): 1311-1320, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29771527

RESUMO

To explore the chemical diversity of metabolites from endophytic fungi, the strain Phomopsis sp. TJ507A, isolated from the medicinal plant Phyllanthus glaucus, was investigated. A 2,3- seco-protoilludane-type sesquiterpenoid (1), eight protoilludane-type sesquiterpenoids (2-9), four illudalane-type sesquiterpenoids (10a/10b, 11, and 12), and a botryane-type sesquiterpenoid (13) in addition to seven known sesquiterpenoids (14-20) were identified from the liquid culture of the fungus. Structures of the isolated compounds, including their absolute configurations, were elucidated based on extensive spectroscopic analyses, a modified Mosher analysis, electronic circular dichroism (ECD) calculations, and [Rh2(OCOCF3)4]-induced ECD spectra as well as X-ray crystallographic analyses. Compound 1 represents the first example of a naturally occurring sesquiterpenoid containing the unusual 2,3- seco-protoilludane scaffold. Compounds 1 ( p < 0.001); 2-6, 15, and 18 ( p < 0.01); and 7, 9, and 20 ( p < 0.05) displayed ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activities ranging from 19.4% to 43.8% at the concentration of 40 µM. LY2811376 was used as the positive control with an inhibitory activity of 38.6% ( p < 0.01). Furthermore, none of these compounds showed obvious hepatotoxicity at concentration of 40 µM.


Assuntos
Ascomicetos/química , Endófitos/química , Sesquiterpenos/química , Terpenos/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Fungos Mitospóricos/química , Sesquiterpenos Policíclicos , Sesquiterpenos/farmacologia , Terpenos/farmacologia
17.
Sci Rep ; 8(1): 5454, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615766

RESUMO

Rising drug resistance limits the treatment options infected by methicillin-resistant Staphylococcus aureus (MRSA). A promising solution for overcoming the resistance of MRSA is to inhibit the penicillin-binding protein 2a (PBP2a). A novel terpene-polyketide hybrid meroterpenoid, aspermerodione (1), characterized by an unusual 2,6-dioxabicyclo[2.2.1]heptane core skeleton, and a new heptacyclic analogue, andiconin C (2), were isolated and identified from the liquid cultures of endophytic fungus Aspergillus sp. TJ23. The structures and their absolute configurations of all chiral centers were elucidated via extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations and determined via single-crystal X-ray diffraction analysis. Aspemerodione (1) was found to be a potential inhibitor of PBP2a, and work synergistically with the ß-lactam antibiotics oxacillin and piperacillin against MRSA.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Aspergillus/metabolismo , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Policetídeos/química , Policetídeos/farmacologia , Terpenos/química , Terpenos/farmacologia , Antibacterianos/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Policetídeos/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Terpenos/metabolismo
18.
Chem Pharm Bull (Tokyo) ; 66(7): 764-767, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29657234

RESUMO

Terreinlactone A (1a/1b), a pair of 3-substituted δ-lactone enantiomers, and terreinlactone B (2), a new biosynthetic intermediate of 1a/1b, were isolated from Aspergillus terreus, along with their biosynthetic precursor (+)-terrein (3) and (+)-isoterrein (4). Compounds 1a and 1b were separated by using a Daicel chiral-pak ASH column eluting with n-hexane-EtOH (80 : 20). The structures of 1a/1b with absolute configurations were determined by comprehensive spectroscopic analyses and electronic circular dichroic (ECD) calculations. Terreinlactone A (1) represents the first example of 1,5-seco-terrein and a biogenetic pathway is proposed from the precursor terrein via the intermediated terreinlactone B (2).


Assuntos
Aspergillus/química , Lactonas/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células , Ciclopentanos , Humanos , Lactonas/química , Estrutura Molecular , Estereoisomerismo
19.
Nucleic Acids Res ; 46(7): 3284-3297, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29554366

RESUMO

Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)-one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Substâncias Intercalantes/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Fenantridinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/química , Caspases/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Substâncias Intercalantes/química , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Camundongos , Simulação de Acoplamento Molecular , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Fenantridinas/química , Proteína da Leucemia Promielocítica/genética , Proteólise/efeitos dos fármacos , Receptor alfa de Ácido Retinoico/genética , Tretinoína/administração & dosagem , Tretinoína/química , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mar Drugs ; 16(4)2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29596354

RESUMO

Marine-derived fungi are a promising and untapped reservoir for discovering structurally interesting and pharmacologically active natural products. In our efforts to identify novel bioactive compounds from marine-derived fungi, four breviane spiroditerpenoids, including a new compound, brevione O (1), and three known compounds breviones I (2), J (3), and H (4), together with a known diketopiperazine alkaloid brevicompanine G (5), were isolated and identified from an ethyl acetate extract of the fermented rice substrate of the coral-derived fungus Penicillium sp. TJ403-1. The absolute structure of 1 was elucidated by HRESIMS, one- and two-dimensional NMR spectroscopic data, and a comparison of its electronic circular dichroism (ECD) spectrum with the literature. Moreover, we confirmed the absolute configuration of 5 by single-crystal X-ray crystallography. All the isolated compounds were evaluated for isocitrate dehydrogenase 1 (IDH1) inhibitory activity and cytotoxicity, and compound 2 showed significant inhibitory activities against HL-60, A-549, and HEP3B tumor cell lines with IC50 values of 4.92 ± 0.65, 8.60 ± 1.36, and 5.50 ± 0.67 µM, respectively.


Assuntos
Antineoplásicos/farmacologia , Diterpenos/química , Penicillium/química , Penicillium/classificação , Antineoplásicos/química , Organismos Aquáticos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular
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