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1.
Sheng Wu Gong Cheng Xue Bao ; 37(6): 2026-2038, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34227292

RESUMO

Podophyllotoxin (PTOX) is an aryl-tetralin lignan of plant origin found in some species of Podophyllum such as Dysosma versipellis, Diphylleia sinensis, and Sinopodophyllum hexandrum. Etoposide and teniposide are produced semisynthetically from PTOX and used clinically to treat several forms of cancer. As a typical representative of new drug discovery from natural products, the production of PTOX solely depends on extraction from plants, resulting in severe contradiction between supply and demand. With the advantages of unconstrained resources and eco-friendly reaction conditions, biosynthesis method has become a trend in the production of PTOX and its derivatives. In this review, we summarize the research progress of PTOX biosynthesis in plants and expound the functions of the key enzymes as well as their subcellular location. The synthetic biology for production of PTOX intermediates in a tobacco chassis is also introduced. Finally, the heterologous expression and biotransformation of PTOX in microorganisms is summarized, which sets the foundation for the efficient microbial production of PTOX using cell factories.


Assuntos
Podofilotoxina/biossíntese , Podophyllum , Genes de Plantas , Podophyllum/genética
2.
Chemosphere ; 279: 130810, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34134431

RESUMO

To improve the remediation efficiency of plants on low concentration uranium-bearing wastewater and clarify its strengthening mechanism, Syngonium podophyllum-Peperomia tetraphylla co-planting system was established, the enhanced effects of plants interaction on uranium removal were investigated, the chemical forms, valence states, and subcellular distribution of uranium in plants were confirmed, and the mechanisms of alleviating uranium stress by plants interaction were revealed. In Syngonium podophyllum-Peperomia tetraphylla co-planting system, the total amount of ethanol-extracted uranium and deionized water-extracted uranium with higher toxicity in their roots were reduced by 10.30% and 7.17%, respectively, which reduced the toxicity of uranium to plants. Plants interaction can inhibit the reduction of U(VI) in the root of Peperomia tetraphylla, which is conducive to the transport of uranium from roots to shoots. In addition, uranium in plants mainly existed in the cell wall (54.44%-66.52%) and the soluble fraction (23.85%-32.89%). These results indicated that Syngonium podophyllum and Peperomia tetraphylla co-planting can enhance their effects of uranium removal by alleviating uranium stress with the cell wall immobilization and vacuole compartmentation, improving biomass of plants, increasing bioaccumulation factor and translocation factor of uranium.


Assuntos
Peperomia , Podophyllum , Urânio , Biodegradação Ambiental , Urânio/análise , Águas Residuárias
3.
Bioorg Med Chem Lett ; 43: 128104, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984477

RESUMO

To explore natural-product-based insecticide candidates, and high value-added application of natural plants in agriculture, a series of twin compounds were prepared from two natural products podophyllotoxin and cytisine, which are isolated from the plants Podophyllum hexandrum and Thermopsis lanceolata, respectively. Compounds IIa (X = Cl, Y = R1 = R2 = H), IIIc (X = Y = R1 = R2 = Cl) and IVd (X = R1 = R2 = Br, Y = H) exhibited >2-fold potent insecticidal activity of podophyllotoxin against armyworm with FMRs greater than 60%. SARs were also observed. It is noteworthy that the idea of twin insecticides was addressed for the first time. We hope this idea will be conducive to design new twin insecticidal agents, and lay the foundation for future high value-added application of the plants P. hexandrum and T. lanceolata as potentially botanical pesticides in agriculture.


Assuntos
Alcaloides/farmacologia , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Podofilotoxina/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Azocinas/química , Azocinas/isolamento & purificação , Azocinas/farmacologia , Relação Dose-Resposta a Droga , Fabaceae/química , Inseticidas/química , Inseticidas/isolamento & purificação , Estrutura Molecular , Podofilotoxina/química , Podofilotoxina/isolamento & purificação , Podophyllum/química , Quinolizinas/química , Quinolizinas/isolamento & purificação , Quinolizinas/farmacologia , Relação Estrutura-Atividade
4.
Biomolecules ; 11(4)2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921719

RESUMO

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Podofilotoxina/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Podofilotoxina/análogos & derivados , Podofilotoxina/uso terapêutico , Podophyllum/química
5.
J Am Chem Soc ; 143(13): 5011-5021, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33780244

RESUMO

Phenylpropanoids are a class of abundant building blocks found in plants and derived from phenylalanine and tyrosine. Phenylpropanoid polymerization leads to the second most abundant biopolymer lignin while stereo- and site-selective coupling generates an array of lignan natural products with potent biological activity, including the topoisomerase inhibitor and chemotherapeutic etoposide. A key step in etoposide biosynthesis involves a plant dirigent protein that promotes selective dimerization of coniferyl alcohol, a common phenylpropanoid, to form (+)-pinoresinol, a critical C2 symmetric pathway intermediate. Despite the power of this coupling reaction for the elegant and rapid assembly of the etoposide scaffold, dirigent proteins have not been utilized to generate other complex lignan natural products. Here, we demonstrate that dirigent proteins from Podophyllum hexandrum in combination with a laccase guide the heterocoupling of natural and synthetic coniferyl alcohol analogues for the enantioselective synthesis of pinoresinol analogues. This route for complexity generation is remarkably direct and efficient: three new bonds and four stereocenters are produced from two different achiral monomers in a single step. We anticipate our results will enable biocatalytic routes to difficult-to-access non-natural lignan analogues and etoposide derivatives. Furthermore, these dirigent protein and laccase-promoted reactions of coniferyl alcohol analogues represent new regio- and enantioselective oxidative heterocouplings for which no other chemical methods have been reported.


Assuntos
Produtos Biológicos/síntese química , Proteínas/química , Produtos Biológicos/química , Lignanas/química , Oxirredução , Fenóis/química , Proteínas de Plantas/química , Podophyllum/química , Estereoisomerismo
6.
J Complement Integr Med ; 18(3): 485-490, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33544520

RESUMO

Podophyllum hexandrum Royle [=Sinopodophyllum hexandrum (Royle) T.S. Ying] is an important, endemic medicinal plant species of Himalaya. It is used in Unani System of Medicine under the name of 'Papra'. The drug was not mentioned in previous literatures, but the first time it introduced in Unani Medicine by a great scholar Hakim Najmul Ghani. He has mentioned its uses and benefits in his classical book Khazainul Advia. In Unani Medicine the plant species has been used to treat various ailments like constipation, fever, jaundice, liver disorders, syphilis, diseases of lymph glands etc. In Kashmir Himalaya it is used to treat various diseases by local medicinemen, but now it is listed in rare drugs. Various pharmacological studies have been done such as antioxidant, antimicrobial, anti-inflammatory, antifungal, radio-protective etc., recently it has also been reported that podophyllotoxin or podophyllin can be used to treat some forms of cancers also.


Assuntos
Plantas Medicinais , Podophyllum , Medicina Unani , Podofilotoxina
7.
Anticancer Agents Med Chem ; 20(7): 865-874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32067620

RESUMO

BACKGROUND: Hepatocellular Carcinoma (HCC), the second leading cause of cancer-related mortality with over half a million new cases diagnosed annually in the world, accounts for nearly 70% of cancer deaths in parts of Asia and Africa. Podophyllum, one of the important members of the lignane class of natural products derived from plants in Podophyllum peltatum L., has been shown to suppress tumor growth in various cancers. However, the effects of Podophyllum compounds on HCC and the mechanisms for its tumor-suppressive function remain unknown. METHODS: A molecular docking study was employed to the analysis of the interaction between compounds and their targeted proteins. Cell proliferation was measured by MTT assay. Western blot analysis was used to evaluate protein expression. qRT-PCR was performed to assess RNA expression. RESULTS: Molecular docking analysis was consistent with the beneficial effect of fluorine atom substituent in the 3-position of 2-aminopyridine in our previous study. Also, P-3F and D-3F displayed the most potent cytotoxicities against PLC/PRF/5 with p53-R249S and weakest inhibition of L02 (normal liver cell) growth. However, these derivatives had no effect on the suppression of HepG2 (wild-type p53) and Hep3B (p53-null) proliferation significantly. Further study showed that both compounds increase γ-H2AX expression in PLC/PRF/5 cell, along with repression of the c-Myc activation, purportedly by induction of p53 level and transcriptional activation. CONCLUSION: The results suggested that podophyllum derivatives containing fluorine atom in the 3-position of 2- aminopyridine could inhibit the growth of HCC harboring p53-R249S by restoring the activity of p53 with decreasing the level of c-Myc.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Podophyllum/química , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
8.
Molecules ; 23(12)2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30551576

RESUMO

This paper reports the in silico prediction of biological activities of lignans from Diphylleia cymosa and Podophyllum hexandrum combined with an in vitro bioassays. The extracts from the leaves, roots and rhizomes of both species were evaluated for their antibacterial, anticholinesterasic, antioxidant and cytotoxic activities. A group of 27 lignans was selected for biological activities prediction using the Active-IT system with 1987 ligand-based bioactivity models. The in silico approach was properly validated and several ethnopharmacological uses and known biological activities were confirmed, whilst others should be investigated for new drugs with potential clinical use. The extracts from roots of D. cymosa and from rhizomes and roots of P. hexandrum were very effective against Bacillus cereus and Staphylococcus aureus, while podophyllotoxin inhibited the growth of Staphylococcus aureus and Escherichia coli. D. cymosa leaves and roots showed anticholinesterasic and antioxidant activities, respectively. The evaluated extracts showed to be moderately toxic to THP-1 cells. The chromatographic characterization indicated that podophyllotoxin was the major constituent of P. hexandrum extract while kaempferol and its hexoside were the main constituents of D. cymosa leaves and roots, respectively. These results suggest that the podophyllotoxin could be the major antibacterial lignan, while flavonoids could be responsible for the antioxidant activity.


Assuntos
Berberidaceae/química , Simulação por Computador , Extratos Vegetais/farmacologia , Podophyllum/química , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Inibidores da Colinesterase/farmacologia , Cromatografia Líquida de Alta Pressão , Humanos , Lignanas/química , Lignanas/isolamento & purificação , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Curva ROC , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
9.
Drug Des Devel Ther ; 12: 3393-3406, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349193

RESUMO

Background: Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of antitumor drugs. Several podophyllotoxin-derived antitumor agents, including etoposide, are currently in clinical use; however, their therapeutic efficacy is often limited due to side effects and the development of resistance by cancer cells. Previous studies have shown that 4ß-1,2,3-triazole derivatives of podophyllotoxin exhibit more potent anticancer activity and better binding to topoisomerase-II than etoposide. The effect of dimerization of such derivatives on the anticancer activity has not been studied. Methods: Two moieties of podophyllotoxin were linked at the C-4 position via 1,2,3-triazole rings to give a series of novel dimeric podophyllotoxin derivatives. 4ß-Azido-substituted podophyllotoxin derivatives (23 and 24) were coupled with various dipropargyl functionalized linkers by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to provide dimeric products in very good yield. The in vitro anticancer activity of the synthesized compounds was evaluated by MTT assay against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). The normal BEAS-2B (lung) cell line was also included for study in order to evaluate the cancer selectivity of the most active compound as compared with normal cells. Results: A group of 16 dimeric podophyllotoxin derivatives with different linkers were synthesized and structurally characterized. Most compounds do not show significant cytotoxicity (IC50 > 40 mM) against all five cancer cell lines. However, one compound (29) which bears a perbutyrylated glucose residue on the glycerol linker is highly potent against all five cancer cell lines tested, with IC50 values ranging from 0.43 to 3.50 µM. This compound (29) also shows good selectivity towards cancer cell lines as compared with the normal BEAS-2B (lung) cell line, showing selectivity indexes from 4.4 to 35.7. Conclusion: The anticancer activity of dimeric podophyllotoxin derivatives is generally speaking not improved as compared to their monomeric counterparts, and the potency of these dimeric derivatives can be largely affected by the nature of the linker between the two moieties. Among the synthesized derivatives, compound 29 is significantly more cytotoxic and selective towards cancer cells than etoposide and cisplatin, which are currently in clinical use. Compound 29 is a promising anticancer drug and needs further studies.


Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Podofilotoxina/síntese química , Podofilotoxina/isolamento & purificação , Podophyllum/química , Relação Estrutura-Atividade
10.
Cell Biol Int ; 42(1): 121-129, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28949066

RESUMO

In previous work, we presented experimental and theoretical evidence that D-3F or 4-N-(2-Amino-3-fluoropyridine)-4-deoxidation-4'-demethylepipofophyllotoxin induced G2 /M phase arrest and apoptosis, purportedly by increasing the expression of P53. However, the precise mechanism of D-3F action is currently unknown. Here, we investigated the mechanism by which D-3F treatment induces increased expression of P53. This study showed that D-3F definitively inhibited the activity of topoisomerase II in a dose-dependent manner and resulted in DNA damage. The results were in overall agreement with modeling and docking studies performed on D-3F. In addition, D-3F increased the levels of P53 and P21 in HeLa cells in a dose-dependent manner, this in turn prolonged the half-life of P53. Taken together, these data suggested that D-3F-mediated transient enhancement of P53 stabilization may be critical for the P53/P21 signalling pathway leading to G2 /M phase arrest on HeLa cells. Furthermore, D-3F downregulated the phosphorylation of E3 ubiquitin-protein ligase murine double minute 2 (Mdm2) at Ser166, inhibited Mdm2-mediated ubiquitination of P53, and released 60S ribosomal protein L11 (RPL11) from the nucleolus into the nucleoplasm. To conclude, the topoisomerase II inhibitor D-3F causes P53 to accumulate in HeLa cell lines by enhancing its stability as a result of DNA-damage induced RPL11 relocalization and subsequent blocking of the P53-Mdm2 feedback loop.


Assuntos
Proteínas Ribossômicas/fisiologia , Inibidores da Topoisomerase II/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Nucléolo Celular , Dano ao DNA , Genes p53/efeitos dos fármacos , Genes p53/fisiologia , Células HeLa , Humanos , Fosforilação , Podophyllum/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Transdução de Sinais , Inibidores da Topoisomerase II/farmacologia
11.
J Med Entomol ; 54(1): 159-166, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28082643

RESUMO

Aedes aegypti L. (Diptera: Culicidae) is a mosquito species that has adapted to urban environments and is the main vector of dengue viruses. Because of the increasing incidence of dengue, a more environmentally acceptable insecticide needs to be found. Natural products have been and continue to be an important source of leading compounds that can be modified in order to develop new drugs. The lignan family of natural products includes compounds with a diverse spectrum of biological activity. Podophyllotoxin and its related lignans represent an exciting class of natural products that can be targeted at different types of biological activity and are therefore worth exploring further. This study had the aim of evaluating the larvicidal activity of an ethanolic extract from the rhizomes and roots of Podophyllum hexandrum (PM-3) and its isolated lignans, podophyllotoxone (1) and desoxypodophyllotoxin (2), on the larvae of the mosquito vector Ae. aegypti. The PM-3 extract and the compounds (1) and (2) were dissolved in a mixture of acetone and dimethylsulfoxide at final concentrations of 1, 10, 30, 50, 100, and 200 µg/ml. After dilution, the solutions were applied (µg/ml) to the larvae-rearing medium. Overall, the ethanolic extract from the rhizomes and roots of P. hexandrum and the compounds (1) and (2) showed larvicidal activity against the larvae of Ae. aegypti According to the results from this study, it can be concluded that podophyllotoxone (1) and desoxypodophyllotoxin (2) exhibited significant toxicity toward Ae. aegypti larvae.


Assuntos
Aedes , Inseticidas , Lignanas , Controle de Mosquitos , Podophyllum/química , Aedes/crescimento & desenvolvimento , Animais , Larva/crescimento & desenvolvimento , Controle de Mosquitos/métodos , Extratos Vegetais , Raízes de Plantas/química , Rizoma/química
12.
Environ Sci Pollut Res Int ; 24(6): 5134-5143, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27023802

RESUMO

The endophyte Pseudomonas sp. XNN8 was separated from Typha orientalis which can secrete indole-3-acetic acid and 1-aminocyclopropane-1-carboxylate deaminase and siderophores and has strong resistance to uranium it was then colonized in the Syngonium podophyllum; and the S. podophyllum-Pseudomonas sp. XNN8 symbiotic purification system (SPPSPS) for uranium-containing wastewater was constructed. Afterwards, the hydroponic experiments to remove uranium from uranium-containing wastewater by the SPPSPS were conducted. After 24 days of treatment, the uranium concentrations of the wastewater samples with uranium concentrations between 0.5 and 5.0 mg/L were lowered to below 0.05 mg/L. Furthermore, the uranium in the plants was assayed using Fourier transform infrared spectroscopy (FTIR) and extended X-ray absorption fine structure (EXAFS) spectroscopy. The Pseudomonas sp. XNN8 was found to generate substantial organic groups in the roots of the Syngonium podophyllum, which could improve the complexing capability of S. podophyllum for uranium. The uranium in the roots of S. podophyllum was found to be the uranyl phosphate (47.4 %) and uranyl acetate (52.6 %).


Assuntos
Araceae , Pseudomonas , Urânio , Águas Residuárias , Purificação da Água/métodos , Carbono-Carbono Liases , Hidroponia , Ácidos Indolacéticos , Compostos Organometálicos , Fosfatos , Raízes de Plantas/química , Podophyllum , Espectroscopia de Infravermelho com Transformada de Fourier , Simbiose , Compostos de Urânio , Espectroscopia por Absorção de Raios X
13.
Pharm Biol ; 55(1): 173-183, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27718769

RESUMO

CONTEXT: Medicinal plants continue to act as a repository for novel drug leads with novel mechanisms of action. Podophyllum hexandrum Royale (Berberideceae) treats diverse conditions in folk medicine. OBJECTIVE: The antimutagenic potential of P. hexandrum was evaluated against endosulfan-induced clastogenicity in a piscine model by cytogenetic endpoints. MATERIALS AND METHODS: Podophyllum hexandrum rhizomes were subjected to successive solvent extraction. Fish were exposed to hexane, chloroform, ethyl acetate, methanol and aqueous extracts (15 mg/L each) of plant and endosulfan (0.05 mg/L) alone followed by their combination for antimutagenicity estimates. Chromosomal aberrations (CA) were made from kidney cells and micronuclei (MN) slides from peripheral blood erythrocytes at 48, 72 and 96 h. Antioxidant activity was analyzed by the DPPH assay. Phytochemical analyses were carried out using chromatographic and spectroscopic techniques. RESULTS: Endosulfan induced significant (p < .05) MN, authenticated by scanning electron microscopy, and CA in a time-dependent manner. However, methanol and ethyl acetate extracts revealed ameliorating effects. The column eluted methanolic fraction-2 (ME-F2) showed highest reduction profile of 83 and 84% in CA and MN, followed in its extent (73 and 72%) by ethyl acetate fraction-4 (EE-F4). ME-F2 and EE-F4 showed three and six major peaks when analyzed by GC-MS. To explore possible mechanism of action, ME-F2 showed potent antioxidant potential and strong correlation (R2 = .900) with antimutagenic activity, whereas EE-F4 seemed to act through a different mechanism. DISCUSSION AND CONCLUSION: This study confirms the antimutagenic potential of the subject plant with the identification of some novel compounds, justifying their use in folk medicine, and their corresponding benefit to mankind.


Assuntos
Antimutagênicos/farmacologia , Carpas/genética , Medicamentos de Ervas Chinesas/farmacologia , Endossulfano/toxicidade , Rim/efeitos dos fármacos , Mutagênese/efeitos dos fármacos , Mutagênicos/toxicidade , Mutação/efeitos dos fármacos , Podophyllum/química , Animais , Antimutagênicos/isolamento & purificação , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Berberidaceae , Compostos de Bifenilo/química , Carpas/metabolismo , Aberrações Cromossômicas/induzido quimicamente , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Eritrócitos/efeitos dos fármacos , Eritrócitos/ultraestrutura , Cromatografia Gasosa-Espectrometria de Massas , Rim/metabolismo , Rim/ultraestrutura , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Microscopia Eletroquímica de Varredura , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Fitoterapia , Picratos/química , Plantas Medicinais , Rizoma , Solventes/química , Fatores de Tempo
14.
Chemistry ; 23(19): 4467-4526, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-27726183

RESUMO

Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, antispasmogenic, and hypolipidemic activities). This Review provides a survey of podophyllotoxin and its analogues isolated from plants. In particular, recent developments in the elegant total chemical synthesis, structural modifications, biosynthesis, and biotransformation of podophyllotoxin and its analogues are summarized. Moreover, a deoxypodophyllotoxin-based chemosensor for selective detection of mercury ion is described. In addition to the most active podophyllotoxin derivatives in each series against human cancer cell lines and insect pests listed in the tables, the structure-activity relationships of podophyllotoxin derivatives as cytotoxic and insecticidal agents are also outlined. Future prospects and further developments in this area are covered at the end of the Review. We believe that this Review will provide necessary information for synthetic, medicinal, and pesticidal chemistry researchers who are interested in the chemistry and biology of podophyllotoxins.


Assuntos
Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Inseticidas/química , Podofilotoxina/análogos & derivados , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/toxicidade , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Humanos , Insetos/crescimento & desenvolvimento , Inseticidas/síntese química , Inseticidas/toxicidade , Larva/efeitos dos fármacos , Podofilotoxina/síntese química , Podofilotoxina/toxicidade , Podophyllum/química , Podophyllum/metabolismo , Relação Estrutura-Atividade
15.
Crit Rev Biotechnol ; 37(6): 739-753, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27644897

RESUMO

Podophyllotoxin is an aryltetralin lignan synthesized in several plant species, which is used in chemotherapies for cancers and tumor treatment. More potent semisynthetic derivatives of podophyllotoxin such as etoposide and teniposide are being developed and evaluated for their efficacy. To meet the ever increasing pharmaceutical needs, species having podophyllotoxin are uprooted extensively leading to the endangered status of selective species mainly Sinopodophyllum hexandrum. This has necessitated bioprospection of podophyllotoxin from different plant species to escalate the strain on this endangered species. The conventional and non-conventional mode of propagation and bioprospection with the integration of biotechnological interventions could contribute to sustainable supply of podophyllotoxin from the available plant resources. This review article is focused on the understanding of different means of propagation, development of genomic information, and its implications for elucidating podophyllotoxin biosynthesis and metabolic engineering of pathways. In addition, various strategies for sustainable production of this valuable metabolite are also discussed, besides a critical evaluation of future challenges and opportunities for the commercialization of podophyllotoxin.


Assuntos
Biotecnologia , Fungos , Podofilotoxina , Podophyllum
16.
Protoplasma ; 254(1): 217-228, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26733390

RESUMO

Podophyllum species (Podophyllum hexandrum Royle and Podophyllum peltatum) are a major source of deriving anticancer drugs from their major chemical constituent, podophyllotoxin. However, information lacks on regulatory components of podophyllotoxin biosynthesis; therefore, different classes of transcription factors were identified through mining transcriptomes of Podophyllum species and validated through qRT-PCR analysis vis-à-vis podophyllotoxin contents in different tissues/organs of Podophyllum hexandrum. A total of 82, 278, 70, and 90 transcripts were identified in shoots and 89, 273, 72, and 91 transcripts in rhizomes of P. hexandrum transcriptome; 70, 268, 48, and 92 transcripts were in shoots and 58, 245, 41, and 85 transcripts in rhizomes of P. peltatum transcriptome corresponding to bZIP, MYB, WRKY, and bHLH families of transcription factors, which have been shown in regulating biosynthesis of secondary metabolites. Two unique transcripts encoding bHLH and MYB/SANT TFs in shoots of P. peltatum (medp_podpe_41091 and medp_podpe_2547) and bZIP and MYB TFs in rhizomes of P. hexandrum (medp_podhe_163581 and medp_podhe_147614) correlated with podophyllotoxin content. Quantification of podophyllotoxin and comparative expression analysis between high (2.51 %) versus low (0.59) podophyllotoxin content accessions revealed 0.04 to ~16-folds increase in transcripts of transcription factors, thereby further supporting the association of identified transcription factors with podophyllotoxin content. bZIP TF showed the highest transcript abundance (19.60-folds) in P. hexandrum rhizomes (2.51 % podophyllotoxin) compared to shoots (0.01 %). In silico analysis of putative promoter regions of pathway genes in other plant species revealed the presence of sequence elements for MYB and WRKY transcription factors, thereby suggesting their role in controlling the production of podophyllotoxin. A repertoire of additional transcription factors has been provided, which can be functionally validated and used in designing a suitable genetic intervention strategy towards enhanced production of podophyllotoxin.


Assuntos
Perfilação da Expressão Gênica , Podofilotoxina/biossíntese , Podophyllum/genética , Fatores de Transcrição/genética , Simulação por Computador , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Brotos de Planta/genética , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Rizoma/genética , Metabolismo Secundário/genética , Especificidade da Espécie , Fatores de Transcrição/metabolismo , Transcriptoma/genética
17.
Bioorg Med Chem Lett ; 27(3): 511-517, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28007447

RESUMO

Podophyllotoxin is a naturally occurring non-alkaloid toxin isolated from the roots and rhizomes of Podophyllum peltatum and P. hexandrum. In continuation of our program aimed at the discovery and development of natural product-based insecticides, two series of ester derivatives of 4'-demethoxyepipodophyllotoxin/2'-chloro-4'-demethoxyepipodophyllotoxin were prepared. The structures of the target compounds were well characterized by 1H NMR, IR, optical rotation and mp. The precise three-dimensional structural information of 8j was further determined by single-crystal X-ray diffraction. Their insecticidal activity was tested against Mythimna separata Walker. These compounds showed delayed insecticidal activity. Among all derivatives, some compounds showed more potent insecticidal activity than toosendanin against M. separata; especially compounds 8k and 9k exhibited the most potent activity with the final mortality rates of 71.4%. Their structure-activity relationships were discussed.


Assuntos
Ésteres/farmacologia , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Podofilotoxina/farmacologia , Podophyllum/química , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Inseticidas/síntese química , Inseticidas/química , Modelos Moleculares , Estrutura Molecular , Podofilotoxina/análogos & derivados , Podofilotoxina/química , Relação Estrutura-Atividade
18.
Plant Mol Biol ; 92(1-2): 1-23, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27387305

RESUMO

Podophyllotoxin (ptox) is a therapeutically important lignan derived from Podophyllum hexandrum and is used as a precursor for the synthesis of anticancer drugs etoposide, teniposide and etopophose. In spite of its enormous economic significance, genomic information on this endangered medicinal herb is scarce. We have performed de novo transcriptome analysis of methyl jasmonate (MeJA)-treated P. hexandrum cell cultures exhibiting enhanced ptox accumulation. The results revealed the maximum up-regulation of several isoforms of cinnamyl alcohol dehydrogenase (CAD). CAD catalyzes the synthesis of coniferyl alcohol and sinapyl alcohol from coniferaldehyde (CAld) and sinapaldehyde respectively. Coniferyl alcohol can produce both lignin and lignan while sinapyl alcohol produces only lignin. To isolate the CAD isoforms favoring ptox, we deduced full length cDNA sequences of four CAD isoforms: PhCAD1, PhCAD2, PhCAD3 and PhCAD4 from the contigs of the transcriptome data. In vitro enzyme assays indicated a higher affinity for CAld over sinapaldehyde for each isoform. In silico molecular docking analyses also suggested that PhCAD3 has a higher binding preference with CAld over sinapaldehyde, followed by PhCAD4, PhCAD2, and PhCAD1, respectively. The transgenic cell cultures overexpressing these isoforms independently revealed that PhCAD3 favored the maximum accumulation of ptox as compared to lignin followed by PhCAD4 and PhCAD2, whereas, PhCAD1 favored both equally. Together, our study reveals transcriptome-wide identification and characterization of ptox specific CAD isoforms from P. hexandrum. It provides a useful resource for future research not only on the ptox biosynthetic pathway but on overall P. hexandrum, an endangered medicinal herb with immense therapeutic importance.


Assuntos
Oxirredutases do Álcool/metabolismo , Podofilotoxina/biossíntese , Podophyllum/enzimologia , Podophyllum/metabolismo , Isoformas de Proteínas/metabolismo , Acetatos/farmacologia , Oxirredutases do Álcool/genética , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/genética , Oxilipinas/farmacologia , Podophyllum/efeitos dos fármacos , Isoformas de Proteínas/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
19.
Plant Physiol Biochem ; 107: 197-203, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27314513

RESUMO

Podophyllotoxin (PPT) and its derivatives, isolated from the rhizome of Podophyllum hexandrum Royle (P. hexandrum), are typically used in clinical settings for anti-cancer and anti-virus treatments. Empirical studies have verified that P. hexandrum had stronger tolerance to chilling, due to involving PPT accumulation in rhizome induced by cold stress. However, the cold-adaptive mechanism and its association with PPT accumulation at a molecular level in P. hexandrum are still limited. In this study, the morpho-physiological traits related to plant growth, PPT accumulation and key gene expressions controlling PPT biosynthesis were assessed by exposing P. hexandrum seedlings to different temperatures (4 °C and 10 °C as chilling stress and 22 °C as the control). The results showed that chilling significantly increased chlorophyll content, net photosynthetic rate, stomatal conductance, and plant biomass, whereas it greatly decreased transpiration rates and intercellular CO2 concentration. Compared to the control, the chilling treatments under 4 °C and 10 °C conditions induced a 5.00- and 3.33-fold increase in PPT contents, respectively. The mRNA expressions of six key genes were also up-regulated by chilling stresses. The findings are useful in understanding the molecular basis of P. hexandrum response to chilling.


Assuntos
Temperatura Baixa , Regulação da Expressão Gênica de Plantas , Podofilotoxina/biossíntese , Podophyllum/crescimento & desenvolvimento , Podophyllum/genética , Vias Biossintéticas/genética , Clorofila/metabolismo , Clorofila A , Genes de Plantas , Fotossíntese/genética , Podofilotoxina/química , Rizoma/metabolismo , Plântula/genética , Plântula/crescimento & desenvolvimento , Estresse Fisiológico/genética
20.
Planta ; 244(2): 505-15, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27097640

RESUMO

MAIN CONCLUSION: Xyloglucan endo-transglycosylase/hydrolase ( Ph XET/H) regulates Podophyllum seed germination via GA mediated up-accumulation of Ph XET protein and subsequent endosperm weakening. Xyloglucan endo-transglycosylase/hydrolase (XET/H) belong to glycosyl hydrolase family 16, which play an important role in endosperm weakening and embryonic expansion during seed germination. Podophyllum hexandrum is a high altitude medicinal plant exploited for its etoposides which are potential anticancer compounds. During seed germination in Podophyllum, accumulation of XET/H transcripts was recorded. This data confirmed its possible role in determining the fate of seed for germination. Full length cDNA of a membrane bound XET/H (here onwards PhXET) was cloned from the germinating seeds of Podophyllum. Analysis of nucleotide sequence revealed PhXET with an open reading frame of 720 bp encoding a protein of 239 amino acids with a molecular mass of 28 kDa and pI of 7.58. In silico structure prediction of PhXET showed homology with that of Populus tremula (1UN1). PhXET was predicted to have a potential GPI-anchor domain and was located in plasma membrane. It was found that the exogenously applied phytohormones (GA and ABA) regulate the expression of PhXET. The obtained data showed that the PhXET regulates seed germination in Podophyllum by supplementing its activity along with other endosperm weakening and embryo expansion genes.


Assuntos
Glicosiltransferases/fisiologia , Proteínas de Plantas/fisiologia , Podophyllum/genética , Ácido Abscísico/farmacologia , Altitude , Clonagem Molecular , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Germinação/efeitos dos fármacos , Germinação/genética , Giberelinas/metabolismo , Giberelinas/farmacologia , Glicosiltransferases/análise , Glicosiltransferases/genética , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas/análise , Proteínas de Plantas/genética , Podophyllum/efeitos dos fármacos , Podophyllum/enzimologia , Podophyllum/crescimento & desenvolvimento , Sementes/efeitos dos fármacos , Sementes/enzimologia , Sementes/genética , Sementes/crescimento & desenvolvimento , Alinhamento de Sequência , Análise de Sequência de Proteína , Transdução de Sinais/genética
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