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1.
Mini Rev Med Chem ; 20(1): 66-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31556858

RESUMO

Plants from the genus Hypericum, one genus of the Hypericaceae family, have attracted a lot of attention for their potential pharmaceutical applications. Most of the studies in the literature focus on H. perforatum L. (common St. John's wort), whose complex spectrum of bioactive compounds makes this species one of the top herbal remedies and supplements in the world. It is also important to compare the studies on other Hypericum species, both from the phytochemical and biological point of view. The aim of this review was to provide an update of most recent studies about biological investigations of plants belonging to Hypericum genus. The metabolic profiles of Hypericum spp. were also discussed in order to present a spectrum of secondary metabolites not previously identified in this genus.


Assuntos
Hypericum/metabolismo , Metaboloma , Extratos Vegetais/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas/métodos , Humanos , Hypericum/química , Metabolômica/métodos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Metabolismo Secundário
2.
Braz J Med Biol Res ; 52(11): e8657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664305

RESUMO

Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Neoplasias da Mama/metabolismo , Proteína HMGB1/metabolismo , Células MCF-7/metabolismo , MicroRNAs/metabolismo , Paclitaxel/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/genética , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGB1/genética , Humanos , MicroRNAs/genética , Paclitaxel/uso terapêutico , Regulação para Cima/genética
3.
Phys Chem Chem Phys ; 21(42): 23501-23513, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617551

RESUMO

YIV-906 (formally PHY906, KD018) is a four-herb formulation that is currently being developed to improve the therapeutic index and ameliorate the side effects of many chemotherapeutic drugs including sorafenib, irinotecan, and capecitabine. However, as a promising anti-cancer adjuvant, the molecular mechanism of action of YIV-906 remains unrevealed due to its multi-component and multi-target features. Since YIV-906 has been shown to induce apoptosis and autophagy in cancer cells through modulating the negative regulators of ERK1/2, namely DUSPs, it is of great interest to elucidate the key components that cause the therapeutic effect of YIV-906. In this work, we investigated the mechanism of YIV-906 inhibiting DUSPs, using a broad spectrum of molecular modelling techniques, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. In total, MD simulations and binding free energy calculations were performed for 99 DUSP-ligand complexes. We found that some herbal components or their metabolites could inhibit DUSPs. Based on the docking scores and binding free energies, the sulfation and glucuronidation metabolites of the S ingredient in YIV-906 play a leading role in inhibiting DUSPs, although several original herbal chemicals with carboxyl groups from the P and Z ingredients also make contributions to this inhibitory effect. It is not a surprise that the electrostatic interaction plays the dominant role in the ligand binding process, given the fact that several charged residues reside in the binding pockets of DUSPs. Our MD simulation results demonstrate that the sulfate moieties and carboxyl moieties of the advantageous ligands from YIV-906 can occupy the enzymes' catalytic sites, mimicking the endogenous phosphate substrates of DUSPs. As such, the ligand binding can inhibit the association of DUSPs and ERK1/2, which in turn reduces the dephosphorylation of ERK1/2 and causes cell cycle arrest in the tumor. Our modelling study provides useful insights into the rational design of highly potent anti-cancer drugs targeting DUSPs. Finally, we have demonstrated that multi-scale molecular modelling techniques are able to elucidate molecular mechanisms involving complex molecular systems.


Assuntos
Antineoplásicos Fitogênicos/química , Medicamentos de Ervas Chinesas/química , Antineoplásicos Fitogênicos/metabolismo , Sítios de Ligação , Domínio Catalítico , Medicamentos de Ervas Chinesas/metabolismo , Fosfatases de Especificidade Dupla/antagonistas & inibidores , Fosfatases de Especificidade Dupla/metabolismo , Humanos , Ligantes , Proteína Quinase 3 Ativada por Mitógeno/química , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Termodinâmica
4.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540428

RESUMO

Cytochrome P450 2C8 (CYP2C8) epoxygenase is responsible for the metabolism of over 60 clinically relevant drugs, notably the anticancer drug Taxol (paclitaxel, PAC). Specifically, there are naturally occurring polymorphisms, CYP2C8*2 and CYP2C8*3, that display altered PAC hydroxylation rates despite these mutations not being located in the active site. Herein, we demonstrate that these polymorphisms result in a greater uncoupling of PAC metabolism by increasing the amount of hydrogen peroxide formed per PAC turnover. Anaerobic stopped-flow measurements determined that these polymorphisms have altered first electron transfer kinetics, compared to CYP2C8*1 (wildtype), that suggest electron transfer from cytochrome P450 reductase (CPR) is disfavored. Therefore, these data demonstrate that these polymorphisms affect the catalytic cycle of CYP2C8 and suggest that redox interactions with CPR are disrupted.


Assuntos
Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C8/metabolismo , Polimorfismo de Nucleotídeo Único , Antineoplásicos Fitogênicos/metabolismo , Transporte de Elétrons , Humanos , Hidroxilação , Modelos Moleculares , Oxirredução , Paclitaxel/metabolismo
5.
Comput Biol Chem ; 83: 107112, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31480006

RESUMO

Prostate cancer is a common cause of death in men and a novel treating methods should be developed. In order to find a new drug for prostate cancer, a series of novel conformationally constrained analogues of (+)-goniofufurone and 7-epi-(+)-goniofufurone, as well as the newly synthesized styryl lactones containing the cinnamic acid ester groups were evaluated for in vitro cytotoxicity against prostate cancer cell (PC-3). Furthermore, prediction of physicochemical characteristics and drugability as well as in silico ADME-Tox tests of investigated compounds were performed. The 3D-QSAR model was established using the comparative molecular field analysis method. According to obtained results, the tricyclic compounds 9 and 10 had the highest potency with IC50 < 20 µM. Evaluation of structural features through 3D-QSAR model identified steric field feature on the cinnamic acid ester groups at C-7 as a crucial for the cytotoxic activity. This research suggests that most of the analysed compounds have desirable properties for drug candidates and high potential in drug development, which recommend them for further research in treatment of prostate cancer. Furthermore, obtained 3D-QSAR model is able to successfully identify styryl lactones that have significant cytotoxic activity and provide information for screening and design of novel inhibitors against PC-3 cell line that could be used as drugs in treatment of the prostate cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Lactonas/farmacologia , Relação Quantitativa Estrutura-Atividade , Estirenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/química , Lactonas/metabolismo , Modelos Moleculares , Células PC-3 , Estirenos/química , Estirenos/metabolismo
6.
Food Chem Toxicol ; 133: 110800, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479710

RESUMO

The stem bark of Calophyllum depressinervosum and Calophyllum buxifolium were extracted and examined for their antioxidant activities, together with cytotoxicity towards human cancer cells. The methanol extract of C. depressinervosum exhibited good DPPH and NO scavenging effects. The strongest BCB inhibition and FIC effects were shown by dichloromethane and ethyl acetate extracts of both species. Overall, DPPH, FRAP and FIC assays showed strong correlation with TPC. For cytotoxicity, hexane extract of C. depressinervosum possessed the strongest anti-proliferative activities towards SNU-1 cells while the hexane extract of C. buxifolium showed the strongest activity towards LS-174T and K562 cells with the IC50 values ranging from 7 to 17 µg/mL. The purification of plant extracts afforded eight xanthones, ananixanthone (1), caloxanthone B (2), caloxanthone I (3), caloxanthone J (4) xanthochymone B (5), thwaitesixanthone (6), 1,3,5,6-tetrahydroxyxanthone (7) and dombakinaxanthone (8). All the xanthones, except 1 were reported for the first time from both Calophyllum species. The xanthones were examined for their cytotoxic effect against K562 leukemic cells. Compounds 1 and 2 showed strong cytotoxicity with the IC50 values of 2.96 and 1.23 µg/mL, respectively. The molecular binding interaction of 2 was further investigated by performing molecular docking study with promising protein receptor Src kinase.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Calophyllum/química , Extratos Vegetais/farmacologia , Xantonas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Ligação Proteica , Xantonas/química , Xantonas/metabolismo , Quinases da Família src/química , Quinases da Família src/metabolismo
7.
Nutrients ; 11(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374888

RESUMO

Breast cancer is one of the most common and malignant cancers among females worldwide. Several epidemiological studies have indicated the inverse correlation between the intake of whole grains and the incidence of breast cancer. Whole grains are the most fundamental and important food source of bioactive phytochemicals, which have well-defined roles in the management of each stage of breast carcinogenesis. To better understand the value of whole grains in future prevention and treatment of breast cancer, the effects and possible mechanisms of six different whole grain cereals, which are the most commonly consumed throughout the world, are introduced in the current review. Moreover, the bioactive compounds extracted from whole grains are adequately formulated and the underlying mechanism of action is illustrated. In addition, the present limitations and future perspective of whole grain consumption for breast cancer are also concluded. The objective of this review is to promote the development of nutraceutical and functional food from whole grains and its application for reducing the risk of breast cancer.


Assuntos
Anticarcinógenos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/dietoterapia , Neoplasias da Mama/prevenção & controle , Valor Nutritivo , Comportamento de Redução do Risco , Grãos Integrais , Animais , Anticarcinógenos/metabolismo , Antineoplásicos Fitogênicos/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Fatores de Proteção , Recomendações Nutricionais , Medição de Risco , Fatores de Risco , Grãos Integrais/metabolismo
8.
Molecules ; 24(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426477

RESUMO

Ginsenoside Ro (Ro), a major saponin derived and isolated from Panax ginseng C.A. Meyer, exerts multiple biological activities. However, the anti-tumour efficacy of Ro remains unclear because of its poor in vitro effects. In this study, we confirmed that Ro has no anti-tumour activity in vitro. We explored the anti-tumour activity of Ro in vivo in B16F10 tumour-bearing mice. The results revealed that Ro considerably suppressed tumour growth with no significant side effects on immune organs and body weight. Zingibroside R1, chikusetsusaponin IVa, and calenduloside E, three metabolites of Ro, were detected in the plasma of Ro-treated tumour-bearing mice and showed excellent anti-tumour effects as well as anti-angiogenic activity. The results suggest that the metabolites play important roles in the anti-tumour efficacy of Ro in vivo. Additionally, the haemolysis test demonstrated that Ro has good biocompatibility. Taken together, the findings of this study demonstrate that Ro markedly suppresses the tumour growth of B16F10-transplanted tumours in vivo, and its anti-tumour effects are based on the biological activity of its metabolites. The anti-tumour efficacy of these metabolites is due, at least in part, to its anti-angiogenic activity.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Melanoma Experimental/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Biotransformação , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacocinética , Hemólise/efeitos dos fármacos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/farmacologia , Panax/química , Extratos Vegetais/química , Saponinas/metabolismo , Saponinas/farmacocinética , Neoplasias Cutâneas/patologia
9.
Int J Mol Sci ; 20(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426351

RESUMO

The plant Ophiorrhiza pumila produces camptothecin (CPT), a kind of terpene indole alkaloid (TIAs) that has been widely used in treatment of cancer. Tryptophan-arginine-lysine-tyrosine (WRKY) transcription factors have been reported to play important roles in plant metabolism and development. In this study, a novel WRKY transcription factor named OpWRKY3 was isolated from O. pumila, with full-length open reading frame (ORF) of 1128 bp, encoding 375 amino acids. Phylogenetic tree analysis revealed that OpWRKY3 shared the highest homology with VvWRKY30, and it is a significant feature belonging to group III. OpWRKY3 was responsive to various treatments, including gibberellin (GA3), methyl jasmonate (MJ), acetylsalicylic acid (ASA), salicylic acid (SA), and abscisic acid (ABA). Besides, OpWRKY3 is expressed predominantly in stems. Subcellular localization analysis showed that OpWRKY3 localized in the nucleus. The biomass of OpWRKY3-SRDX transgenic hairy roots (S line) was visibly suppressed, while there were slight changes between overexpression of the OpWRKY3 line (OE line) and the control. In addition, the concentration and total production of camptothecin precursors including loganin and secologanin were significantly changed in both OE and S lines while total production of CPT was significantly changed in most transgenic lines. Thus, the present work revealed that OpWRKY3 may act as a regulator in the growth and development of O. pumila, and in production of camptothecin and its precursors.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Camptotecina/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Rubiaceae/metabolismo , Fatores de Transcrição/metabolismo , Vias Biossintéticas , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Plantas/genética , Raízes de Plantas/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Rubiaceae/genética , Fatores de Transcrição/genética
10.
J Food Sci ; 84(8): 2347-2356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313311

RESUMO

This study determined the effects of blueberry fermentation by Lactobacillus plantarum on antioxidant and anticancer activities. The fermented blueberries extracted with 80% ethanol (FBE) showed increased superoxide dismutase-like activity, increased scavenging of DPPH and alkyl radicals, and increased antiproliferative activity against human cervical carcinoma HeLa cells by inducing apoptosis. Seven representative phenolic compounds (malvidin 3-O-glucopyranoside, gallic acid, protocatechuic acid, catechol, chlorogenic acid, syringic acid, and epigallocatechin) in FBE were measured by high-performance liquid chromatography at different fermentation times. The content of each phenolic compound in the FBE was dependent on the fermentation period. Protocatechuic acid and catechol levels increased significantly with fermentation time. Of these three major compounds (protocatechuic acid, catechol, and chlorogenic acid), catechol showed the most significant anticancer activity when HeLa cells were treated with each of these three compounds alone or mixed in various ratios. Pearson's product-moment correlation analysis revealed that the increases in antioxidant and anticancer activities following blueberry fermentation were positively correlated with the phenolic acids present in FBE. PRACTICAL APPLICATION: Blueberries fermented with a tannase-producing lactic acid bacteria (LAB), Lactobacillus plantarum showed higher antioxidant activities and antiproliferative activities against human cervical carcinoma HeLa cells than did raw blueberries. L. plantarum fermentation biotransformed blueberry polyphenols into active phenol metabolites with strong antioxidant and antiproliferative activities. Our results suggest that fermented blueberries are rich in phenolic acids, which are a promising source of natural antioxidants and anticancer drugs and can be used as additives in food, pharmaceuticals, and cosmetic preparations.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Mirtilos Azuis (Planta)/química , Lactobacillus plantarum/metabolismo , Fenóis/química , Fenóis/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Mirtilos Azuis (Planta)/microbiologia , Cromatografia Líquida de Alta Pressão , Fermentação , Células HeLa , Humanos , Fenóis/farmacologia
11.
Biomater Sci ; 7(9): 3683-3692, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31361291

RESUMO

Synergistic cancer starvation/ROS-mediated/chemo-therapy is developed through a cascade reaction with enzyme glucose oxidase (GOX) modified on the surface of an Fe-based metal organic framework (MOF(Fe)) and drug camptothecin (CPT) loaded into the cavities of MOF(Fe). Once internalized by tumor cells, GOX catalyzes endogenous glucose into hydrogen peroxide (H2O2) and gluconic acid (H+) enabling starvation therapy through choking off energy (glucose) supply. Meanwhile, the acidic micro-environment of tumor enhanced by the generated H+ degrades the MOF(Fe) simultaneously releasing CPT for chemotherapy and Fe3+, catalyzing H2O2 into one of the strongest reactive oxygen species (ROS) ˙OH enabling ROS-mediated therapy. Both in vitro and in vivo results show remarkable tri-modal synergistic anticancer effects. This work may shed some light on the development of novel multi-modal cancer therapies without any external intervention.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Cloretos/farmacologia , Compostos Férricos/farmacologia , Glucose Oxidase/metabolismo , Estruturas Metalorgânicas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Biocatálise , Camptotecina/química , Camptotecina/metabolismo , Proliferação de Células/efeitos dos fármacos , Cloretos/química , Cloretos/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Férricos/química , Compostos Férricos/metabolismo , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Phytochemistry ; 165: 112051, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31234093

RESUMO

Parmelia Acharius is one of the most representative genera within Parmeliaceae family which is the largest and the most widespread family of lichen-forming fungi. Parmelia lichens present a medium to large foliose thallus and they are distributed from the Artic to the Antartic continents, being more concentrated in temperate regions. According to its current description, the genus encompasses up to 41 different species and it is phylogenetically located within the Parmelioid clade (the largest group in the family). Interestingly, some of its species are among the most common epiphytic lichens in Europe such as Parmelia sulcata Taylor and Parmelia saxatilis (L.) Ach. The present work aims at providing a complete overview of the existing knowledge on the genus, from general concepts such as taxonomy and phylogeny, to their ecological relevance and biological interest for pharmaceutical uses. As reported, Parmelia lichens arise as valuable tools for biomonitoring environmental pollution due to their capacity to bioaccumulate metal elements and its response to acid rain. Moreover, they produce a wide array of specialized products/metabolites including depsides, depsidones, triterpenes and dibenzofurans, which have been suggested to exert promising pharmacological activities, mainly antimicrobial, antioxidant and cytotoxic activities. Herein, we discuss past and recent data regarding to the phytochemical characterization of more than 15 species. Even though the knowledge is still scarce in comparsion to other groups of organisms such as higher plants and other non-lichenized fungi. Reviewed works suggest that Parmelia lichens are worthy of further research for determining their actual possibilities as sources of bioactive compounds with potential therapeutic applications.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Parmeliaceae/química , Compostos Fitoquímicos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Humanos , Estrutura Molecular , Filogenia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo
14.
J Pharm Biomed Anal ; 172: 26-32, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31022613

RESUMO

We have developed a high performance liquid chromatography mass spectrometry method for quantitating paclitaxel and its 6-alpha-OH and 3-para-OH metabolites in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 µm, 2 mm × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000Q with electrospray, positive-mode ionization. The assay was linear from 10-10,000 ng/mL for paclitaxel and 1-1000 ng/mL for both metabolites and proved to be accurate (94.3-110.4%) and precise (<11.3%CV). Recovery from plasma was 59.3-91.3% and matrix effect was negligible (-3.5 to 6.2%). Plasma freeze thaw stability (90.2-107.0%), stability for 37 months at -80 °C (89.4-112.6%), and stability for 4 h at room temperature (87.7-100.0%) were all acceptable. This assay will be an essential tool to further define the metabolism and pharmacology of paclitaxel and metabolites in the clinical setting. The assay may be utilized for therapeutic drug monitoring of paclitaxel and may also reveal the CYP2C8 and CYP3A4 activity phenotype of patients.


Assuntos
Antineoplásicos Fitogênicos/sangue , Coleta de Amostras Sanguíneas/métodos , Monitoramento de Medicamentos/métodos , Paclitaxel/sangue , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Clínicos Fase I como Assunto , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Estabilidade de Medicamentos , Humanos , Paclitaxel/metabolismo , Paclitaxel/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
15.
Org Lett ; 21(5): 1534-1537, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775925

RESUMO

Garsubelone A (1), the first dimeric polycyclic polyprenylated acylphloroglucinols type metabolite featuring a complicated 6/6/6/6/6/6/6 heptacyclic architecture containing 10 stereogenic centers, was isolated from Garcinia subelliptica. Biogenetically, this compound was constructed by the plausible monomeric precursor, garsubelone B (2) and secohyperforin, via a key Diels-Alder cycloaddition to form an unique 2-oxabicyclo[3.3.1]nonane core. Their structures and absolute configurations were determined by comprehensive spectroscopic and X-ray diffraction techniques. The cytotoxic activities of these isolates were also evaluated.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Garcinia/química , Floroglucinol/análogos & derivados , Compostos Policíclicos/química , Compostos Policíclicos/metabolismo , Terpenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Floroglucinol/química , Compostos Policíclicos/isolamento & purificação , Difração de Raios X
16.
Nanoscale ; 11(4): 1847-1855, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30637420

RESUMO

The starting hypothesis for this work was that microwave synthesis could enable the rapid assembly of polymers into size-specific nanoparticles (NPs). The Zapped Assembly of Polymeric (ZAP) NPs was initially realized using poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) block copolymers and distinct microwave reaction parameters. A library of polymeric NPs was generated with sizes ranging from sub-20 nm to 350 nm and low polydispersity. Select ZAP NPs were synthesized in 30 seconds at different scales and concentrations, up to 200 mg and 100 mg mL-1, without substantial size variation. ZAP NPs with diameters of 25 nm, 50 nm, and 100 nm were loaded with the chemotherapeutic paclitaxel (PXL), demonstrated unique release profiles, and exhibited dose-dependent cytotoxicity similar to Taxol. Incorporation of d-alpha tocopheryl polyethylene glycol succinate (TPGS) and PLGA33k allowed for the production of a sub-40 nm NP with an exceptionally high loading of PXL (12.6 wt%, ca. 7 times the original NP) and a slower release profile. This ZAP NP platform demonstrated scalable, flexible, and tunable synthesis with potential toward clinical scale production of size-specific drug carriers.


Assuntos
Antineoplásicos Fitogênicos/química , Portadores de Fármacos/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Células HeLa , Humanos , Micro-Ondas , Paclitaxel/química , Paclitaxel/farmacologia , Tamanho da Partícula
17.
Arch Biochem Biophys ; 663: 165-172, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30653963

RESUMO

DNA topoisomerases are key enzyme responsible for modulating the topological state of the DNA by breaking and rejoining of DNA strand. Characterization of a Gly717Asp mutation in the human topoisomerase was performed using several catalytic assays. The mutant enzyme was shown to have comparable cleavage and fast religation rate as compared to the wild-type protein. Addition of the anticancer drug camptothecin significantly reduced the religation step. The simulative approaches and analysis of the cleavage/religation equilibrium indicate that the mutation is able to modify the architecture of the drug binding site, increasing the persistence of the drug for the enzyme-DNA covalent complex. Taken together these results indicate that the structure modification of the drug binding site is the key reason for the increasing CPT persistence and furthermore provide the possibility for new anti-cancer drug discovery.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ácido Aspártico/química , Camptotecina/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Glicina/química , Mutação , Antineoplásicos Fitogênicos/metabolismo , Sítios de Ligação , Camptotecina/metabolismo , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Cinética , Proteólise
18.
Nanoscale ; 11(9): 3814-3826, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30600823

RESUMO

In cancer therapy, chemotherapeutic drugs frequently encounter multidrug resistance (MDR) induced by the overexpression of drug transporters such as P-glycoprotein (P-gp). Herein, in order to overcome MDR and improve the effectiveness of chemotherapy, we developed a novel pH-sensitive charge-reversal and NO generation liposomal system by modifying a pH-sensitive polymer (PEG-PLL-DMA) on the surface of cationic liposomes for delivering a NO donor (DETA NONOate) and a chemotherapy drug (paclitaxel, PTX) into MDR cells. The proposed liposomal system (PTX/NO/DMA-L) exhibited a distinctive charge-reversal capacity, which was negatively charged under physiological conditions (pH 7.4) but could reverse to positive charge in a tumor microenvironment (pH 6.5) due to the cleavable amide linkages formed between PEG-PLL and DMA, leading to the improvement of cell uptake. Once arrived in the endosomes and lysosomes (pH 5.0), DETA NONOate was triggered to decompose and release NO, which further promoted the quick release of PTX and inhibited the P-gp mediated efflux. The charge-reversal, NO generation and NO-triggered rapid release of drugs could significantly increase the accumulation of PTX in tumors and eventually improve the antitumor efficacy. These results indicate that this dual pH-sensitive liposomal system is a highly promising approach for chemotherapy and may pave a new avenue for overcoming MDR in cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipossomos/química , Óxido Nítrico/metabolismo , Paclitaxel/química , Células A549 , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Microscopia Confocal , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Polímeros/química , Distribuição Tecidual , Transplante Heterólogo
19.
Mar Drugs ; 17(2)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678253

RESUMO

Macroalgae have been reported as an important source of halogenated aromatic secondary metabolites, being the majority of these derivatives isolated from red algae. Halophenols and haloindoles are the most common haloaryl secondary metabolites isolated from these marine organisms. Nevertheless, some halogenated aromatic sesquiterpenes and naphthalene derivatives have also been isolated. Most of these secondary metabolites showed interesting biological activities, such as antitumor, antimicrobial, antidiabetic, and antioxidant. This review describes in a systematic way the distribution and natural occurrence of halogenated aromatic secondary metabolites from extracts of red, brown, and green algae, as well as biological activities reported for these compounds.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/farmacologia , Alga Marinha/química , Alga Marinha/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Clorófitas/química , Clorófitas/metabolismo , Estrutura Molecular , Feófitas/química , Feófitas/metabolismo , Rodófitas/química , Rodófitas/metabolismo
20.
Anticancer Agents Med Chem ; 19(1): 48-65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29692264

RESUMO

Cancer continues to be one of the major causes of death worldwide. Despite many advances in the understanding of this complex disease, new approaches are needed to improve the efficacy of current therapeutic treatments against aggressive tumors. Natural products are one of the most consistently successful sources of drug leads. In recent decades, research activity into the clinical potential of this class of compounds in cancer has increased. Furthermore, a highly promising field is the use of metals and their complexes in the design and development of metal-based drugs for the treatment of cancer. Metal complexes offer unique opportunities due to their ability to alter pharmacology, improving the efficacy and/or reducing the negative side effects of drug molecules. In addition, transition metals as copper, iron, and manganese, among others, can interact with active sites of enzymes, playing important roles in multiple biological processes. Thus, these complexes not only possess higher activities but also reach their targets more efficiently. This review article highlights recent advances on the emerging and expanding field of metal-based drugs. The emphasis is on new therapeutic strategies consisting of metal complexes with natural product like-compounds as a starting point for the rational design of new antitumor agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Complexos de Coordenação/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia
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