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[PMID]:28637373
[Au] Autor:Phillips RM; Hendriks HR; Sweeney JB; Reddy G; Peters GJ
[Ad] Endereço:a Department of Pharmacy , University of Huddersfield , Huddersfield , UK.
[Ti] Título:Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer.
[So] Source:Expert Opin Drug Metab Toxicol;13(7):783-791, 2017 Jul.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Apaziquone (also known as EO9 and Qapzola ) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Aziridinas/administração & dosagem
Indolquinonas/administração & dosagem
Neoplasias da Bexiga Urinária/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Intravesical
Animais
Antineoplásicos/farmacocinética
Antineoplásicos/farmacologia
Aziridinas/farmacocinética
Aziridinas/farmacologia
Seres Humanos
Indolquinonas/farmacocinética
Indolquinonas/farmacologia
Invasividade Neoplásica
Recidiva Local de Neoplasia
Neoplasias da Bexiga Urinária/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Aziridines); 0 (Indolequinones); H464ZO600O (apaziquone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2017.1341490


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[PMID]:28634178
[Au] Autor:Ma Z; Davidson VL
[Ad] Endereço:Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL 32827, U.S.A.
[Ti] Título:Ascorbate protects the diheme enzyme, MauG, against self-inflicted oxidative damage by an unusual antioxidant mechanism.
[So] Source:Biochem J;474(15):2563-2572, 2017 Jul 17.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ascorbate protects MauG from self-inactivation that occurs during the autoreduction of the reactive -Fe state of its diheme cofactor. The mechanism of protection does not involve direct reaction with reactive oxygen species in solution. Instead, it binds to MauG and mitigates oxidative damage that occurs via internal transfer of electrons from amino acid residues within the protein to the high-valent hemes. The presence of ascorbate does not inhibit the natural catalytic reaction of MauG, which catalyzes oxidative post-translational modifications of a substrate protein that binds to the surface of MauG and is oxidized by the high-valent hemes via long-range electron transfer. Ascorbate was also shown to prolong the activity of a P107V MauG variant that is more prone to inactivation. A previously unknown ascorbate peroxidase activity of MauG was characterized with a of 0.24 s and a of 2.2 µM for ascorbate. A putative binding site for ascorbate was inferred from inspection of the crystal structure of MauG and comparison with the structure of soybean ascorbate peroxidase with bound ascorbate. The ascorbate bound to MauG was shown to accelerate the rates of both electron transfers to the hemes and proton transfers to hemes which occur during the multistep autoreduction to the diferric state which is accompanied by oxidative damage. A structural basis for these effects is inferred from the putative ascorbate-binding site. This could be a previously unrecognized mechanism by which ascorbate mitigates oxidative damage to heme-dependent enzymes and redox proteins in nature.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Ácido Ascórbico/farmacologia
Proteínas de Bactérias/metabolismo
Heme/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Paracoccus denitrificans/enzimologia
[Mh] Termos MeSH secundário: Ascorbato Peroxidases/química
Ascorbato Peroxidases/metabolismo
Proteínas de Bactérias/química
Cristalografia por Raios X
Peróxido de Hidrogênio/metabolismo
Hidroxiureia/farmacologia
Indolquinonas/química
Indolquinonas/metabolismo
Ferro/metabolismo
Cinética
Proteínas Mutantes/metabolismo
Oxirredução/efeitos dos fármacos
Análise Espectral
Fatores de Tempo
Triptofano/análogos & derivados
Triptofano/química
Triptofano/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Bacterial Proteins); 0 (Indolequinones); 0 (Mutant Proteins); 134645-25-3 (tryptophan tryptophylquinone); 42VZT0U6YR (Heme); 8DUH1N11BX (Tryptophan); BBX060AN9V (Hydrogen Peroxide); E1UOL152H7 (Iron); EC 1.11.1.11 (Ascorbate Peroxidases); PQ6CK8PD0R (Ascorbic Acid); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170349


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[PMID]:28633106
[Au] Autor:Uzelac L; Skalamera D; Mlinaric-Majerski K; Basaric N; Kralj M
[Ad] Endereço:Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia.
[Ti] Título:Selective photocytotoxicity of anthrols on cancer stem-like cells: The effect of quinone methides or reactive oxygen species.
[So] Source:Eur J Med Chem;137:558-574, 2017 Sep 08.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). This study describes preparation of QM precursor, 2-hydroxy-3-hydroxymethylanthracene (2) and a detailed photochemical and photobiological investigation on similar anthracene derivatives 3 and 4. Upon photoexcitation with near visible light at λ > 400 nm 1 and 2 give QMs, that were detected by laser flash photolysis and their reactivity with nucleophiles has been demonstrated in the preparative irradiation experiments where the corresponding adducts were isolated and characterized. 3 and 4 cannot undergo photodehydration and deliver QM, but lead to the formation of phenoxyl radical and singlet oxygen, respectively. The activity of 1-4 was tested on a panel of human tumor cell lines, while special attention was devoted to demonstrate their potential selectivity towards the cells with CSC-like properties (HMLEshEcad). Upon the irradiation of cell lines treated with 1-4, an enhancement of antiproliferative activity was demonstrated, but the DNA was not the target molecule. Confocal microscopy revealed that these compounds entered the cell and, upon irradiation, reacted with cellular membranes. Our experiments demonstrated moderate selectivity of 2 and 4 towards CSC-like cells, while necrosis was shown to be a dominant cell death mechanism. Especially interesting was the selectivity of 4 that produced higher levels of ROS in CSC-like cells, which forms the basis for further research on cancer phototherapy, as well as for the elucidation of the underlying mechanism of the observed CSC selectivity based on oxidative stress activation.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Indolquinonas/metabolismo
Células-Tronco Neoplásicas/efeitos dos fármacos
Fotoquimioterapia
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Indolquinonas/farmacocinética
Estrutura Molecular
Espécies Reativas de Oxigênio/análise
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Indolequinones); 0 (Reactive Oxygen Species); 138230-21-4 (quinone methide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE


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[PMID]:28395199
[Au] Autor:Xu S; Yao H; Pei L; Hu M; Li D; Qiu Y; Wang G; Wu L; Yao H; Zhu Z; Xu J
[Ad] Endereço:State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
[Ti] Título:Design, synthesis, and biological evaluation of NAD(P)H: Quinone oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation.
[So] Source:Eur J Med Chem;132:310-321, 2017 May 26.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The enzyme NQO1 is a potential target for selective cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC = 0.263-2.904 µM), while NQO1-defficient lung adenosquamous carcinoma cells (H596) were less sensitive to these compounds, among which, compound 29h exhibited the most potent antiproliferative activity against both A549 and HT-29 cells, with IC values of 0.386 and 0.263 µM, respectively. Further HPLC and docking studies demonstrated that 29h is a good substrate of NQO1. Moreover, the investigation of anticancer mechanism showed that the representative compound 29h affected cell cycle and induced NQO1 dependent apoptosis through an oxidative stress triggered mitochondria-related pathway in A549 cells. Besides, the antitumor activity of 29h was also verified in a liver cancer xenograft mouse model. Biological evaluation of these compounds concludes that there is a strong correlation between NQO1 enzyme and induction of cancer cell death. Thus, this suggests that some of the target compounds activated by NQO1 are novel prodrug candidates potential for selective anticancer therapy.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Diterpenos Caurânicos/química
Indolquinonas/química
NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores
Pró-Fármacos/síntese química
[Mh] Termos MeSH secundário: Células A549
Animais
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Desenho de Drogas
Células HT29
Xenoenxertos
Seres Humanos
Hipóxia
Camundongos
Simulação de Acoplamento Molecular
NAD(P)H Desidrogenase (Quinona)/metabolismo
Pró-Fármacos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Diterpenes, Kaurane); 0 (Indolequinones); 0 (Prodrugs); 0APJ98UCLQ (oridonin); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE


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[PMID]:28388522
[Au] Autor:Wang Y; Fan H; Balakrishnan K; Lin Z; Cao S; Chen W; Fan Y; Guthrie QA; Sun H; Teske KA; Gandhi V; Arnold LA; Peng X
[Ad] Endereço:Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
[Ti] Título:Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells.
[So] Source:Eur J Med Chem;133:197-207, 2017 Jun 16.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Quinone methide (QM) formation induced by endogenously generated H O is attractive for biological and biomedical applications. To overcome current limitations due to low biological activity of H O -activated QM precursors, we are introducing herein several new arylboronates with electron donating substituents at different positions of benzene ring and/or different neutral leaving groups. The reaction rate of the arylboronate esters with H O and subsequent bisquinone methides formation and DNA cross-linking was accelerated with the application of Br as a leaving group instead of acetoxy groups. Additionally, a donating group placed meta to the nascent exo-methylene group of the quinone methide greatly improves H O -induced DNA interstrand cross-link formation as well as enhances the cellular activity. Multiple donating groups decrease the stability and DNA cross-linking capability, which lead to low cellular activity. A cell-based screen demonstrated that compounds 2a and 5a with a OMe or OH group dramatically inhibited the growth of various tissue-derived cancer cells while normal cells were less affected. Induction of H2AX phosphorylation by these compounds in CLL lymphocytes provide evidence for a correlation between cell death and DNA damage. The compounds presented herein showed potent anticancer activities and selectivity, which represent a novel scaffold for anticancer drug development.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Derivados de Benzeno/farmacologia
DNA/química
Peróxido de Hidrogênio/metabolismo
Indolquinonas/farmacologia
Substâncias Intercalantes/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/metabolismo
Sequência de Bases/efeitos dos fármacos
Derivados de Benzeno/química
Derivados de Benzeno/metabolismo
Ácidos Borônicos/química
Ácidos Borônicos/metabolismo
Ácidos Borônicos/farmacologia
Linhagem Celular Tumoral
Seres Humanos
Indolquinonas/química
Indolquinonas/metabolismo
Substâncias Intercalantes/química
Substâncias Intercalantes/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzene Derivatives); 0 (Boronic Acids); 0 (Indolequinones); 0 (Intercalating Agents); 138230-21-4 (quinone methide); 9007-49-2 (DNA); BBX060AN9V (Hydrogen Peroxide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE


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[PMID]:28192140
[Au] Autor:Garcia-Jimenez A; Teruel-Puche JA; Garcia-Ruiz PA; Berna J; Rodríguez-López JN; Tudela J; Garcia-Canovas F
[Ad] Endereço:GENZ-Group of Research on Enzymology(1), Department of Biochemistry and Molecular Biology-A, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, E-30100, Espinardo, Murcia, Spain.
[Ti] Título:Action of 2,2',4,4'-tetrahydroxybenzophenone in the biosynthesis pathway of melanin.
[So] Source:Int J Biol Macromol;98:622-629, 2017 May.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:2,2',4,4'-tetrahydroxybenzophenone (Uvinul D50), a sunscreen used in cosmetics, has two effects in the melanin biosynthesis pathway. On the one hand, it acts a weak inhibitor of tyrosinase and on the other, it accelerates the conversion of dopachrome to melanin. Uvinul D50 was seen to behave as a weak competitive inhibitor: apparent constant inhibition=2.02±0.09mM and IC50=3.82±0.39mM established in this work. These values are higher than those in the bibliography, which tend to be undersetimated. This discrepancy could be explained by the reaction of Uvinul D50 with the dopachrome produced from l-tyrosine or l-dopa, which would interfere in the measurement. Based on studies of its docking to tyrosinase, it seems that Uvinul D50 interacts with the active site of the enzyme (oxytyrosinase) both in its protonated and deprotonated forms (pKa=7). However, it cannot be hydroxylated, meaning that it acts as a weak inhibitor, not as an alternative substrate, despite its resorcinol structure. Uvinul D50 can be used as sunscreen, in low concentrations without significant adverse effects on melanogenesis.
[Mh] Termos MeSH primário: Benzofenonas/química
Melaninas/biossíntese
Monofenol Mono-Oxigenase/antagonistas & inibidores
Protetores Solares/química
[Mh] Termos MeSH secundário: Benzofenonas/uso terapêutico
Vias Biossintéticas
Seres Humanos
Indolquinonas/química
Indolquinonas/metabolismo
Melaninas/química
Protetores Solares/uso terapêutico
Tirosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzophenones); 0 (Indolequinones); 0 (Melanins); 0 (Sunscreening Agents); 3571-34-4 (dopachrome); 42HK56048U (Tyrosine); EC 1.14.18.1 (Monophenol Monooxygenase); PRR8K3H9VN (2,2',4,4'-tetrahydroxybenzophenone)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170324
[Lr] Data última revisão:
170324
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170214
[St] Status:MEDLINE


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[PMID]:28140566
[Au] Autor:Williamson HR; Sehanobish E; Shiller AM; Sanchez-Amat A; Davidson VL
[Ad] Endereço:Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida 32827, United States.
[Ti] Título:Roles of Copper and a Conserved Aspartic Acid in the Autocatalytic Hydroxylation of a Specific Tryptophan Residue during Cysteine Tryptophylquinone Biogenesis.
[So] Source:Biochemistry;56(7):997-1004, 2017 Feb 21.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The first posttranslational modification step in the biosynthesis of the tryptophan-derived quinone cofactors is the autocatalytic hydroxylation of a specific Trp residue at position C-7 on the indole side chain. Subsequent modifications are catalyzed by modifying enzymes, but the mechanism by which this first step occurs is unknown. LodA possesses a cysteine tryptophylquinone (CTQ) cofactor. Metal analysis as well as spectroscopic and kinetic studies of the mature and precursor forms of a D512A LodA variant provides evidence that copper is required for the initial hydroxylation of the precursor protein and that if alternative metals are bound, the modification does not occur and the precursor is unstable. It is shown that the mature native LodA also contains loosely bound copper, which affects the visible absorbance spectrum and quenches the fluorescence spectrum that is attributed to the mature CTQ cofactor. When copper is removed, the fluorescence appears, and when it is added back to the protein, the fluorescence is quenched, indicating that copper reversibly binds in the proximity of CTQ. Removal of copper does not diminish the enzymatic activity of LodA. This distinguishes LodA from enzymes with protein-derived tyrosylquinone cofactors in which copper is present near the cofactor and is absolutely required for activity. Mechanisms are proposed for the role of copper in the hydroxylation of the unactivated Trp side chain. These results demonstrate that the reason that the highly conserved Asp512 is critical for LodA, and possibly all tryptophylquinone enzymes, is not because it is required for catalysis but because it is necessary for CTQ biosynthesis, more specifically to facilitate the initial copper-dependent hydroxylation of a specific Trp residue.
[Mh] Termos MeSH primário: Aminoácido Oxirredutases/química
Ácido Aspártico/metabolismo
Cobre/metabolismo
Dipeptídeos/metabolismo
Indolquinonas/metabolismo
Triptofano/metabolismo
[Mh] Termos MeSH secundário: Aminoácido Oxirredutases/metabolismo
Ácido Aspártico/química
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Cobre/química
Dipeptídeos/química
Hidroxilação
Indolquinonas/química
Marinomonas/enzimologia
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Espectrometria de Fluorescência
Triptofano/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Dipeptides); 0 (Indolequinones); 0 (Recombinant Proteins); 0 (cysteine tryptophylquinone); 30KYC7MIAI (Aspartic Acid); 789U1901C5 (Copper); 8DUH1N11BX (Tryptophan); EC 1.4.- (Amino Acid Oxidoreductases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170517
[Lr] Data última revisão:
170517
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b01137


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[PMID]:27986568
[Au] Autor:Kolossov VL; Ponnuraj N; Beaudoin JN; Leslie MT; Kenis PJ; Gaskins HR
[Ad] Endereço:Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: viadimer@illinois.edu.
[Ti] Título:Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.
[So] Source:Biochem Biophys Res Commun;483(1):680-686, 2017 Jan 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (E ) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (ß-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of E in both the cytosol and mitochondrial matrix was observed in response to DNQ and ß-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of ß-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while ß-lap elicits off-target responses at its effective doses.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Glutationa/metabolismo
NAD(P)H Desidrogenase (Quinona)/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Quinonas/farmacologia
[Mh] Termos MeSH secundário: Técnicas Biossensoriais
Linhagem Celular Tumoral
Citosol/efeitos dos fármacos
Citosol/metabolismo
Dicumarol/farmacologia
Corantes Fluorescentes/análise
Glutarredoxinas/análise
Glutarredoxinas/genética
Glutationa/análise
Proteínas de Fluorescência Verde/análise
Proteínas de Fluorescência Verde/genética
Seres Humanos
Indolquinonas/farmacologia
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Imagem Molecular
Sondas Moleculares/genética
Terapia de Alvo Molecular
NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores
Naftoquinonas/metabolismo
Oxirredução/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-methoxy-1,2-dimethyl-3-((4-nitrophenoxy)methyl)indole-4,7-dione); 0 (Antineoplastic Agents); 0 (Fluorescent Dyes); 0 (Glutaredoxins); 0 (Indolequinones); 0 (Molecular Probes); 0 (Naphthoquinones); 0 (Quinones); 0 (Reactive Oxygen Species); 0 (deoxynyboquinone); 147336-22-9 (Green Fluorescent Proteins); 4707-32-8 (beta-lapachone); 7QID3E7BG7 (Dicumarol); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161218
[St] Status:MEDLINE


  9 / 695 MEDLINE  
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[PMID]:27902864
[Au] Autor:Sun Y; Yao T; Li H; Peng Y; Zheng J
[Ad] Endereço:School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.
[Ti] Título:In vitro and in vivo metabolic activation of berbamine to quinone methide intermediate.
[So] Source:J Biochem Mol Toxicol;31(4), 2017 Apr.
[Is] ISSN:1099-0461
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Berbamine (BBM) is a bisbenzylisoquinoline alkaloid isolated from herbal medicine Berberis amurensis. BBM has been widely used for the treatment of leukemia. Recent studies demonstrated that exposure to BBM can give rise to cytotoxicity. The major objective of this study was to explore the metabolic activation of BBM in vitro and in vivo. Two oxidative metabolites (M1 and M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in human liver microsomal incubations of BBM supplemented with NAC, and the formation of all metabolites was NADPH dependent. Microsomal inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the major enzyme responsible for the metabolic activation of BBM. In addition, a BBM-cysteine conjugate (M4) was detected in the urine of rats given BBM. The metabolism study will facilitate the understanding of the biochemical mechanisms of BBM-induced cytotoxicity.
[Mh] Termos MeSH primário: Benzilisoquinolinas/metabolismo
Citocromo P-450 CYP3A/metabolismo
Indolquinonas/metabolismo
Microssomos Hepáticos/enzimologia
[Mh] Termos MeSH secundário: Ativação Metabólica
Animais
Seres Humanos
Masculino
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzylisoquinolines); 0 (Indolequinones); 138230-21-4 (quinone methide); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); V5KM4XJ0WM (berbamine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161201
[St] Status:MEDLINE
[do] DOI:10.1002/jbt.21876


  10 / 695 MEDLINE  
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[PMID]:27731333
[Au] Autor:Guo Z; Pan G; Xu Z; Yang D; Hindra; Zhu X; Huang Y; Zhao LX; Jiang Y; Duan Y; Shen B
[Ad] Endereço:Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
[Ti] Título:New isofuranonaphthoquinones and isoindolequinones from Streptomyces sp. CB01883.
[So] Source:J Antibiot (Tokyo);70(4):414-422, 2017 Apr.
[Is] ISSN:0021-8820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Isofuranonaphthoquinones (IFQs) and Isoindolequinones (IIQs) comprise a small family of natural products, with the latter ones are especially uncommon in nature. Here we report the discovery of seven new IFQs, IFQ A-G (1-7), and three new IIQs, IIQ A-C (8-10), along with the known anthraquinone desoxyerythrolaccin (11), from Streptomyces sp. CB01883, expanding the chemical diversity of this family of natural products. The structures of these natural products were established on the basis of their HR-ESI-MS and nuclear magnetic resonance (NMR) spectroscopic data. All compounds were assessed for antibacterial activity, with 11 and 1, 5-7 exhibiting moderate and weak activities, respectively, against several Gram-positive bacteria tested. Bioinformatics analysis of the Streptomyces sp. CB01883 genome revealed the ifq gene cluster that showed identical genetic organization, with high-sequence identity, to the ifn gene cluster recently cloned from Streptomyces sp. RI-77 and confirmed to encode the biosynthesis of two IFQs, JBIR-76 and JBIR-77. Co-isolation of IFQs with IIQs from Streptomyces sp. CB01883 and facile chemical transformation of selected IFQs to IIQs, as exemplified by 1 to 9, together with the finding of the ifq cluster that most likely only encodes IFQ biosynthesis, support the proposal that IIQs may be derived nonenzymatically from IFQs in the presence of an amine.
[Mh] Termos MeSH primário: Antibacterianos/química
Indolquinonas/química
Naftoquinonas/química
Streptomyces/química
[Mh] Termos MeSH secundário: Antibacterianos/isolamento & purificação
Antibacterianos/farmacologia
Produtos Biológicos/química
Produtos Biológicos/isolamento & purificação
Biologia Computacional
Escherichia coli/efeitos dos fármacos
Fermentação
Bactérias Gram-Positivas/efeitos dos fármacos
Indolquinonas/isolamento & purificação
Indolquinonas/farmacologia
Testes de Sensibilidade Microbiana
Estrutura Molecular
Família Multigênica/genética
Naftoquinonas/isolamento & purificação
Naftoquinonas/farmacologia
Ressonância Magnética Nuclear Biomolecular
Espectrometria de Massas por Ionização por Electrospray
Streptomyces/classificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Biological Products); 0 (Indolequinones); 0 (Naphthoquinones)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170504
[Lr] Data última revisão:
170504
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161013
[St] Status:MEDLINE
[do] DOI:10.1038/ja.2016.122



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