Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 293
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chem Pharm Bull (Tokyo) ; 67(9): 966-976, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257308

RESUMO

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4'-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4'-alkylated derivative.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Inflamação/metabolismo , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Estereoisomerismo
2.
J Agric Food Chem ; 67(28): 7880-7885, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31250636

RESUMO

Ninety-two new 9-norlignan derivatives containing more effective compounds against both cancer and insect cells than lead compounds were synthesized. Against HeLa cells, 7-(3,4-dimethoxyphenyl)-7'-(3'-hydroxy-4'-methoxyphenyl) derivative 63 (IC50 = 0.9 ± 0.2 µM) was to be around 6-fold more potent than lead compound 5. Moreover, against HL-60 cells, 7-(4-trifluoromethylphenyl)-7'-(3'/4'-hydroxyphenyl) derivatives 78 and 79 (IC50 = 2.2 ± 0.4 µM and 2.4 ± 0.6 µM) were 3-fold more potent than lead compound 5. Furthermore, against Sf9 cells from the common cutworm, the 7-(4-trifluoromethylphenyl) derivatives bearing electron-withdrawing groups 76-96 showed a wider range of activity (around 20-fold difference), giving valuable information on the structure-activity relationship. The 7-(4-trifluoromethylphenyl)-7'-(2'/3'-hydroxyphenyl) derivatives 77 and 78 (IC50 = 4.7 ± 0.6 µM and 4.9 ± 0.9 µM) had around 2-fold higher activity against Sf9 cells than lead compound 5. The 7-(4-trifluoromethylphenyl)-7'-(3'-hydroxyphenyl) derivative 78 was also effective against mosquito NIAS-AcAl-2 cells with an IC50 value of 5.4 ± 0.3.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Lignanas/química , Lignanas/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Culicidae , Desenho de Drogas , Células HL-60 , Células HeLa , Humanos , Lignanas/síntese química , Spodoptera , Relação Estrutura-Atividade
3.
Fitoterapia ; 137: 104198, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175951

RESUMO

The concise syntheses of three new natural diphyllin L-arabinopyranosides, Phyllanthusmin D (1), Phyllanthusmin B (4), Phyllanthusmin C (6) and a known analogue 7-O-[(2,3,4-tri-O-acetyl)-α-Larabinopyranosyl)] diphyllin (7) have been achieved employing phase transfer catalysis glycosylation and orthoester rearrangement. In biological assays, 4 showed the best cytotoxicity against human gastric carcinoma MGC803 Cells with the IC50 value 39 µg/mL. Transwell invasion assay showed that glycosides 1, 4, and 7 significantly suppressed MGC-803 cell invasion compared with control.


Assuntos
Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Glicosídeos/farmacologia , Lignanas/farmacologia , Antineoplásicos/síntese química , Benzodioxóis/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/síntese química , Humanos , Lignanas/síntese química , Estrutura Molecular
4.
Eur J Med Chem ; 176: 162-174, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103897

RESUMO

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 µM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 µM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 µM. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.


Assuntos
Anisóis/farmacologia , Lignanas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Anisóis/síntese química , Anisóis/química , Anisóis/toxicidade , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Humanos , Lignanas/síntese química , Lignanas/química , Lignanas/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/toxicidade , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo
5.
Molecules ; 24(2)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634427

RESUMO

Lignans, neolignans, norlignans and norneolignans constitute a large class of phenolic natural compounds. 9-Norlignans, here defined to contain a ß⁻ß' bond between the two phenylpropanoid units and to lack carbon number 9 from the parent lignan structure, are the most rarely occurring compounds within this class of natural compounds. We present here an overview of the structure, occurrence and biological activity of thirty-five 9-norlignans reported in the literature to date. In addition, we report the semisynthetic preparation of sixteen 9-norlignans using the natural lignan hydroxymatairesinol obtained from spruce knots, as starting material. 9-Norlignans are shown to exist in different species and to have various biological activities, and they may therefore serve as lead compounds for example for the development of anticancer agents. Hydroxymatairesinol is shown to be a readily available starting material for the preparation of norlignans of the imperanene, vitrofolal and noralashinol family.


Assuntos
Antineoplásicos/síntese química , Lignanas/síntese química , Picea/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HL-60 , Células HeLa , Humanos , Lignanas/química , Lignanas/farmacologia , Estrutura Molecular
6.
Biomacromolecules ; 20(1): 109-117, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30179461

RESUMO

Magnolol, a neolignan natural product with antioxidant properties, contains inherent, orthogonal, phenolic, and alkenyl reactive groups that were used in both direct thermoset synthesis, as well as the stepwise synthesis of a small library of monomers, followed by transformation into thermoset materials. Each monomer from the small library was prepared via a single step functionalization reaction of the phenolic groups of magnolol. Thermoset materials were realized through solvent-free, thiol-ene reactions, and the resulting cross-linked materials were each comprised of thioether and ester linkages, with one retaining the hydrophilic phenols from magnolol, another having the phenols protected as an acetonide, and two others incorporating the phenols into additional cross-linking sites via hydrolytically labile carbonates or stable ether linkages. With this diversity of chemical compositions and structures, the thermosets displayed a range of thermomechanical properties including glass transition temperatures, Tg, 29-52 °C, onset of thermal degradation, Td, from about 290-360 °C, and ultimate strength up to 50 MPa. These tunable materials were studied in their degradation and biological properties with the aim of exploiting the antioxidant properties of the natural product. Hydrolytic degradation occurred under basic conditions (pH = 11) in all thermosets, but with kinetics that were dependent upon their chemical structures and mechanical properties: 20% mass loss was observed at 5, 7, 27, and 40 weeks for the thermosets produced from magnolol directly, acetonide-protected magnolol, bis(allyl carbonate)-functionalized magnolol, and bis(allyl ether)-functionalized magnolol, respectively. Isolated degradation products and model compounds displayed antioxidant properties similar to magnolol, as determined by both UV-vis and in vitro reactive oxygen species (ROS) assays. As these magnolol-based thermosets were found to also allow for extended cell culture, these materials may serve as promising degradable biomaterials.


Assuntos
Antioxidantes/síntese química , Plásticos Biodegradáveis/síntese química , Compostos de Bifenilo/química , Lignanas/síntese química , /síntese química , Ácido 3-Mercaptopropiônico/análogos & derivados , Ácido 3-Mercaptopropiônico/química , Animais , Antioxidantes/farmacologia , Bovinos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Lignanas/química , Fenóis/química , Propilenoglicóis/química , Estresse Mecânico , Temperatura Ambiente
7.
J Asian Nat Prod Res ; 21(1): 76-85, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29281889

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S)-3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 µmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Lignanas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Descoberta de Drogas , Lignanas/síntese química , Inibidores da Transcriptase Reversa/síntese química
8.
Bioorg Med Chem Lett ; 29(2): 329-333, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472026

RESUMO

Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC50 values of 8.9 and 1.2 µM, respectively, than honokiol.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Produtos Biológicos/farmacologia , Compostos de Bifenilo/farmacologia , Compostos Heterocíclicos/farmacologia , Lignanas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 163: 183-194, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508667

RESUMO

Infectious hematopoietic necrosis virus (IHNV) is a common pathogen that causes severe disease and huge economic losses in the salmonid aquaculture industry. Herein, a series of arctigenin derivatives are synthesized to evaluate their antiviral activity against IHNV. The results indicate that the length of linker and imidazole substituent groups play an important role in decreasing IHNV replication. In this study, the arctigenin-imidazole hybrid derivative 15 with an eight carbon atoms length of the linker reduces IHNV replication with an IC50 value of 1.3 µM. In addition, derivative 15 significantly inhibits apoptosis and cellular morphological damage induced by IHNV. Mechanistically, derivative 15 can not damage the viral particle directly. While time-of-addition and viral binding assays reveal that derivative 15 mainly affect the early replication of IHNV but do not interfere with IHNV adsorption. Overall, derivative 15 could be considered to develop as a promising agent to treat IHNV infection.


Assuntos
Antivirais/síntese química , Furanos/uso terapêutico , Vírus da Necrose Hematopoética Infecciosa/efeitos dos fármacos , Lignanas/uso terapêutico , Infecções por Rhabdoviridae/tratamento farmacológico , Animais , Antivirais/farmacologia , Furanos/síntese química , Imidazóis/química , Imidazóis/farmacologia , Lignanas/síntese química , Salmão/virologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
10.
Molecules ; 23(12)2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30572693

RESUMO

Lignans comprise a family of secondary metabolites existing widely in plants and also in human food sources. As important components, these compounds play remarkable roles in plants' ecological functions as protection against herbivores and microorganisms. Meanwhile, foods rich in lignans have revealed potential to decrease of risk of cancers. To date, a number of promising bioactivities have been found for lignan natural products and their unnatural analogues, including antibacterial, antiviral, antitumor, antiplatelet, phosphodiesterase inhibition, 5-lipoxygenase inhibition, HIV reverse transcription inhibition, cytotoxic activities, antioxidant activities, immunosuppressive activities and antiasthmatic activities. Therefore, the synthesis of this family and also their analogues have attracted widespread interest from the synthetic organic chemistry community. Herein, we outline advances in the synthesis of lignan natural products in the last decade.


Assuntos
Produtos Biológicos/síntese química , Química Orgânica/métodos , Lignanas/síntese química
11.
Molecules ; 23(11)2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30469319

RESUMO

Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-ß- and γ-apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin. The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were easily accessed from a nickel-catalyzed reductive cascade approach developed in our group.


Assuntos
Lactonas/síntese química , Lignanas/síntese química , Podofilina/química , Catálise , Ciclização , Lactonas/química , Lignanas/química , Modelos Moleculares , Estrutura Molecular , Podofilotoxina
12.
J Nat Prod ; 81(12): 2630-2637, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485098

RESUMO

1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4-benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3-deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4-benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Flavonolignanos/síntese química , Flavonolignanos/farmacologia , Lignanas/síntese química , Lignanas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Hepacivirus/efeitos dos fármacos , Humanos , Estrutura Molecular , Silibina/química
13.
Molecules ; 23(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467285

RESUMO

Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.


Assuntos
Furanos/síntese química , Lactonas/síntese química , Lignanas/síntese química , 4-Butirolactona/análogos & derivados , Sobrevivência Celular/efeitos dos fármacos , Furanos/química , Furanos/farmacologia , Humanos , Células Jurkat , Lactonas/química , Lactonas/farmacologia , Lignanas/química , Lignanas/farmacologia , Estrutura Molecular , Estereoisomerismo
14.
ChemMedChem ; 13(24): 2664-2676, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30335906

RESUMO

Many viruses use endosomal pathways to gain entry into cells and propagate infection. Sensing of endosomal acidification is a trigger for the release of many virus cores into the cell cytosol. Previous efforts with inhibitors of vacuolar ATPase have been shown to block endosomal acidification and affect viral entry, albeit with limited potential for therapeutic selectivity. In this study, four novel series of derivatives of the vacuolar ATPase inhibitor diphyllin were synthesized to assess their potential for enhancing potency and anti-filoviral activity over cytotoxicity. Derivatives that suitably blocked cellular entry of Ebola pseudotyped virus were further evaluated as inhibitors of endosomal acidification and isolated human vacuolar ATPase activity. Several compounds with significant increases in potency over diphyllin in these assays also separated from cytotoxic doses in human cell models by >100-fold. Finally, three derivatives were shown to be inhibitors of replication-competent Ebola viral entry into primary macrophages with similar potencies and enhanced selectivity toward antiviral activity.


Assuntos
Antivirais/síntese química , Benzodioxóis/síntese química , Ebolavirus/efeitos dos fármacos , Lignanas/síntese química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Antivirais/farmacologia , Benzodioxóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ebolavirus/fisiologia , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Lignanas/farmacologia , Relação Estrutura-Atividade
15.
Org Biomol Chem ; 16(38): 7019-7028, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30232493

RESUMO

Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand-target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Lignanas/química , Lignanas/farmacologia , PPAR gama/metabolismo , Compostos de Bifenilo/síntese química , Cristalografia por Raios X , Dimerização , Descoberta de Drogas , Células HEK293 , Humanos , Ligantes , Lignanas/síntese química , Simulação de Acoplamento Molecular , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Ligação Proteica , Receptor X Retinoide alfa/metabolismo
16.
Eur J Med Chem ; 158: 414-427, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30237124

RESUMO

Four new series of arctigenin derivatives were designed, synthesised, and evaluated for their anti-Toxoplasma gondii activity in vitro and in vivo. Among the synthesised compounds, 4-(3,4-dimethoxybenzyl)-3-(4-((1-(2-fluorobenzyl)-1H- 1,2,3-triazol-4-yl)methoxy)-3-methoxybenzyl)dihydrofuran-2(3H)-one (D4) exhibited the most potent anti-T. gondii activity and low cytotoxicity (IC50 in T. gondii: 17.1 µM; IC50 in HeLa cells: ≥ 600.0 µM; Selectivity: 35.09), demonstrating better results than the lead compound arctigenin (IC50 in T. gondii: 586.4 µM; IC50 in HeLa cells: 572.7 µM; Selectivity: 0.98) and the clinically applied positive-control drug spiramycin (IC50 in T. gondi: 262.2 µM; IC50 in HeLa cells: 189.0 µM; Selectivity: 0.72) in vitro. Furthermore, 2-(4-((4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2- methoxyphenoxy)N-phenylacetamide (E5) had better inhibitory effects on T. gondii in vivo than spiramycin did. Compound D4 and E5 not only significantly reduced the number of tachyzoites in the peritoneal cavity of mice, but also resulted in their partial malformation (P < 0.05) in vivo. The determination of liver and spleen index and biochemical parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione (GSH) and malondialdehyde (MDA), were comprehensively evaluated for compound D4 and E5's anti-T. gondii activity and some damage to the liver. In addition, the results of a docking study of D4 into the T. gondii calcium-dependent protein kinase 1 (TgCDPK1) receptor protein-binding site revealed that its mode of action was possibly as a TgCDPK1 inhibitor. Overall, the results revealed that D4 and E5 are promising lead compounds for the further development and identification of arctigenin derivatives as anti-T. gondii agents.


Assuntos
Antiparasitários/química , Antiparasitários/uso terapêutico , Furanos/química , Furanos/uso terapêutico , Lignanas/química , Lignanas/uso terapêutico , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Animais , Antiparasitários/síntese química , Antiparasitários/farmacologia , Feminino , Furanos/síntese química , Furanos/farmacologia , Células HeLa , Humanos , Lignanas/síntese química , Lignanas/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Proteínas Quinases/metabolismo , Toxoplasma/metabolismo
17.
Eur J Med Chem ; 156: 381-393, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30015074

RESUMO

Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 µM agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs.


Assuntos
Antidepressivos/química , Antidepressivos/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Depressão/tratamento farmacológico , Lignanas/química , Lignanas/uso terapêutico , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Encéfalo/metabolismo , Depressão/metabolismo , Feminino , Células HEK293 , Elevação dos Membros Posteriores , Humanos , Lignanas/síntese química , Lignanas/farmacologia , Masculino , Camundongos , Ratos Sprague-Dawley , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo
18.
Eur J Med Chem ; 156: 190-205, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30006164

RESUMO

EGFR T790 M accounts for 50% to 60% of cases of non-small-cell lung carcinoma (NSCLC) resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs). Hence, identifying novel compounds with activity against TKIs resistant is of great value. In this study, twenty honokiol and magnolol derivatives were isolated from the EtOH extract of Magnolia officinalis and the antiproliferative activity was evaluated on HCC827 (19del EGFR mutation), H1975 (L858 R/T790 M EGFR mutation), and H460 (KRAS mutation) cell lines. Among the isolated compounds, piperitylmagnolol (a 3-substituted magnolol derivative) showed the best antiproliferative activity against those three cell lines with the IC50 values of 15.85, 15.60 and 18.60 µM, respectively, which provided a direction for the structural modification of magnolol. Further structural modification led to the synthesis of thirty-one magnolol derivatives, and compounds A13, C1, and C2 exhibited significant and broad-spectrum antiproliferative activity with the IC50 values ranging from 4.81 to 13.54 µM, which were approximately 4- and 8-fold more potent than those of honokiol and magnolol, respectively. Moreover, their aqueous solubility was remarkably improved with 12-, 400- and 105 fold greater than those of honokiol and magnolol. Anti-tumor mechanism research revealed that these three compounds were able to induce cell cycle arrest at G0/G1 phase, cause efficient apoptosis in H1975 cells, and also prevent the migration of HUVECs in a dose-dependent manner through Cdk2, Cdk4, Cyclin E, and Cyclin D1 inhibition as well as up-regulation of cleaved-PARP and cleaved-caspase 3 levels. In in vivo antitumor activity, C2 (10, 30 and 100 mg/kg, po) dose-dependently inhibited the tumor growth in H1975 xenograft model with the tumor inhibition rate of 46.3%, 59.3% and 61.2% respectively, suggesting that C2 is a potential oral anticancer agent deserving further investigation.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Lignanas/química , Lignanas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Lignanas/síntese química , Lignanas/farmacologia , Neoplasias Pulmonares/patologia , Magnolia/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Bioorg Med Chem ; 26(14): 3953-3957, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29934219

RESUMO

The natural product magnolol (1) and a selection of its bioinspired derivatives 2-5, were investigated by Inverse Virtual Screening in order to identify putative biological targets from a panel of 308 proteins involved in cancer processes. By this in silico analysis we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for experimental evaluations. The Surface Plasmon Resonance assay revealed that 3-5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as reference compound.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Tanquirases/antagonistas & inibidores , Algoritmos , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lignanas/síntese química , Lignanas/química , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Tanquirases/metabolismo , Termodinâmica , Células Tumorais Cultivadas
20.
Chem Biodivers ; 15(7): e1800134, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29754441

RESUMO

We have evaluated the antischistosomal activity of synthetic dihydrobenzofuran neolignans (DBNs) derived from (±)-trans-dehydrodicoumaric acid dimethyl ester (1) and (±)-trans-dehydrodiferulic acid dimethyl ester (2) against adult Schistosoma mansoni worms in vitro. Compound 4 ((±)-trans-4-O-acetyldehydrodiferulic acid dimethyl ester) displayed the most promising activity; at 200 µm, it kills 100 ± 0% of worms after 24 h, which resembles the result achieved with praziquantel (positive control) at 1.56 µm. The hydrogenation of the double bond between C7' and C8', the introduction of an additional methyl group at C3', and a double bond between C7 and C8 decreased the schistosomicidal activity of DBNs. On the other hand, the presence of the acetoxy group at C4 played an interesting role in this activity. These results demonstrated the interesting schistosomicidal potential of DBNs, which could be further exploited.


Assuntos
Lignanas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Lignanas/síntese química , Lignanas/química , Estrutura Molecular , Esquistossomicidas/síntese química , Esquistossomicidas/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA