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1.
Bioorg Med Chem ; 27(7): 1370-1381, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30827868

RESUMO

On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 167: 485-498, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30784881

RESUMO

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 29(1): 89-96, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30446312

RESUMO

The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3-L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPß, C/EBPα, and PPARγ and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Furthermore, we observed that rotenoisin A substantially increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target phosphorylated acetyl CoA carboxylase (ACC). However, co-treatment with Compound C, an AMPK inhibitor, reversed the rotenoisin A-induced inhibition of the expression of the adipogenic transcription factors C/EBPα and PPARγ and decreased the levels of phosphorylated AMPK in differentiated 3T3-L1 cells. These results demonstrated that the anti-adipogenesis mechanism involves the down-regulation of critical adipogenic transcription factors, including C/EBPß, C/EBPα, and PPARγ, through activation of the AMPK signaling pathway by rotenoisin A.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Rotenona/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Fármacos Antiobesidade/química , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Rotenona/análogos & derivados , Rotenona/química , Relação Estrutura-Atividade
4.
Viruses ; 10(11)2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405048

RESUMO

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus for which there is no vaccine or cure. This viral infection, once acquired, is life-long, residing latently in hematopoietic cells. However, latently infected individuals with weakened immune systems often undergo HCMV reactivation, which can cause serious complications in immunosuppressed and immunocompromised patients. Current anti-viral therapies target late stages of viral replication, and are often met with therapeutic resistance, necessitating the development of novel therapeutics. In this current study, we identified a naturally-occurring flavonoid compound, deguelin, which inhibits HCMV lytic replication. Our findings reveal that nanomolar concentrations of deguelin significantly suppress the production of the infectious virus. Further, we show that deguelin inhibits the lytic cycle during the phase of the replication cycle consistent with early (E) gene and protein expression. Importantly, our data reveal that deguelin inhibits replication of a ganciclovir-resistant strain of HCMV. Together, our findings identify a novel, naturally occurring compound that may prove useful in the treatment of HCMV replication.


Assuntos
Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Flavonoides/farmacologia , Rotenona/análogos & derivados , Replicação Viral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Viral , Flavonoides/química , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Rotenona/química , Rotenona/farmacologia , Internalização do Vírus/efeitos dos fármacos
5.
J Nat Prod ; 81(4): 1055-1059, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29442505

RESUMO

A concise and protecting-group-free total synthesis of the antiproliferative natural product (±)-deguelin (2) was accomplished in four steps and 62% overall yield from commercially available precursors. The key transformation employed a vinyl iodide as the pivotal building block to construct the 4-acylchromene substructure present in deguelin. Subsequent Cu2O-mediated α-hydroxylation of deguelin (2) afforded tephrosin (3) in 90% yield.


Assuntos
Produtos Biológicos/química , Rotenona/análogos & derivados , Compostos de Vinila/química , Hidroxilação , Rotenona/química , Estereoisomerismo
6.
Planta Med ; 84(11): 779-785, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29346807

RESUMO

The plants in the genus Derris have proven to be a rich source of rotenoids, of which cytotoxic effect against cancer cells seem to be pronounced. However, their effect on angiogenesis playing a crucial role in both cancer growth and metastasis has been seldom investigated. This study aimed at investigating the effect of the eight rotenoids (1: -8: ) isolated from Derris trifoliata stems on three cancer cells and angiogenesis. Among them, 12a-hydroxyrotenone (2: ) exhibited potent inhibition on both cell growth and migration of HCT116 colon cancer cells. Further, anti-angiogenic assay in an ex vivo model was carried out to determine the effect of the isolated rotenoids on angiogenesis. Results revealed that 12a-hydroxyrotenone (2: ) displayed the most potent suppression of microvessel sprouting. The in vitro assay on human umbilical vein endothelial cells was performed to determine whether compound 2: elicits anti-angiogenic effect and its effect was found to occur via suppression of endothelial cells proliferation and tube formation, but not endothelial cells migration. This study provides the first evidence that compound 2: could potently inhibit HCT116 cancer migration and anti-angiogenic activity, demonstrating that 2: might be a potential agent or a lead compound for cancer therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Derris/química , Neovascularização Patológica/tratamento farmacológico , Rotenona/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Caules de Planta/química , Rotenona/química , Rotenona/isolamento & purificação
7.
J Nat Prod ; 80(10): 2751-2755, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29039664

RESUMO

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aß-hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer-Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aß-hydroxyelliptone was achieved via a diastereoselective chromium-mediated Étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aß-hydroxyelliptone is also described.


Assuntos
Benzopiranos/síntese química , Derris/química , Rotenona/síntese química , Benzopiranos/química , Estrutura Molecular , Rotenona/química , Estereoisomerismo
8.
Vet Parasitol ; 244: 172-175, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28917310

RESUMO

The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n=400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to some vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes, and to assess its potential as an anthelmintic candidate.


Assuntos
Antinematódeos/farmacologia , Hemoncose/tratamento farmacológico , Haemonchus/efeitos dos fármacos , Rotenona/análogos & derivados , Animais , Antinematódeos/química , Antinematódeos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Resistência a Medicamentos , Hemoncose/parasitologia , Haemonchus/fisiologia , Larva , Rotenona/química , Rotenona/isolamento & purificação , Rotenona/farmacologia
9.
J Nat Prod ; 80(7): 2060-2066, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28665590

RESUMO

A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 µM, respectively.


Assuntos
Isoflavonas/isolamento & purificação , Millettia/química , Folhas de Planta/química , Rotenona/isolamento & purificação , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Isoflavonas/química , Isoflavonas/farmacologia , Quênia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Rotenona/química , Rotenona/farmacologia
10.
Nat Prod Res ; 31(21): 2520-2526, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28403640

RESUMO

A phytochemical investigation of the MeOH extract of twigs and leaves of Tephrosia preussi was carried out to give a new kaempferol triglycoside, named tephrokaempferoside (1), together with five known compounds: tephrosin (2), betulinic acid (3), lupeol (4), ß-sitosterol (5) and 3-O-ß-d-glucopyranoside of ß-sitosterol (6). The structure of the new compound was characterised by analyses of NMR (1D and 2D) and MS data, and chemical conversion. Tephrokaempferoside (1) had weak antibacterial activity against Klebsiella pneumoniae with an MIC value of 150 µg/mL.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Glicosídeos/química , Quempferóis/química , Tephrosia/química , Avaliação Pré-Clínica de Medicamentos/métodos , Klebsiella pneumoniae/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Folhas de Planta/química , Rotenona/análogos & derivados , Rotenona/química , Rotenona/isolamento & purificação , Sitosteroides/química , Sitosteroides/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação
11.
Planta Med ; 83(14-15): 1194-1199, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28427102

RESUMO

Over the past half a century, the structure and configuration of the rotenoids, a group of natural products showing multiple promising bioactivities, have been established by interpretation of their NMR and electronic circular dichroism spectra and confirmed by analysis of single-crystal X-ray diffraction data. The chemical shift of the H-6' 1H NMR resonance has been found to be an indicator of either a cis or trans C/D ring system. In the present study, four structures representing the central rings of a cis-, a trans-, a dehydro-, and an oxadehydro-rotenoid have been plotted using the Mercury program based on X-ray crystal structures reported previously, with the conformations of the C/D ring system, the local bond lengths or interatomic distances, hydrogen bond angles, and the H-6' chemical shift of these compounds presented. It is shown for the first time that a trans-fused C/D ring system of rotenoids is preferred for the formation of a potential intramolecular C6'-H6'•••O=C4 H-bond, and that such H-bonding results in the 1H NMR resonance for H-6' being shifted downfield.


Assuntos
Millettia/química , Modelos Moleculares , Rotenona/química , Cristalografia por Raios X , Frutas/química , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Conformação Molecular , Difração de Raios X
12.
Org Biomol Chem ; 15(7): 1593-1596, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28134391

RESUMO

We describe stereocontrolled semi-syntheses of deguelin and tephrosin, anti-cancer rotenoids isolated from Tephrosia vogelii. Firstly, we present a new two-step transformation of rotenone into rot-2'-enonic acid via a zinc-mediated ring opening of rotenone hydrobromide. Secondly, following conversion of rot-2'-enonic acid into deguelin, a chromium-mediated hydroxylation provides tephrosin as a single diastereoisomer. An Étard-like reaction mechanism is proposed to account for the stereochemical outcome. Our syntheses of deguelin and tephrosin are operationally simple, scalable and high yielding, offering considerable advantages over previous methods.


Assuntos
Rotenona/análogos & derivados , Conformação Molecular , Rotenona/síntese química , Rotenona/química , Estereoisomerismo
13.
Bioorg Med Chem ; 24(22): 6082-6093, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27745993

RESUMO

Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Rotenona/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Neovascularização Patológica/patologia , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
14.
Adv Exp Med Biol ; 929: 363-375, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27771933

RESUMO

Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function. Deguelin has also been implicated as a regulator of apoptosis through signaling pathways, such as the (PI3K)/Akt pathway, as well as an initiator of cell cycle arrest. Consequently, this compound has accrued great interest as a potential chemopreventive and chemotherapeutic. Additionally, deguelin exposure has been linked to Parkinson's disease (PD). PD is a neurodegenerative disorder, characterized by a substantial loss of dopaminergic neurons in the substantia nigra, as well the manifestation of symptoms such as bradykinesia, rigidity, and rest tremor. While exploring the genetic impact of PD is imperative, environmental factors, such as exposure to pesticides, herbicides, and insecticides, have also been connected to the development of PD. The etiology and pathogenesis of PD are yet to be fully understood and elucidated, but mitochondrial dysfunction is gaining recognition as a molecular hallmark of PD. In fact, deguelin has been reported to elicit PD-like symptoms (degeneration of the dopaminergic pathway) in rats administered with deguelin (6 mg/kg/day for 6 days), possibly through the inhibition of mitochondrial complex I. Further research investigating the mechanisms by which deguelin inhibits central cellular processes is essential in order to advance any prospective research addressing potential applications and risks of deguelin.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Doença Crônica/tratamento farmacológico , Descoberta de Drogas/métodos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Rotenona/análogos & derivados , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Antioxidantes/efeitos adversos , Antioxidantes/química , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Doença de Parkinson Secundária/induzido quimicamente , Fitoterapia , Plantas Medicinais , Fatores de Risco , Rotenona/efeitos adversos , Rotenona/química , Rotenona/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
15.
Arch Biochem Biophys ; 607: 8-19, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27523732

RESUMO

Heart phosphorylating electron transfer particles (ETPH) produced NO at 1.2 ± 0.1 nmol NO. min(-1) mg protein(-1) by the mtNOS catalyzed reaction. These particles showed a NAD(+) reductase activity of 64 ± 3 nmol min(-1) mg protein(-1) sustained by reverse electron transfer (RET) at expenses of ATP and succinate. The same particles, without NADPH and in conditions of RET produced 0.97 ± 0.07 nmol NO. min(-1) mg protein(-1). Rotenone inhibited NO production supported by RET measured in ETPH and in coupled mitochondria, but did not reduce the activity of recombinant nNOS, indicating that the inhibitory effect of rotenone on NO production is due to an electron flow inhibition and not to a direct action on mtNOS structure. NO production sustained by RET corresponds to 20% of the total amount of NO released from heart coupled mitochondria. A mitochondrial fraction enriched in complex I produced 1.7 ± 0.2 nmol NO. min(-1) mg protein(-1) and reacted with anti-75 kDa complex I subunit and anti-nNOS antibodies, suggesting that complex I and mtNOS are located contiguously. These data show that mitochondrial NO production can be supported by RET, and suggest that mtNOS is next to complex I, reaffirming the idea of a functional association between these proteins.


Assuntos
Mitocôndrias/metabolismo , Óxido Nítrico/metabolismo , Trifosfato de Adenosina/química , Animais , Catálise , Bovinos , Relação Dose-Resposta a Droga , Elétrons , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Álcool Oxidorredutases Dependentes de NAD(+) e NADP(+)/metabolismo , NADP/química , Consumo de Oxigênio , Ratos , Proteínas Recombinantes/química , Rotenona/química , Partículas Submitocôndricas/química , Ácido Succínico/química
16.
Planta Med ; 82(11-12): 1096-104, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27280936

RESUMO

Three new rotenoids (1-3), two new isoflavonoids (4 and 5), and six known analogues (6-11) were isolated from an n-hexane partition of a methanol extract of the fruits of Millettia caerulea, with the structures of the new compounds elucidated by analysis of their spectroscopic data. The relative configurations of the rotenoids were determined by interpretation of their NMR spectroscopic data, and their absolute configurations were established using electronic circular dichroism spectra and specific rotation values. All compounds isolated were evaluated for their cell growth inhibitory activity against the HT-29 human colon cancer cell line, and the known compounds, (-)-3-hydroxyrotenone (6) and (-)-rotenone (7), were found to be potently active. When tested in an NF-κB inhibition assay, compound 6 showed activity. This compound, along with the new compound, (-)-caeruleanone D (1), and the known compound, ichthynone (8), exhibited K-Ras inhibitory potency. Further bioactivity studies showed that the new compounds, (-)-3-deoxycaeruleanone D (2) and (-)-3-hydroxycaeruleanone A (3), and the known compounds 8 and 11 induced quinone reductase in murine Hepa 1c1c7 cells.


Assuntos
Isoflavonas/isolamento & purificação , Millettia/química , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Indução Enzimática/efeitos dos fármacos , Frutas/química , Genes ras/efeitos dos fármacos , Células HT29 , Células HeLa , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Camundongos , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Rotenona/química
17.
Int J Biol Macromol ; 88: 263-72, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27041651

RESUMO

In this study, an amphiphilic chitosan derivative namely N,N-dimethylhexadecyl carboxymethyl chitosan (DCMC) was synthesised and applied for the first time as a carrier agent for rotenone. The physical and chemical properties of DCMC were characterised by using Fourier Transform Infrared Spectrometer (FTIR), Proton Nuclear Magnetic Resonance Spectrometer ((1)H NMR), CHN-O Elemental Analyser, Thermogravimetric Analyser (TGA) and Differential Scanning Calorimeter (DSC). DCMC was soluble in acidic (except pH 4), neutral and basic media with percent of transmittance (%T) values ranged from 67.2 to 99.4%. The critical micelle concentration (CMC) was determined as 0.095mg/mL. Transmission Electron Microscopy (TEM) analysis confirmed that DCMC has formed self-aggregates and exhibited spherical shape with the size of 65.5-137.0nm. The encapsulation efficiency (EE) and loading capacity (LC) of DCMC micelles with different weight ratios (DCMC:rotenone; 5:1, 50:1 and 100:1) were determined by using High Performance Liquid Chromatography (HPLC). The weight ratio of 100:1 gave the best EE with the value of more than 95.0%. DCMC micelles performed an excellent ability to control the release of rotenone, of which 99.0% of rotenone was released within 48h. Overall, DCMC has several key features to be an effective carrier agent for pesticide formulations.


Assuntos
Quitosana/análogos & derivados , Portadores de Fármacos , Inseticidas/química , Rotenona/química , Desacopladores/química , Quitosana/síntese química , Composição de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Micelas , Tamanho da Partícula
18.
Nat Commun ; 7: 11173, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27029645

RESUMO

Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson's disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer's disease and Huntington's disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.


Assuntos
Transtorno Autístico/genética , Encéfalo/efeitos dos fármacos , Exposição Ambiental , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças Neurodegenerativas/genética , Transcrição Genética/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Transtorno Autístico/prevenção & controle , Células Cultivadas , Fungicidas Industriais/química , Fungicidas Industriais/toxicidade , Camundongos , Microtúbulos/efeitos dos fármacos , Doenças Neurodegenerativas/prevenção & controle , Praguicidas/química , Praguicidas/toxicidade , Medição de Risco , Fatores de Risco , Rotenona/química , Rotenona/toxicidade
19.
J Phys Chem A ; 120(15): 2372-9, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27014924

RESUMO

Compounds of the rotenoid class are naturally occurring in the Leguminosae and Nyctaginacae families. Rotenoids have found a myriad of uses, for example, in the agricultural industry as an insecticide and piscicide, and as an anticancer therapeutic. The scientific literature questions whether cyclization of the rotenoid B-ring occurs via a pathway containing either cationic or free-radical intermediates. In this work, both propositions are analyzed using DFT (B3LYP and M06-2X) and the G3 composite method in gas- and (implicit) solution-phase. The accuracy of these methods is compared to several experimental C-H bond dissociation energies (BDEs). We find that of the methods surveyed M06-2X provides the most accurate BDEs. Further, there is a clear thermodynamic preference for the free-radical pathway.


Assuntos
Produtos Biológicos/química , Cátions/química , Radicais Livres/química , Teoria Quântica , Rotenona/química , Ciclização , Modelos Moleculares , Termodinâmica
20.
PLoS One ; 11(1): e0145780, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26745145

RESUMO

This study has been undertaken to explore the therapeutic effects of deguelin and specific siRNAs in HeLa cells. The data provided clearly show the silencing of ERK 1/2 with siRNAs and inhibition of ERK1/2 with deguelin treatment in HeLa cells. Additionally, we are providing information that deguelin binds directly to anti-apoptotic Bcl-2, Bcl-xl and Mcl-1 in the hydrophobic grooves, thereby releasing BAD and BAX from dimerization with these proteins. This results in increased apoptotic activity through the intrinsic pathway involved in rupture of mitochondrial membrane and release of cytochrome C. Evidence for inhibition of ERK1/2 by deguelin and escape of BAD phosphorylation at serine 112 through ERK/RSK pathway has been further fortified by obtaining similar results by silencing ERK 1/2 each with specific siRNAs. Increase in BAD after treatment with deguelin or siRNAs has been interpreted to mean that deguelin acts through several alternative pathways and therefore can be used as effective therapeutic agent.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Rotenona/análogos & derivados , Proteína de Morte Celular Associada a bcl/metabolismo , Sítios de Ligação , Citocromos c/metabolismo , Células HeLa , Humanos , Membranas Mitocondriais/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Simulação de Acoplamento Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Rotenona/química , Rotenona/farmacologia , Proteína de Morte Celular Associada a bcl/química , Proteína bcl-X/química , Proteína bcl-X/metabolismo
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