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1.
Chem Biodivers ; 17(1): e1900516, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31725193

RESUMO

In this study, 13 panaxadiol (PD) derivatives were synthesized via reactions with aromatic compounds and amino acids. Following this, the cytotoxicity of these compounds was evaluated against four cancer cell lines (human hepatoma cells HepG-2, human lung cancer cells A549, human breast cancer cells MCF-7, and human colon cancer cells HCT-116) and one normal cell lines (human gastric epithelial cells GES-1). The results showed that the panaxadiol derivatives 3, 12, and 13 showed significant inhibition of cellular proliferation against cancer cells compared with PD, and the panaxadiol derivative 12 had the lowest IC50 value for A549 (IC50 =18.91±1.03 µm). For MCF-7 cells, most compounds exhibited good inhibition of cellular proliferation, and the panaxadiol derivative 13 showed the strongest inhibitory effect (IC50 =8.62±0.23 µm), which significantly increased the cytotoxicity of PD and was stronger than the positive control (mitomycin). For normal cells, all compounds exhibited low or no toxic effects; thus, these derivatives can be used to develop novel antiproliferative agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ginsenosídeos/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 185: 111729, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655431

RESUMO

Panaxatriol (PT) is a natural product derived from ginseng that possesses cardioprotective effects in isolated rat hearts. To develop more potent therapeutic agents against myocardial ischemia/reperfusion (MI/R) injury from natural products, a novel series of heterocycle ring-fused panaxatriol derivatives were designed and synthesized. In vitro results showed that approximately half of them exhibited increased cytoprotective activity compared with PT in a cardiomyocyte model of oxygen-glucose deprivation and reperfusion (OGD/R) injury. Furthermore, the in vitro activity of the representative derivative, compound 18, was also confirmed in a rat model of MI/R injury. In vivo results showed that 18 can markedly reduce myocardial infarction size, decrease circulating cardiac troponin I (cTnI) leakage, and alleviate cardiac tissue damage in the rats. Therefore, these findings provide the basis for further development of novel anti-MI/R injury agents.


Assuntos
Ginsenosídeos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ginsenosídeos/síntese química , Ginsenosídeos/química , Masculino , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Troponina I/sangue
3.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3758-3762, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602950

RESUMO

Ginsenoside Rh_2,firstly isolated from red ginseng,is protopanaxadiol type of steroidal saponin. Rh_2 possessed variety of activities,but bioavailability of oral administration Rh_2 was extremely low due to poor absorption. Moreover,ginsenoside Rh_2 exhibited toxicity on human normal cells. Therefore,to improve stronger anti-tumor activity and attenuate toxicity,it was essential to design and optimize chemical structure of ginsenoside Rh_2. Through n-octanoylchloride modifications,a novel ester derivative of ginsenoside Rh_2 named caprylic acid monoester of Rh_2( C-Rh_2) was designed and synthesized. Structure of novel ginsenoside derivative was identified by1 D and 2 D NMR,as well as ESI-MS analyses. Anti-tumor effect of C-Rh_2 was tested on H22 tumor bearing mice. C-Rh_2 displayed certain anti-tumor activities and exhibited less toxicity than Rh_2. In the present study,C-Rh_2 as ester form of ginsenoside Rh_2 showed better anti-tumor activity and less toxicity,but the specific mechanism needs further investigation.


Assuntos
Ginsenosídeos/síntese química , Ginsenosídeos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Caprilatos , Camundongos , Estrutura Molecular , Saponinas
4.
Chem Biodivers ; 16(8): e1900188, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31298488

RESUMO

Panaxadiol is a dammarane-type ginsenoside having high ginseng content. The 3-hydroxy group of panaxadiol (PD) was modified by fatty acids and diacids. The modified panax glycol had enhanced anticancer activity. Twelve PD derivatives were evaluated and purified by chemical synthesis, column chromatography, co-synthesis, and identification. The human leukemia cells THP-1, HL-60, and human prostate cancer cell lines PC-3 were evaluated; PD derivatives were tested and evaluated in vitro by MTT assay. The results showed that the antitumor activities of some derivatives on three tumor cell lines were better than those of PD.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Ginsenosídeos/química , Panax/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Ginsenosídeos/síntese química , Ginsenosídeos/farmacologia , Células HL-60 , Humanos , Células PC-3 , Panax/metabolismo
5.
Fitoterapia ; 137: 104279, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31356850

RESUMO

20(R)-25-hydroxyprotopanaxadiol (25-OH-PPD) is a natural compound showing a variety of anti-tumor effects. In an attempt to search for a new anti-cancer compound with higher antitumor activities, we designed and synthesized a series of 25-OH-PPD derivatives. Cytotoxicity assay of these derivatives towards MCF-7, A549, U87, HO-8901, Hela cancer cell lines and normal IOSE144 cell lines were tested by MTT assay. Results showed that compared with compound 25-OH-PPD, Compounds 4, 5, 6, 10, 11 showed strong anticancer activity, and all compounds showed low toxicity or no toxicity for normal cells. In particular, compound 6 exhibited the best anti-tumor activity in all cancer cell lines (MCF-7, A549, U87, HO-8901, and Hela) with IC50 values of 5.04 µM, 1.36 µM, 3.24 µM, 3.47 µM, 4.57 µM, respectively. Among the five cell lines, all the compounds showed strong inhibition on A549 cells. Further studies showed that Compound 6 significantly inhibited the proliferation of A549 cells by inducing apoptosis. Our results indicate that Compound 6 is a potential anticancer inhibitor and provides a theoretical basis for further research.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ginsenosídeos/farmacologia , Acilação , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ginsenosídeos/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
6.
Planta Med ; 85(4): 292-301, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30380571

RESUMO

Ginseng is a perennial herb that contains various medicinal substances. The major active constituents of ginseng are ginsenosides, which have multifarious biological activities. Some pharmacological activities are closely dependent on the stereoisomers derived from the configuration at C20. In this study, the in vitro anti-inflammatory activity of C20 epimeric ocotillol-type triterpenes (2, 3, 9: , and 10: ) and protopanaxadiol [20(S/R)-protopanaxadiol] were investigated. Epimers 2: and 3: were prepared starting from 20(S)-protopanaxadiol. Epimers 9: and 10: were synthesized from 20(R)-3-acetylprotopanaxadiol (7: ). The anti-inflammatory activity of 2, 3, 9, 10: , 20(S)-protopanaxadiol, and 20(R)-protopanaxadiol was evaluated in cultured mouse macrophage RAW 264.7 cells. The MTT assay was used to measure the cytotoxicity. RAW 264.7 cells were stimulated by lipopolysaccharide to release the inflammatory mediators nitric oxide, prostaglandin E2, TNF-α, and interleukin-6 and anti-inflammatory mediator interleukin-10. The effect of the compounds on the overproduction of nitric oxide, prostaglandin E2, TNF-α, interleukin-6, and interleukin-10 was determined using Griess and ELISA methods. The results demonstrated that the in vitro anti-inflammatory activities of C20 epimeric ocotillol-type triterpenes and protopanaxadiol were different. Both the 20S-epimers (2: and 3: ) and 20R-epimers (9: and 10: ) inhibited the release of inflammatory mediator nitric oxide, while mainly the 20S-epimers inhibited the release of inflammatory mediator prostaglandin E2, and the 20R-epimers inhibited the release of inflammatory cytokine TNF-α. Both the 20S-epimers [2, 3: , and 20(S)-protopanaxadiol] and 20R-epimers [9, 10: , and 20(R)-protopanaxadiol] inhibited the release of inflammatory cytokine interleukin-6, but mainly the 20S-epimers [2, 3: , and 20(S)-protopanaxadiol] increased the release of anti-inflammatory mediator interleukin-10.


Assuntos
Anti-Inflamatórios/farmacologia , Ginsenosídeos/farmacologia , Sapogeninas/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Dinoprostona/antagonistas & inibidores , Ginsenosídeos/síntese química , Interleucina-10/metabolismo , Camundongos , Óxido Nítrico/antagonistas & inibidores , Panax/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Células RAW 264.7/efeitos dos fármacos , Sapogeninas/síntese química , Triterpenos/síntese química , Difração de Raios X
7.
Bioorg Med Chem Lett ; 29(2): 189-193, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30527868

RESUMO

Previously we have reported that 25-OCH3-PPD could suppress the reproduction of cancer cells and cause apoptosis without obvious toxicity. Herein, we aimed to enhance its bioactivity by introducing aromatic groups to its dammarane-type skeleton. These synthesized derivatives were tested for their inhibitory activities against five cancer cell lines. Of them, compounds 3a, 14a and 18a had the strongest antiproliferative activities against tumor cells (IC50 < 15 µM, 5-fold to 10-fold increases than 25-OCH3-PPD). Especially compound 14a displayed the most potent activity against DU145, MCF-7 and HepG2 cells (IC50 = 6.7 ±â€¯0.8, 4.3 ±â€¯0.8 and 5.8 ±â€¯0.6 µM, respectively). Structure-activity relationships demonstrated that having aromatic ester at the C3 position could improve the bioactivity. The data provided new insights into exploring novel antiproliferative lead compounds.


Assuntos
Antineoplásicos/farmacologia , Ginsenosídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ginsenosídeos/síntese química , Ginsenosídeos/química , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 29(1): 51-55, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448233

RESUMO

Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti-asthmatic effects (IgE value = 1237.11 ±â€¯106.28, 975.82 ±â€¯160.32, 1136.96 ±â€¯121.85, 1191.08 ±â€¯107.59 and 1258.27 ±â€¯148.70 ng/mL, respectively) in comparison with CK (1501.85 ±â€¯184.66 ng/mL). These potent compounds could serve as leads for further development.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Ginsenosídeos/farmacologia , Animais , Antiasmáticos/síntese química , Antiasmáticos/química , Asma/induzido quimicamente , Asma/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ginsenosídeos/síntese química , Ginsenosídeos/química , Imunoglobulina E/imunologia , Camundongos , Conformação Molecular , Ovalbumina/antagonistas & inibidores , Relação Estrutura-Atividade
9.
Int J Nanomedicine ; 13: 6249-6264, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349248

RESUMO

Background: Fluorescent carbon-based nanomaterials have promising properties such as biosensing, cell imaging, tracing and drug delivery. However, carbon dots (CDs) with specific inherent biological functions have not been investigated. Ginsenosides are the components with multiple bioactivities found in plants of the genus Panax, which have attracted a lot of attention for their anticancer effect. Materials and methods: In this study, we prepared a kind of novel photoluminescent CDs from ginsenoside Re by one-step hydrothermal synthesis method. The conventional methods including transmission electron microscopy, Fourier transform infrared spectroscopy, HPLC and fluorescence spectrum were used for characterization of CDs. In vitro anticancer effect was investigated by cytotoxicity assay, flow cytometry and Western blot analysis. Results: The as-prepared Re-CDs had an average diameter of 4.6±0.6 nm and excellent luminescent properties. Cellular uptake of Re-CDs was facilitated by their tiny nanosize, with evidence of their bright excitation-dependent fluorescent images. Compared with ginsenoside Re, the Re-CDs showed greater inhibition efficiency of cancer cell proliferation, with lower toxicity to the normal cells. The anticancer activity of Re-CDs was suggested to be associated with the generation of large amount of ROS and the caspase-3 related cell apoptosis. Conclusion: Hopefully, the dual functional Re-CDs, which could both exhibit bioimaging and anticancer effect, are expected to have great potential in future clinical applications.


Assuntos
Carbono/química , Ginsenosídeos/síntese química , Ginsenosídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Pontos Quânticos/química , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Diagnóstico por Imagem , Fluorescência , Corantes Fluorescentes/química , Ginsenosídeos/química , Humanos , L-Lactato Desidrogenase/metabolismo , Microscopia Eletrônica de Transmissão , Nanoestruturas/química , Necrose , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Padrões de Referência , Soluções , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
10.
Molecules ; 23(11)2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30373312

RESUMO

Glycosylation, which is catalyzed by UDP-glycosyltransferases (UGTs), is an important biological modification for the structural and functional diversity of ginsenosides. In this study, the promiscuous UGT109A1 from Bacillus subtilis was used to synthesize unnatural ginsenosides from natural ginsenosides. UGT109A1 was heterologously expressed in Escherichia coli and then purified by Ni-NTA affinity chromatography. Ginsenosides Re, Rf, Rh1, and R1 were selected as the substrates to produce the corresponding derivatives by the recombinant UGT109A1. The results showed that UGT109A1 could transfer a glucosyl moiety to C3-OH of ginsenosides Re and R1, and C3-OH and C12-OH of ginsenosides Rf and Rh1, respectively, to produce unnatural ginsenosides 3,20-di-O-ß-d-glucopyranosyl-6-O-[α-l-rhamnopyrano-(1→2)-ß-d-glucopyranosyl]-dammar-24-ene-3ß,6α,12ß,20S-tetraol (1), 3,20-di-O-ß-d-glucopyranosyl-6-O-[ß-d-xylopyranosyl-(1→2)-ß-d-glucopyranosyl]-dammar-24-ene-3ß,6α,12ß,20S-tetraol (6), 3-O-ß-d-glucopyranosyl-6-O-[ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranosyl]-dammar-24-ene-3ß,6α,12ß,20S-tetraol (3), 3,12-di-O-ß-d-glucopyranosyl-6-O-[ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranosyl]-dammar-24-ene-3ß,6α,12ß,20S-tetraol (2), 3,6-di-O-ß-d-glucopyranosyl-dammar-24-ene-3ß,6α,12ß,20S-tetraol (5), and 3,6,12-tri-O-ß-d-glucopyranosyl-dammar-24-ene-3ß,6α,12ß,20S-tetraol (4). Among the above products, 1, 2, 3, and 6 are new compounds. The maximal activity of UGT109A1 was achieved at the temperature of 40 °C, in the pH range of 8.0⁻10.0. The activity of UGT109A1 was considerably enhanced by Mg2+, Mn2+, and Ca2+, but was obviously reduced by Cu2+, Co2+, and Zn2+. The study demonstrated that UGT109A1 was effective in producing a series of unnatural ginsenosides through enzymatic reactions, which could pave a way to generate promising leads for new drug discovery.


Assuntos
Bacillus subtilis/enzimologia , Ginsenosídeos/síntese química , Glucosiltransferases/química , Bacillus subtilis/genética , Cromatografia Líquida de Alta Pressão , Ativação Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Ginsenosídeos/química , Glucosiltransferases/genética , Glucosiltransferases/isolamento & purificação , Glicosilação , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Íons/química , Metais/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação
11.
Chem Pharm Bull (Tokyo) ; 66(9): 901-906, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175750

RESUMO

Ginsenoside Rb1 is an important saponin of ginseng(s); however, Rb1, with 3-O- and 20-O-sugar moieties, has low bioavailability. Here, we report the derivatization of ginsenoside Rb1 to completely generate six types of highly bioactive minor ginsenoside Rg3 and its derivatives by FeCl3 catalysis, the reaction conditions are similar to enzymatic reaction conditions. In FeCl3 catalysis, the only 20-O-sugar-moiety of ginsenoside Rb1 was decomposed into the minor ginsenosides Rk1 and Rg5 with newly produced C-20 ethylene bands; but also hydrolyzed into 20(S)-Rg3 and 20(R)-Rg3; subsequently the C-24(25) ethylene bands of 20(S)-Rg3 and 20(R)-Rg3 were hydrated to 20(S)-25-OH-Rg3 and 20(R)-25-OH-Rg3. After separation of reaction mixture from 34 g ginsenoside-Rb1 by silica-gel-column, the 3.3 g sample I of TLC top-band consisting of Rg5 and Rk1, 8.7 g sample II of TLC middle-band consisting of 20(S)-Rg3 and 20(R)-Rg3, 3.5 g sample III of TLC bottom-band consisting of unknown product-I and -II including 20(S)-25-OH-Rg3, were obtained. The sample III consisting of unknown product-I and -II was purified by crystallization, and identified to 20(S)-25-OH-Rg3 and 20(R)-25-OH-Rg3 by HPLC-Evaporative Light Scattering Detector (ELSD) and NMR. Therefore, six types of minor-ginsenosides Rk1, Rg5, 20(S)-Rg3, 20(R)-Rg3, 20(S)-25-OH-Rg3 and 20(R)-25-OH-Rg3 were successfully prepared from ginsenoside Rb1 by FeCl3 catalysis. FeCl3 has low toxicity and is inexpensive, and the reaction conditions are similar to enzymatic reaction conditions; thus, this method is applicable to the development of ginseng-based drugs.


Assuntos
Cloretos/química , Compostos Férricos/química , Ginsenosídeos/química , Catálise , Cristalização , Ginsenosídeos/síntese química , Hidrólise , Peso Molecular
12.
Bioorg Med Chem Lett ; 28(17): 2885-2889, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30049579

RESUMO

Panaxatriol, a triterpene bearing a steroid-like structure similar to cardiac glycosides, was presumed to share the same bioactivity with cardiac glycosides, and may be a potential Na+, K+-ATPase inhibitor. In this paper, a series of panaxatriol derivatives were synthesized and evaluated for Na+, K+-ATPase inhibitory activities. The results of biological tests showed that more than half of the synthesized derivatives presented increased inhibitory activities compared with panaxatriol. Of these compounds, 13a with a 3, 4-seco skeleton showed the most potent inhibitory activity, which was equal to that of the standard drug digoxin. To understand the binding mode of the most active compound, molecular docking study of 13a with Na+, K+-ATPase was conducted. Therefore, 13a may serve as a new lead compound for the development of novel Na+, K+-ATPase inhibitors.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Inibidores Enzimáticos/farmacologia , Ginsenosídeos/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ginsenosídeos/síntese química , Ginsenosídeos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Panax/química , Folhas de Planta/química , Caules de Planta/química , ATPase Trocadora de Sódio-Potássio/metabolismo , Relação Estrutura-Atividade
13.
Molecules ; 23(6)2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29882854

RESUMO

A green solvent extraction technology involving a microwave processing method was used to increase the content of minor ginsenosides from Panax notoginseng. This article aims to investigate the optimization of preparation of the minor ginsenosides by this microwave processing method using single-factor experiments and response surface methodology (RSM), and discuss the blood-enriching activity and hemostatic activity of the extract of microwave processed P. notoginseng (EMPN) The RSM for production of the minor ginsenosides was based on a three-factor and three-level Box-Behnken design. When the optimum conditions of microwave power, temperature and time were 495.03 W, 150.68 °C and 20.32 min, respectively, results predicted that the yield of total minor ginsenosides (Y9) would be 93.13%. The actual value of Y9 was very similar to the predicted value. In addition, the pharmacological results of EMPN in vivo showed that EMPN had the effect of enriching blood in N-acetylphenylhydrazine (APH) and cyclophosphamide (CTX)-induced blood deficient mice because of the increasing content of white blood cells (WBCs) and hemoglobin (HGB) in blood. Hemostatic activity in vitro of EMPN showed that it had significantly shortened the clotting time in PT testing (p < 0.05). The hemostatic effect of EMPN was mainly caused by its components of Rh4, 20(S)-Rg3 and 20(R)-Rg3. This microwave processing method is simple and suitable to mass-produce the minor ginsenosides from P. notoginseng.


Assuntos
Células Sanguíneas/efeitos dos fármacos , Ginsenosídeos/síntese química , Ginsenosídeos/farmacologia , Química Verde/métodos , Hemostáticos/farmacologia , Micro-Ondas , Panax notoginseng/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Ciclofosfamida/toxicidade , Feminino , Ginsenosídeos/química , Hemoglobinas/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Fenil-Hidrazinas/toxicidade , Extratos Vegetais/química , Saponinas/química , Temperatura
14.
Chem Pharm Bull (Tokyo) ; 66(5): 535-540, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29515052

RESUMO

Twelve pseudo-ginsenosides were synthesized under a mild condition, via a simple three-step called acetylation, elimination-addition and saponification. The inhibitory effects of these twelve pseudo-ginsenosides were screened on the hemolysis of rabbit erythrocytes caused by 2,2'-azobis (2-amidinopropane hydrochloride) (AAPH). It was found that the IC50 values followed the sequence of (20Z) pseudo-protopanaxatriol (pseudo-PPT)<(20Z) pseudo-protopanaxadiol (pseudo-PPD)<(20Z) pseudo-Rh2<(20E) pseudo-PPT<(20E) pseudo-PPD<(20E) pseudo-Rh2<(20Z) pseudo-Rg2<(20E) pseudo-Rg2

Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Eritrócitos/efeitos dos fármacos , Ginsenosídeos/síntese química , Ginsenosídeos/farmacologia , Amidinas/antagonistas & inibidores , Amidinas/farmacologia , Animais , Antioxidantes/química , Relação Dose-Resposta a Droga , Radicais Livres/química , Ginsenosídeos/química , Hemólise/efeitos dos fármacos , Conformação Molecular , Coelhos , Estereoisomerismo , Relação Estrutura-Atividade
15.
J Org Chem ; 83(5): 2601-2610, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29431441

RESUMO

Four representative Δ20-ginsenosides, namely, ginsenosides Rh4 (1), (20E)-Rh3 (2), Rg6 (3), and Rk1 (4) from Panax Ginseng, were chemically synthesized for the first time. Dehydration of the naturally occurring 20(S)-protopanaxatriol and 20(S)-protopanaxadiol provided all types of Δ20-sapogenins, which were separated due to a judicious choice of protecting groups. The Δ20-sapogenins were then directly glycosylated with glycosyl ortho-alkynylbenzoate donors under the catalysis of Ph3PAuNTf2 as key steps. The neutral conditions of the glycosylations were crucial to prevent the acid-labile Δ20,21 double bond from isomerization.


Assuntos
Ginsenosídeos/química , Ginsenosídeos/síntese química , Catálise , Técnicas de Química Sintética , Ouro/química , Água/química
16.
Bioorg Med Chem Lett ; 27(17): 4204-4211, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28757064

RESUMO

In the current work, 13 novel panaxadiol (PD) derivatives were synthesized by reacting with chloroacetyl chloride and bromoacetyl bromide. Their in vitro antitumor activities were evaluated on three human tumor cell lines (HCT-116, BGC-823, SW-480) and three normal cells (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line-HHDPC and rat myocardial cell line-H9C2) by MTT assay. Compared with PD, the results demonstrated that compound 1e, 2d, 2e showed significant anti-tumor activity against three tumor cell lines, the IC50 value of compound 2d against HCT-116 was the lowest (3.836µM). The anti-tumor activity of open-ring compounds are significantly better than the compounds of C-25 cyclization. Compound 1f, 2f, 2g showed the strong anti-tumor activity. The IC50 value of compound 2g against BGC-823 and SW-480 were the lowest (0.6µM and 0.1µM, respectively). Combined with cytotoxicity test, the IC50 value of compound 1e, 2d, 2e are greater than 100. the open-ring compounds (1f, 2f, 2g) showed a strong toxicity. The toxicity of 1f is lower than 2f and 2g. These compounds may be useful for the development of novel antiproliferative agents.


Assuntos
Antineoplásicos/farmacologia , Ginsenosídeos/farmacologia , Halogênios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ginsenosídeos/síntese química , Ginsenosídeos/química , Halogênios/síntese química , Halogênios/química , Humanos , Conformação Molecular , Relação Estrutura-Atividade
17.
Molecules ; 22(4)2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-28387737

RESUMO

Due to the rapidly growing bacterial antibiotic-resistance and the scarcity of novel agents in development, bacterial infection is still a global problem. Therefore, new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, are urgently needed. In this paper, a series of antibacterial ocotillol-type C-24 epimers modified from natural 20(S)-protopanaxadiol were synthesized and evaluated for their antibacterial activity. According to the screening results of Gram-positive bacteria (B. subtilis 168 and MRSA USA300) and Gram-negative bacteria (P. aer PAO1 and A. baum ATCC19606) in vitro, the derivatives exhibited good antibacterial activity, particularly against Gram-positive bacteria with an minimum inhibitory concentrations (MIC) value of 2-16 µg/mL. The subsequent synergistic antibacterial assay showed that derivatives 5c and 6c enhanced the susceptibility of B. subtilis 168 and MRSA USA300 to chloramphenicol (CHL) and kanamycin (KAN) (FICI < 0.5). Our data showed that ocotillol-type derivatives with long-chain amino acid substituents at C-3 were good leads against antibiotic-resistant pathogens MRSA USA300, which could improve the ability of KAN and CHL to exhibit antibacterial activity at much lower concentrations with reduced toxicity.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Ginsenosídeos/síntese química , Ginsenosídeos/farmacologia , Antibacterianos/química , Sinergismo Farmacológico , Ginsenosídeos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
18.
Curr Aging Sci ; 10(1): 68-75, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27659265

RESUMO

BACKGROUND: Rb1 is a ginsenoside steroid glycoside found exclusively in the plant Panax ginseng. In an earlier report, we showed that Rb1 increased cell proliferation and reduced VEGF (vascular endothelial growth factor) secretion by human retinal pigment epithelial (ARPE19) cells. OBJECTIVE: In the present study, we hypothesized that chemical modification of Rb1 changes the level of VEGF secretion by ARPE19 cells. METHOD: Three derivatives of Rb1 were chemically synthesized by hydrogenation (Rb1-H2), acetylation (Rb1-Acyl), and epoxidation (Rb1-Epoxy). Structural modifications were confirmed by 1H Nuclear Magnetic Resonance (NMR) spectra and Mass Spectrometry (MS). To test the biological activity, chemically modified compounds were added to cell culture media and incubated for 72 hours at a concentration of 250 nM at 37°C. Conditioned media were collected and cells were harvested/ counted after treatment. Viable cell numbers were determined by the trypan blue dye exclusion method and VEGF levels by Enzyme-Linked Immunosorbent Assays (ELISA). RESULTS: Consistent with the prior report, results of the present study show Rb1 increased cell proliferation and decreased VEGF secretion. Similar to Rb1's effect on cell proliferation, treatment with Rb1-H2, Rb1-Acyl and Rb1-Epoxy resulted in an increase in cell numbers. In contrast to Rb1- induced decrease in VEGF secretion, treatment with Rb1-H2, Rb-Acyl and Rb1-Epoxy resulted in increased VEGF levels. CONCLUSION: Chemical modifications of the ginsenoside Rb1 significantly affect the biological activity of VEGF secretion by ARPE19 cells. Additional SAR (Structure Activity Relationship) experiments will be conducted to study the detailed mechanisms by which how specific modifications of Rb1 functional groups alter biological activities.


Assuntos
Citocinas/biossíntese , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Neovascularização de Coroide/tratamento farmacológico , Ginsenosídeos/síntese química , Humanos , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/biossíntese
19.
Bioorg Med Chem Lett ; 26(19): 4763-4768, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27561718

RESUMO

A previous study involving 25-hydroxyprotopanaxadiol (25-OH-PPD) illustrated that the anti-cancer activity increased by 1-3 times after C-3/C-12-OH was substituted by short-chain fatty acids. In addition, 25-OCH3-PPD was also one of our research interests; the unique difference in structure between 25-OH-PPD and 25-OCH3-PPD is that in C-25, the latter activity was 2-5 times higher than that of 25-OH-PPD. These data serves as the scientific basis of our continuing research. To further confirm the effect of short chain acylated and methylated products on the activity and to identify more potent, higher selectivity compounds, we modified 25-OH-PPD with a green environment-friendly and non-toxic chemical dimethyl carbonate (DMC), which plays the role of both solvent and reagent. This experiment yielded 14 derivatives. Their in vitro anti-tumor activities were tested on two different human tumor cell lines (HeLa and DU145) and one normal cell line (IOSE144) by standard MTT assay. The results showed that compounds 3, 5, 6, 10, 11, 12, and 13 exhibited higher cytotoxic activity on two cell lines, with IC50 values within the range of 1.1-12µM. Compounds 12 and 13 exhibited the highest potent activity, with IC50 values of 1.1 and 1.2µM, respectively, on HeLa cells. Antitumor activity significantly increased after the hydroxyl groups are substituted by methyl. The results of the present study may provide useful data for evaluating the structure-activity relationships of other dammarane-type sapogenins and developing new antitumor agents.


Assuntos
Antineoplásicos/síntese química , Formiatos/química , Ginsenosídeos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ginsenosídeos/farmacologia , Células HeLa , Humanos , Indicadores e Reagentes/química , Concentração Inibidora 50
20.
J Org Chem ; 81(21): 10279-10294, 2016 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-27400182

RESUMO

A total of 14 ocotillol-type ginsenosides were conveniently synthesized employing glycosylation of ocotillol sapogenin derivatives with glucosyl ortho-alkynylbenzoate donors under the promotion of a gold(I) catalyst as the key step. Relying on a rational protecting group strategy and the unexpected regioselectivity of the glycosylation of the 3,25-diol sapogenins (2a/2b, 5a/5b) for the tertiary 25-OH, mono 3-O-glucosyl ocotillol-PPD, 6-O-glucosyl ocotillol-PPT, 25-O-glucosyl ocotillol-PPD/PPT and 3,25-di-O-glucosyl ocotillol-PPD/PPT ginsenosides were prepared in which the configuration at the C-24 is either R or S.


Assuntos
Ginsenosídeos/síntese química , Cristalografia por Raios X , Ginsenosídeos/química , Glicosilação , Estrutura Molecular , Análise Espectral/métodos
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