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1.
J Agric Food Chem ; 67(28): 8020-8028, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31259548

RESUMO

In this study, a monoglucosyl rebaudioside A product was isolated from the mixture of glucosylated rebaudioside A obtained from the most reported and industrial used cyclodextrin glycosyl transferase, Toruzyme 3.0 L (CGTase, Toruzyme 3.0 L). The molecular structure of the monoglucosyl rebaudioside A was characterized using LC-MS/MS and methylation analysis combined with 1D and 2D NMR, indicating that it is 13-[(2-O-(3-α-O-D-glucopyranosyl)-ß-D-glucopyranosyl-3-O-ß-D-glucopyranosyl-ß-D-glucopyranosyl)oxy] ent-kaur-16-en-19-oic acid ß-D-glucopyranosyl ester (also known as RQ3, which naturally exists in Stevia extract as an isomer of rebaudioside D). This study may help to further understand the reaction mechanism of glucosylation of steviol glycoside assisted by Toruzyme 3.0 L in the aspect of molecule linkage pattern, and also benefit the application of the glucosylated rebaudiosides.


Assuntos
Diterpenos de Caurano/química , Glucosiltransferases/química , Glicosídeos/química , Biocatálise , Glicosilação , Isomerismo , Estrutura Molecular , Espectrometria de Massas em Tandem
2.
BMC Plant Biol ; 19(1): 274, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234787

RESUMO

BACKGROUND: miRNAs are major regulators of gene expression and have proven their role in understanding the genetic regulation of biosynthetic pathways. Stevioside and rebaudioside-A, the two most abundant and sweetest compounds found in leaf extract of Stevia rebaudiana, have been used for many years in treatment of diabetes. It has been found that the crude extract is more potent than the purified extract. Stevioside, being accumulated in higher concentration, imparts licorice like aftertaste. Thus, in order to make the sweetener more potent and palatable, there is a need to increase the intrinsic concentration of steviol glycosides and to alter the ratio of rebaudioside-A to stevioside. Doing so would significantly increase the quality of the sweeteners, and the potential to be used on a wider scale. To do so, in previous report, miRNAs associated with genes of steviol glycosides biosynthetic pathway were identified in S. rebaudiana. In continuation to that in this study, the two miRNAs (miR319g and miRStv_11) targeting key genes of steviol glycosides biosynthetic pathway were modulated and their impact was evaluated on steviol glycosides contents. RESULTS: The over-expression results showed that miRStv_11 induced, while miR319g had repressive action on its target genes. The knock-down constructs for miR319g and miRStv_11 were then prepared and it was demonstrated that the expression of anti-miR319g produced inhibitory effect on its target miRNA, resulting in enhanced expression of its target genes. On the other hand, anti-miRStv_11 resulted in down-regulation of miRStv_11 and its target gene. Further miRStv_11 and anti-miR319gwere co-expressed which resulted in significant increase in stevioside (24.5%) and rebaudioside-A (51%) contents. CONCLUSION: In conclusion, the role of miR319g and miRStv_11 was successfully validated in steviol gycosides biosynthetic pathway gene regulation and their effect on steviol gycosides contents. In this study, we found the positively correlated miRNA-mRNA interaction network in plants, where miRStv_11 enhanced the expression of KAH gene. miRNAs knock-down was also successfully achieved using antisense precursors. Overall, this study thus reveals more complex nature and fundamental importance of miRNAs in biosynthetic pathway related gene networks and hence, these miRNAs can be successfully employed to enhance the ratio of rebaudioside-A to stevioside, thus enhancing the sweetening indices of this plant and making it more palatable.


Assuntos
Diterpenos de Caurano/biossíntese , Glucosídeos/biossíntese , MicroRNAs/metabolismo , RNA de Plantas/metabolismo , Stevia/metabolismo , Diterpenos de Caurano/química , Diterpenos de Caurano/genética , Regulação da Expressão Gênica de Plantas , Técnicas de Inativação de Genes , Inativação Gênica , Glucosídeos/química , Glucosídeos/genética , MicroRNAs/genética , Folhas de Planta/química , Regiões Promotoras Genéticas , RNA de Plantas/genética , Stevia/genética , Edulcorantes/química
3.
Eur J Med Chem ; 178: 365-379, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200238

RESUMO

The biological function of the natural ent-kaurene diterpenoid isolated from genus Isodon, oridonin, has been intensively studied. However, its mechanism studies and clinical applications were hampered by its moderate biological activities. In order to enlarge the applied range of oridonin and explore its mechanism of action, a series of derivatives were designed and synthesized based on the structure of oridonin. Some of the derivatives were significantly more potent than oridonin against four cancer cell lines. Especially, the most potent compound 20 markedly inhibited the proliferation of well differentiated HepG2 and poorly differentiated PLC/PRF/5 cells, with IC50 values as low as 1.36 µM and 0.78 µM respectively, while the IC50 values of oridonin are 8.12 µM and 7.41 µM. We found that compound 20 inhibited liver cancer cell proliferation via arresting cell cycle at G1 phase. Moreover, it induced liver cancer cell apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular reactive oxygen species level and inducing the expression of apoptosis-related proteins. Furthermore, compound 20 significantly inhibited growth of PLC/PRF/5 xenograft tumors in nude mice and had no observable toxic effect. Altogether, these results indicated that compound 20 is a promising lead for liver cancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Humanos , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Eur J Med Chem ; 178: 446-457, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202992

RESUMO

Motivated by our interest in hydrogen sulfide bio-chemistry and ent-kaurane diterpenoid chemistry, 14 hydrogen sulfide donating derivatives (9, 11a-c, 12a-c, 13, 14, 16a-c and 17a-b) of ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane were designed and synthesized. Four human cancer cell lines (K562, Bel-7402, SGC-7901 and A549) and two normal cell lines (L-02 and PBMC) were selected for antiproliferative assay. Most derivatives showed more potent activities than the lead ent-kaurane oridonin. Among them, compound 12b exhibited the most potent antiproliferative activities, with IC50 values of 1.01, 0.88, 4.36 and 5.21 µM against above human cancer cell lines, respectively. Further apoptosis-related mechanism study indicated that 12b could arrest Bel-7402 cell cycle at G1 phase and induce apoptosis through mitochondria related pathway. Through Western blot assay, 12b was shown to influence the intrinsic pathway by increasing the expression of Bax, cleaved caspase-3, cytochrome c and cleaved PARP, meanwhile suppressing procaspase-3, Bcl-2, Bcl-xL and PARP.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Desenho de Drogas , Sulfeto de Hidrogênio/farmacologia , Espironolactona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Sulfeto de Hidrogênio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Espironolactona/química , Relação Estrutura-Atividade
5.
J Nat Med ; 73(4): 841-846, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31197550

RESUMO

Celastrus orbiculatus is a medicinal plant belonging to the Celastraceae family. In this survey on the secondary metabolites of plants for obtaining antitumor substances, the chemical constituents of the stems of C. orbiculatus were investigated. Nortriptonoterpene (1), a new C19-norabietane diterpenoid, together with six other known abietane-type diterpenoids (2-7) and five known kaurane-type diterpenoids (8-12) were isolated and identified from the EtOAc extract of C. orbiculatus. Their structures were elucidated on the basis of extensive spectroscopic methods, including UV, IR, HR-ESI-MS, ECD, and NMR experiments, and by comparison with literature data. Compound 1 is a new C19-norabietane diterpenoid with 19 carbons. All compounds except for 10 and 11 were isolated from C. orbiculatus for the first time. The NMR data of 9 were reported for the first time. Compounds 1, 7 and 11 showed cytotoxicities against SGC-7901 with IC50 values of 63.2, 80.9 and 56.7 µM, respectively.


Assuntos
Celastrus/química , Diterpenos de Abietano/isolamento & purificação , Diterpenos de Caurano/isolamento & purificação , Diterpenos de Abietano/química , Diterpenos de Caurano/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Plantas Medicinais/química
6.
Chem Biol Interact ; 307: 158-166, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059706

RESUMO

Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-ß1 (TGF-ß1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-ß-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-ß1-induced EMT by inhibiting TGF-ß1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.


Assuntos
Diterpenos de Caurano/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos de Caurano/química , Diterpenos de Caurano/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosforilação/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Vimentina/metabolismo
7.
Chem Biodivers ; 16(7): e1900141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087758

RESUMO

Bioguided fractionation of Xylopia sericea antiplasmodial dichloromethane leaves extract led to the isolation of (-)-7-oxo-ent-kaur-16-en-19-oic acid (C20 H28 O3 ) that was identified by a combination of 1D and 2D NMR experiments (COSY, HMBC, HSQC, HSQC-TOCSY, HSQC-NOESY and NOESY) and by X-ray crystallography. A feature to be pointed out is its (4R) configuration that was inferred from the NOE experiments (HSQC-NOESY and NOESY) and X-ray crystallography. In vitro evaluation of this rare diterpene acid against the chloroquine-resistant strain Plasmodium falciparum W2 by the PfLDH method showed it disclosed a low antiplasmodial activity and was not cytotoxic to HepG2 cells (CC50 862.6±6.7 µm) by the MTT assay. The unequivocal NMR signals assignments, the X-ray crystallographic structure, the assessment to the bioactivities and the occurrence this diterpene in X. sericea are reported here for the first time.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Caurano/farmacologia , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Xylopia/química , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos de Caurano/química , Diterpenos de Caurano/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
8.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934766

RESUMO

In this study, the influence of stevia addition and sonication processing parameters on the phenolic content and profile as well as the steviol glycosides of strawberry juice-based samples was investigated. For this purpose, three matrices-control samples of strawberry juices without green stevia powder (CS), strawberry juices with green stevia powder (JGSP), and sonicated juices with green stevia powder (SJGSP)-were prepared. For sonication purposes, different conditions regarding probe diameters (7 mm and 22 mm), amplitudes (50%, 75%, and 100%), and time (15 min, 20 min, and 25 min) were tested. The results that were obtained upon the measurement of the total phenolic content, total flavonoids, steviol glycosides, and antioxidant capacity showed significant differences according to the matrices evaluated, obtaining overall higher values in the samples with stevia added. Moreover, when sonication was evaluated, it was found that a higher amplitude (100%), a larger probe diameter (22 mm), and a longer sonication period (25 min) led to higher values. Flavones such as luteolin and apigenin were identified and quantified in JGSP and SJGSP, while they were not found in CS. Besides these phenolic compounds, kaempferol, quercetin, pyrogallic acid, 4-methylcatechol, and 4-methoxybenzoic acid were also identified and quantified. Similarly to the total phenolic compounds, total flavonoids, and total antioxidant capacity, an increased amount of these compounds was found in SJGSP, especially after using the most intense sonication conditions. Therefore, the use of sonication together with stevia added could be a useful tool to preserve strawberry juices, increasing at the same time the sweetness and the antioxidant value of the beverages.


Assuntos
Diterpenos de Caurano/farmacologia , Fragaria/química , Glucosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão , Diterpenos de Caurano/química , Flavonoides/química , Glucosídeos/química , Fenóis/química , Extratos Vegetais/química
9.
Eur J Med Chem ; 173: 15-31, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981113

RESUMO

A series of novel oridonin derivatives bearing various substituents on the 14-OH position were designed and synthesised. Their antitumour activity was evaluated in vitro against three human cancer cell lines (HCT116, BEL7402, and MCF7). Most tested derivatives showed improved anti-proliferative activity compared to the lead compound oridonin and the positive control drug 5-fluorouracil (5-Fu). Among them, compound C7 (IC50 = 0.16 µM) exhibited the most potent anti-proliferative activity against HCT116 cells; it was about 43- and 155-fold more efficacious than that of oridonin (IC50 = 6.84 µM) and 5-Fu (IC50 = 24.80 µM) in HCT116 cancer cells. Interestingly, the IC50 value of compound C7 in L02 normal cells was 23.6-fold higher than that in HCT116 cells; it exhibited better selective anti-proliferative activity and specificity than oridonin and 5-Fu. Furthermore, compound C7 possibly induced cell cycle arrest and apoptosis by regulating the p53-MDM2 signalling pathway. Notably, C7 displayed more significant suppression of tumour growth than oridonin in colon tumour xenograft models where the tumour growth inhibition rate was 85.82%. Therefore, compound C7 could be a potential lead compound for the development of a novel antitumour agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo
10.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003485

RESUMO

Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance, Isodon (formerly Rabdosia), a genus of the Lamiaceae (formerly Labiatae) family, has been reported as a rich source of natural diterpenes. In the current study, we evaluated the in vitro anti-proliferative property of flexicaulin A (FA), an Isodon diterpenoid with an ent-kaurane structure, in human carcinoma cells, by means of cell viability assay, flow cytometric assessment, quantitative polymerase chain reaction array, Western blotting analysis, and staining experiments. Subsequently, we validated the in vivo antitumor efficacy of FA in a xenograft mouse model of colorectal carcinoma. From our experimental results, FA appears to be a potent antitumor molecule, since it significantly attenuated the proliferation of human colorectal carcinoma cells in vitro and restricted the growth of corresponsive xenograft tumors in vivo without causing any adverse effects. Regarding its molecular mechanism, FA considerably elevated the expression level of p21 and induced cell cycle arrest in the human colorectal carcinoma cells. While executing a non-apoptotic mechanism, we believe the antitumor potential of FA opens up new horizons for the therapy of colorectal malignancy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Diterpenos de Caurano/farmacologia , Isodon/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Diterpenos de Caurano/química , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Camundongos , Plantas Medicinais/química , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Ativadas por p21/genética
11.
Eur J Med Chem ; 171: 169-179, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30921757

RESUMO

A series of enmein-type diterpenoid amino acid ester derivatives (14-22) were designed and synthesized according to l-alanine-(14-oridonin) ester trifluoroacetate (clinical candidate HAO472). Their antiproliferative activities were tested against SGC-7901, Bel-7402, HL-60, PC-3, A549 and K562 cancer cell lines and L-02 normal liver cells. The results showed that compound 19 possessed the most potent cytotoxicity with IC50 s at sub-micromolar level against human hepatoma Bel-7402 and chronic myelogenous leukemia K562 cells and more potent than l-alanine-(14-oridonin) ester (23). More importantly, 19 displayed 70-fold less cytotoxicity than parent 3 (IC50 = 25.47 µM) against L-02 cells, which exhibited certain selectivity. Further mechanism study in Bel-7402 cells revealed that 19 could induce apoptosis, G1 phase cell cycle arrest and mitochondrial dysfunction. Western blot results of caspase-3, Bax and cytochrome c upregulation and pro-caspase-3, Bcl-2 and Bcl-xL downregulation confirmed the intrinsic pathways. Overall, these data collectively demonstrated the high efficiency and selectivity of 19, l-phenylalanine-enmein-type diterpenoid ester, which inspires further and effective application as a potential antitumor candidate.


Assuntos
Alanina/análogos & derivados , Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Diterpenos/farmacologia , Desenho de Drogas , Alanina/síntese química , Alanina/química , Alanina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
12.
J Agric Food Chem ; 67(8): 2255-2264, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30729785

RESUMO

In this work, the interaction of the soybean Bowman-Birk inhibitor (BBI) with stevioside (STE) was studied by stopped-flow-fluorescence and molecular docking. STE's inactivation of protease-inhibitor activities in soymilk and the influence of STE addition on the sensory character of soymilk were also evaluated. The results indicate that STE binds BBI with a binding constant ( Ka) of 3.38 × 105 L mol-1 to form a 1:1 complex. The docking study reveals that two hydrogen bonds are formed between the side-chain of Lys16 (reactive site 1) of BBI and the glucose-ring hydroxyl groups of STE, which may block BBI from contacting trypsin and thus deactivate the trypsin-inhibitor activity (TIA) of BBI. Moreover, the residual TIA in soymilk could also be inactivated by STE. A mixture of 159 mg/L STE and 60 g/L sucrose could be used for sweetening soymilk without affecting the sensory characteristics when compared to a reference product sweetened with 9% sucrose.


Assuntos
Diterpenos de Caurano/química , Glucosídeos/química , Leite de Soja/química , Soja/química , Edulcorantes/química , Inibidor da Tripsina de Soja de Bowman-Birk/química , Aditivos Alimentares , Cinética , Simulação de Acoplamento Molecular
13.
Molecules ; 24(4)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769819

RESUMO

Steviosides, rebaudiosides and their analogues constitute a major class of naturally occurring biologically active diterpene compounds. The wide spectrum of pharmacological activity of this group of compounds has developed an interest among medicinal chemists to synthesize, purify, and analyze more selective and potent isosteviol derivatives. It has potential biological applications and improves the field of medicinal chemistry by designing novel drugs with the ability to cope against resistance developing diseases. The outstanding advancement in the design and synthesis of isosteviol and its derivative has proved its effectiveness and importance in the field of medicinal chemical research. The present review is an effort to integrate recently developed novel drugs syntheses from isosteviol and potentially active pharmacological importance of the isosteviol derivatives covering the recent advances.


Assuntos
Química Farmacêutica , Diterpenos de Caurano/química , Diterpenos/química , Diterpenos/síntese química , Diterpenos/uso terapêutico , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/uso terapêutico , Desenho de Drogas , Humanos , Relação Estrutura-Atividade
14.
Molecules ; 24(1)2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609810

RESUMO

Adenanthin, a natural ent-kaurane diterpenoid extracted from the herb Isodon adenantha, has been reported to increase intracellular reactive oxygen species in leukemic and hepatocellular carcinoma cells. However, the function and mechanism of the compound in adipogenesis and the development of obesity is still unknown. In this study, we demonstrated that adenanthin inhibited adipogenesis of 3T3-L1 and mouse embryonic fibroblasts, and the underlying mechanism included two processes: a delayed mitotic clonal expansion via G0/G1 cell cycle arrest by inhibiting the RB-E2F1 signaling pathway and a reduced C/EBPß signaling by inhibiting the expression and activity of C/EBPß during mitotic clonal expansion. Furthermore, adenanthin significantly reduced the growing body weight and adipose tissue mass during high-fat diet-inducing obesity of mice, indicating the beneficial effects of adenanthin as a potential agent for prevention of obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Diterpenos de Caurano/isolamento & purificação , Diterpenos de Caurano/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Isodon/química , Obesidade/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica , Diterpenos de Caurano/química , Medicamentos de Ervas Chinesas/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Masculino , Camundongos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismo
15.
Int J Nanomedicine ; 14: 557-571, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666114

RESUMO

Purpose: Rebaudioside A (RA) has nanocarrier characteristics that allow it to self-assemble into micelles in aqueous solutions. The purpose of this study was to determine if a self-nanomicellizing solid dispersion based on RA could be utilized as an oral nano-drug delivery system. Materials and methods: Curcumin (Cur) served as a model hydrophobic drug, and a Cur-loaded self-nanomicellizing solid dispersion based on RA (RA-Cur) was formulated. The properties of RA-Cur in the solid state and in aqueous solution were characterized. The antioxidant activity and mechanism of RA-Cur endocytosis were also investigated. The pharmacokinetics, biodistribution in the intestinal tract, and anti-inflammation properties were also evaluated in vivo. Results: RA-Cur could be easily fabricated, and it self-assembled into ultrasmall micelles (particle size ~4 nm) in a homogeneous distribution state (polydispersity index <0.2) when dissolved in water. Cur was readily encapsulated into RA micelles and this improved its water solubility (to 14.34±1.66 mg/mL), as well as its in vitro release and membrane permeability. The antioxidant activities of Cur in RA-Cur were also significantly improved. Biodistribution in the intestinal tract confirmed a significant enhancement of Cur absorption in the duodenum, jejunum, and ileum by encapsulation in RA-Cur, and the absorption of RA-Cur was governed by mixed transcytosis mechanisms. Pharmacokinetic tests of RA-Cur in rats revealed a dramatic 19.06-fold enhancement of oral bioavailability when compared to free Cur. More importantly, oral administration of RA-Cur could efficiently ameliorate ulcerative colitis in a mouse model induced by dextran sodium sulfate. Conclusion: Self-nanomicellizing solid dispersions based on RA have great potential as novel oral nano-drug delivery systems for hydrophobic drugs such as Cur.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colite/tratamento farmacológico , Curcumina/administração & dosagem , Diterpenos de Caurano/química , Sistemas de Liberação de Medicamentos , Micelas , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Colite/induzido quimicamente , Curcumina/química , Curcumina/farmacocinética , Sulfato de Dextrana/toxicidade , Masculino , Camundongos , Ratos , Distribuição Tecidual
16.
Biomolecules ; 9(1)2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646526

RESUMO

Zero-calorie high-intensity sweeteners from natural sources perform very well in the market place. This has encouraged food scientists to continue the effort to search for novel natural ingredients to satisfy consumer demand. Rebaudioside C (reb C) is the third most prevalent steviol glycoside in the leaves of the Stevia rebaudiana Bertoni plant, but has limited applications in food and beverage products due to its low sweetness and high lingering bitterness compared to other major steviol glycosides, such as rebaudioside A (reb A). Here we present a new enzyme modification strategy to improve the taste profile of reb C by using Cargill's propriety enzyme and sucrose as a glucose donor. A novel α-1→6-glucosyl reb C derivative was produced and its structure was elucidated by mass spectrometry and NMR spectroscopy. Sensory analysis demonstrated that this new reb C derivative has improved sweetness, reduced bitterness, and enhanced solubility in water.


Assuntos
Diterpenos de Caurano/biossíntese , Glicosiltransferases/metabolismo , Oligossacarídeos/biossíntese , Edulcorantes/química , Cromatografia Líquida de Alta Pressão , Diterpenos de Caurano/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Oligossacarídeos/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Stevia/química , Stevia/metabolismo , Edulcorantes/metabolismo
17.
Molecules ; 23(12)2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30563165

RESUMO

We have designed and synthesized 6 ent-Kaurane-type diterpenoid derivatives containing α,ß-unsaturated ketone moieties. In vitro, activity was evaluated against three human tumor cell lines and a rat myogenic cell line (HepG2, NSCLC-H292, SNU-1040, L6) by MTT assay. All the tested compounds exhibited comparable or higher activity than DDP and eriocalyxin B. Compounds 16, 17 and 18 are promising anti-tumor leads due to their cytotoxic potencies and higher selectivity, with SI values of 161.06, 47.80 and 128.20, respectively.


Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Diterpenos de Caurano/química , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia
18.
Chem Pharm Bull (Tokyo) ; 66(11): 1057-1064, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381658

RESUMO

From the leaves of Diospyros maritima, collected from Okinawa Island, eight new glycosides based on ent-kaurane-type diterpenoids, entitled diosmariosides A-H, were isolated. The absolute structure of diosmarioside E (5) was determined by X-ray crystallographic analysis. The structure of diosmarioside H was elucidated to be a dimeric compound between diosmarioside A and a sugeroside through a ketal bond. An assay of cytotoxicity towards the lung adenocarcinoma (A549) cell line was performed. Among the compounds isolated, only diosmarioside D (4) and sugeroside 9 showed strong activity. The anti-microbial activity toward multi-drug resistant strains was also determined, but no activity was observed.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Diospyros/química , Diterpenos de Caurano/farmacologia , Glicosídeos/farmacologia , Folhas de Planta/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos de Caurano/química , Diterpenos de Caurano/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Japão , Testes de Sensibilidade Microbiana , Modelos Moleculares
19.
Eur J Med Chem ; 157: 1249-1263, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30193221

RESUMO

As a continuation of our research on developing potent and potentially safe anti-proliferative agents, two series of novel Jiyuan Oridonin A-1,2,3-triazole-azole hybrids were designed, synthesized and evaluated for their anti-proliferative activity against four selected cancer cell lines (MGC-803, MCF-7, PC-3, Eca-109). Some compounds with better growth inhibitory effects were chosen to carry out further studies in A549 and SMMC-7721. Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, the most active agent 8b showed high potency against human cancer cells with IC50 ranging from 0.2 ±â€¯0.0 to 5.0 ±â€¯0.9 µM. Cellular mechanism studies elucidated compound 8b arrests cell cycle at G1 phase and induce a strong apoptotic response in SMMC-7721 cells. Furthermore, 8b could inhibit the colony formation and migration via Wnt signaling pathway in SMMC-7721 cells. For all these reasons, compound 8b holds promising potential as anti-proliferative agent.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais Cultivadas
20.
Int J Mol Sci ; 19(8)2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104472

RESUMO

Although many attempts have been made to improve the efficacy of radiotherapy to treat cancer, radiation resistance is still an obstacle in lung cancer treatment. Oridonin is a natural compound with promising antitumor efficacy that can trigger cancer cell death; however, its direct cellular targets, efficacy as a radiosensitizer, and underlying mechanisms of activity remain unclear. Herein, we report that oridonin exhibits additive cytotoxic and antitumor activity with radiation using the H460 non-small cell lung cancer cell lines. We assessed the effect of oridonin by proliferation, clonogenic, reactive oxygen species (ROS) production, DNA damage, and apoptosis assays. In vitro, oridonin enhanced the radiation-induced inhibition of cell growth and clonogenic survival. Oridonin also facilitated radiation-induced ROS production and DNA damage and enhanced apoptotic cell death. In vivo, the combination of oridonin and radiation effectively inhibited H460 xenograft tumor growth, with higher caspase-3 activation and H2A histone family member X (H2AX) phosphorylation compared with that of radiation alone. Our findings suggest that oridonin possesses a novel mechanism to enhance radiation therapeutic responses by increasing DNA damage and apoptosis. In conclusion, oridonin may be a novel small molecule to improve radiotherapy in non-small cell lung cancer.


Assuntos
Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Radiação Ionizante , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos da radiação , Diterpenos de Caurano/química , Diterpenos de Caurano/uso terapêutico , Feminino , Histonas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Radiossensibilizantes/química , Radiossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transplante Heterólogo
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