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Naphthoquinone Antibiotics from 'Fusarium solani'.  

National Technical Information Service (NTIS)

The invention relates to new naphthoquinone derivatives which exhibit antibiotic activity. Three naphthoquinones isolated from cultures of Fusarium solani were found to be effective antibiotics against gram-positive bacteria. Controlling the dissolved oxy...

R. A. Baker J. H. Tatum



Bioactive naphthoquinones from Cordyceps unilateralis  

Microsoft Academic Search

Six bioactive naphthoquinone derivatives, erythrostominone, deoxyerythrostominone, 4-O-methyl erythrostominone, epierythrostominol, deoxyerythrostominol and 3,5,8-trihydroxy-6-methoxy-2-(5-oxohexa-1,3-dienyl)-1,4-naphthoquinone, were isolated from the insect pathogenic fungus Cordyceps unilateralis BCC1869. While the latter is synthetically known, both it and 4-O-methyl erythrostominone are products of fungus strain C. unilateralis BCC1869.

Prasat Kittakoop; Juntira Punya; Palangpon Kongsaeree; Yuwapin Lertwerawat; Amnuay Jintasirikul; Morakot Tanticharoen; Yodhathai Thebtaranonth



The trypanocidal activity of naphthoquinones: a review.  


Naphthoquinones are compounds present in several families of higher plants. Their molecular structures confer redox properties, and they are involved in multiple biological oxidative processes. In folk medicine, especially among Indian populations, plants containing naphthoquinones have been employed for the treatment of various diseases. The biological redox cycle of quinones can be initiated by one electron reduction leading to the formation of semiquinones, unstable intermediates that react rapidly with molecular oxygen, generating free radicals. Alternatively, the reduction by two electrons, mediated by DT-diphorase, leads to the formation of hydroquinone. Lapachol, alpha-lapachone and beta-lapachone, which are isolated from the heartwood of trees of the Bignoniaceae family, are examples of bioactive naphthoquinones. In this review, we will discuss studies investigating the activity of these natural products and their derivatives in the context of the search for alternative drugs for Chagas disease, caused by Trypanosoma cruzi, a neglected illness that is endemic in Latin America. PMID:19924086

Pinto, Antônio Ventura; de Castro, Solange Lisboa



A new dimeric naphthoquinone from Diospyros anisandra.  


From the hexane extract of stem bark of Diospyros anisandra was isolated a new plumbagin dimer, epoxide of zeylanone, along with 14 known compounds, including seven naphthoquinones, four triterpenoids and three sesquiterpenoids. The structures were elucidated by the application of IR, UV, MS, 1D- and 2D-NMR spectroscopic analysis and by comparison with literature data. PMID:22963268

Uc-Cachón, A H; Molina-Salinas, G M; Said-Fernández, S; Méndez-González, M; Cáceres-Farfán, M; Borges-Argáez, R



Naphthoquinones as allelochemical triggers of programmed cell death  

Microsoft Academic Search

Juglone and plumbagin are plant bioactive derivatives of 1,4-naphthoquinone occurring in plants, whereas lots of these plants belong to invasive species. Clarifying of action of juglone and plumbagin applied on plant cell model represented by tobacco BY-2 cells was the basic aim of this work. It was shown that naphthoquinones are able to induce various structural, functional and enzymatic changes

Petr Babula; Vojt?ch Adam; René Kizek; Zden?k Sladký; Ladislav Havel



Leishmanicidal activity of two naphthoquinones against Leishmania donovani.  


Here we studied ability of two naphthoquinones to inhibit Leishmania growth (2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (TR 001) and 2,3-dibromo-1,4-naphthoquinone (TR 002). TR 001 was more efficient than TR 002 in inducing killing of promastigotes and intracellular amastigotes. These values compare well to those obtained with the standard first-line antileishmanial agent sodium stibogluconate (SSG). TR 001 also induced significantly more nitric oxide (NO) production than TR 002 or SSG. Taken together, these data show that TR 001 and TR 002 could be promising new drugs for treatment of visceral leishmaniasis. PMID:23037165

Lezama-Dávila, Claudio Manuel; Isaac-Márquez, Angelica Patricia; Kapadia, Govind; Owens, Katherine; Oghumu, Steve; Beverley, Stephen; Satoskar, Abhay Rajaninath



Formation of 5-Hydroxy-3-methoxy-1,4-naphthoquinone and 8-Hydroxy-4-methoxy-1,2-naphthoquinone from Juglone  

PubMed Central

From the treatment of 5-hydroxy-1,4-naphthoquinone (juglone) with acetic anhydride and H2SO4 followed subsequently by treatment with methanolic HCl, 5-hydroxy-3-methoxy-1,4-naphthoquinone (3-methoxy juglone) and 8-hydroxy-4-methoxy-1,2-naphthoquinone were obtained as products rather than the anticipated product 2,5-dihydroxy-1,4-naphthoquinone (2-hydroxy juglone). The reaction and the identification of the products are discussed in terms of NMR and DFT calculations.

Blauenburg, Bastian; Metsa-Ketela, Mikko; Klika, Karel D.



Naphthoquinone glucosides of Drosera gigantea from in vitro cultures.  


From the shoots of Drosera gigantea propagated under in vitro culture, the rare naphthoquinone glucosides droserone (3,5-dihydroxy-2-methyl-1,4-naphthoquinone) and hydroxydroserone (3,5,8-trihydroxy-2-methyl-1,4-napthoquinone) 5-O-beta-glucosides, together with the free naphthoquinones droserone, hydroxydroserone and plumbagin were isolated. The structures of the glucosides and hydroxydroserone were studied by 2D NMR techniques. The glucosides appear to be responsible for the brown-red (maroon) colour of this plant. Of the other naphthoquinones typical for the family Droseraceae only hydroplumbagin glucoside could be detected, whereas the presence of 7-methyljuglone and rossoliside (= 7-methylhydrojuglone glucoside) was excluded. PMID:11105579

Budzianowski, J



Study on cytotoxicity and structure-activity relationship of HL-7702 cell exposed to naphthoquinones.  


The acute cytotoxicities of six naphthoquinone compounds, including Atovaquone, Buparvaquone, Menadione, 2-acetoxy-1,4-naphthoquinone and 2-ethoxy-1,4-naphthoquinone, to HL-7702 cells were determined. The results showed that the toxicities of these naphthoquinones were characterized by a steep response pattern except for 2-hydroxy-1,4-naphthoquinone. Meanwhile, the cellular injuries were unrecoverable. Several molecular descriptors, such as the octanol-water partition coefficients (LogP), diameter (Dia) and topological index (TIndx), played an important role in the toxicity of naphthoquinones to HL-7702 cell. Our results provide a foundation for further investigation using 3D-QSAR and HQSAR to evaluate the aquatic ecological risk and the possible mechanisms of toxicity of naphthoquinones. PMID:22387353

Guo, Jing; Song, Wenhua; Ding, Feng; Zhang, Jinyang; Sun, Zengtian




EPA Science Inventory

The Health and Environmental Effects Profile for 1,4-Naphthoquinone was prepared to support listings of hazardous constituents of a wide range of waste streams under Section 3001 of the Resource Conservation and Recovery Act (RCRA) and to provide health-related limits for emergen...


Dihydrolindbladiones, three new naphthoquinone pigments from a myxomycete Lindbladia tubulina.  


Three new naphthoquinone pigments, 6,7-dimethoxydihydrolindbladione (1), dihydrolindbladione (2), and 6-methoxydihydrolindbladione (3), have been isolated from a myxomycete Lindbladia tubulina, and their structures were elucidated by spectral data. Compound 3 appreciably exhibited a reversal effect of multidrug resistance. Lindbladione (4), the major pigment of this myxomycete, was also isolated from Cribraria intricata. PMID:12880324

Misono, Yuka; Ishikawa, Yae; Yamamoto, Yukinori; Hayashi, Masahiko; Komiyama, Kanki; Ishibashi, Masami




EPA Science Inventory

Naphthalene is an important industrial chemical, which has recently been shown to cause tumors of the respiratory tract in rodents. It is thought that one or more reactive metabolites of naphthalene, namely, naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ), and 1,4-na...


An antileishmanial prenyloxy-naphthoquinone from roots of Plumbago zeylanica.  


Leishmania donovani, an obligate intracellular parasite of genus Leishmania causes visceral leishmaniasis that affects millions of people worldwide, especially in the Indian subcontinent and East Africa. Generic pentavalent antimonials have been the mainstay for therapy in the endemic regions due to efficacy and cost effectiveness but the growing incidence of their resistance has seriously hampered their use. This study discloses strong in vitro antileishmanial activity of 2-methyl-5?-(3'-methyl-but-2'-enyloxy)-[1,4]naphthoquinone (1), a prenyloxy-naphthoquinone isolated and characterised from roots of the plant Plumbago zeylanica (family-Plumbaginaceae). The observed EC50 for the compound 1 against promastigote and amastigote forms of L. donovani was significantly (p<0.001) lower than miltefosine, a reference drug. In context to limited treatment options and growing resistance for available drugs, compound 1 offers a greater prospect towards antileishmanial drug discovery and development. PMID:22708724

Mishra, Bhuwan B; Gour, Jalaj K; Kishore, Navneet; Singh, Rakesh K; Tripathi, Vyasji; Tiwari, Vinod K



Redox cycling of o-naphthoquinones in yrypanosomatids  

Microsoft Academic Search

?-Lapachone and structurally related lipophilic o-naphthoquinones, namely, CG 8-935, CG 9-442, CG 10-248 and mansonones A, C, E, and F, were investigated for redox cycling, production of reactive oxygen species, and cytotoxicity in the trypanosomatids Crithidia fasciculata and Leptomonas seymouri. Structural analysis of the assayed quinones indicated that a tricyclic structure, including a naphthalene ring, a 1,2b or l,8bc pyran

Maria P. Molina Portela; Silvia H. Fernandez Villamil; Luis J. Perissinotti; Andres O. M. Stoppani



Naphthalene SOA: redox activity and naphthoquinone gas-particle partitioning  

NASA Astrophysics Data System (ADS)

Chamber secondary organic aerosol (SOA) from low-NOx photooxidation of naphthalene by hydroxyl radical was examined with respect to its redox cycling behaviour using the dithiothreitol (DTT) assay. Naphthalene SOA was highly redox-active, consuming DTT at an average rate of 118 ± 14 pmol per minute per ?g of SOA material. Measured particle-phase masses of the major previously identified redox active products, 1,2- and 1,4-naphthoquinone, accounted for only 21 ± 3% of the observed redox cycling activity. The redox-active 5-hydroxy-1,4-naphthoquinone was identified as a new minor product of naphthalene oxidation, and including this species in redox activity predictions increased the predicted DTT reactivity to 30 ± 5% of observations. These results suggest that there are substantial unidentified redox-active SOA constituents beyond the small quinones that may be important toxic components of these particles. A gas-to-SOA particle partitioning coefficient was calculated to be (7.0 ± 2.5) × 10-4 m3 ?g-1 for 1,4-naphthoquinone at 25 °C. This value suggests that under typical warm conditions, 1,4-naphthoquinone is unlikely to contribute strongly to redox behaviour of ambient particles, although further work is needed to determine the potential impact under conditions such as low temperatures where partitioning to the particle is more favourable. Also, higher order oxidation products that likely account for a substantial fraction of the redox cycling capability of the naphthalene SOA are likely to partition much more strongly to the particle phase.

McWhinney, R. D.; Zhou, S.; Abbatt, J. P. D.



Biomimetic synthesis of zeylanone and zeylanone epoxide by dimerization of 2-methyl-1,4-naphthoquinone.  


A biomimetic synthesis of zeylanone and zeylanone epoxide, which are natural dimeric naphthoquinones, has been accomplished starting from plumbagin, a natural monomeric naphthoquinone. The key features of our synthesis are cascade intermolecular and intramolecular Michael reactions, followed by epoxidation of the resultant hydroquinone with molecular oxygen. PMID:23527796

Maruo, Sayako; Nishio, Kazuyuki; Sasamori, Takahiro; Tokitoh, Norihiro; Kuramochi, Kouji; Tsubaki, Kazunori



Laccase-generated quinones in naphthoquinone synthesis via Diels–Alder reaction  

Microsoft Academic Search

The tandem synthesis of naphthoquinones was conducted from the reaction of laccase-generated quinones and acyclic dienes via Diels–Alder reaction. This reaction was carried out under mild condition in aqueous medium and yielded naphthoquinones up to 80%. In addition, the effect of solvent was also investigated and water was shown to be optimal for this reaction.

Suteera Witayakran; Abdullah Zettili; Arthur J. Ragauskas



Photoreactions of 1,4-Naphthoquinones: effects of substituents and water on the intermediates and reactivity.  


The photochemistry of lapachol and other 1,4-naphthoquinone (NQ) derivatives, e.g. 2-methoxy-1,4-naphthoquinone (MeONQ), 2-hydroxy-1,4-naphthoquinone (2-HONQ) or 5-hydroxy-1,4-naphthoquinone (5-HONQ) and 2-methyl-5-hydroxy-1,4-naphthoquinone (P-NQ) in solution at room temperature was studied by ultraviolet-visible spectroscopy after nanosecond laser pulses at 248 nm. The triplet state and semiquinone radicals were observed for MeONQ, HONQ and P-NQ, whereas for lapachol, intramolecular H-atom and charge transfer processes take place, as in the case of vitamin K1. The photoinduced reaction of NQ into HONQ is initiated by nucleophilic water addition to the triplet state, and for the secondary reactions, a modified mechanism is proposed. PMID:15560739

Görner, Helmut


Cytotoxicity of new alkylamino- and phenylamino-containing polyfluorinated derivatives of 1,4-naphthoquinone.  


Fluorinated derivatives of 1,4-naphthoquinone are highly potent inhibitors of Cdc25A and Cdc25 phosphatases and growth of tumor cells. Five new N-substituted polyfluorinated derivatives of 2-amino-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-tert-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) inhibited the growth of normal control and tumor cells at the same concentration. Three compounds: 2-diethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (2), 2-ethylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-phenylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4) exhibited a 50% decrease in the growth of cancer cells at low and comparable concentrations (2.4-8.6 microM) while being remarkably less cytotoxic toward normal LMTK and PMF cells. Quinones (1)-(4), but not 2-phenylamino-3-methyl-5,6,7,8-tetrafluoro-1,4-naphthoquinone (5), efficiently suppressed spontaneous mutagenesis in Salmonella cells, while all compounds 1-5 decreased the mutagenic effect of H2O2 on bacterial cells. Their possible perspectives as anticancer drugs are shortly discussed. PMID:20189692

Zakharova, Ol'ga D; Ovchinnikova, Ludmila P; Goryunov, Leonid I; Troshkova, Nadezhda M; Shteingarts, Vitalij D; Nevinsky, Georgy A



Coproduction and ecological significance of naphthoquinones in carnivorous sundews (Drosera).  


While the 1,4-naphthoquinone derivatives 7-methyljuglone (1) and plumbagin (2) possess a diverse and well documented array of biological activities, relatively little remains known about the functional significance of these compounds in planta and, in particular, their possible relation to carnivorous syndromes. In addition, the chemotaxonomic distribution of naphthoquinones (NQs) amongst species of Drosera L. is of phytopharmaceutical interest. Following the quantitative assessment of interspecific variation of 1 and 2 in 13 species and cultivars of Drosera, our findings demonstrate that these NQs are ubiquitously coproduced in, generally, species-specific ratios, and that 1 appears negatively associated with the occurrence of pigmentation in sundews. The prospective antifeedant function of 1 was evaluated in relation to allocation in various organs and ontogenetic phases of D. capensis L., revealing that significantly higher levels were accumulated in young and reproductive organs, most likely for defensive purposes. Investigation into the relationship between the biosynthesis of NQs and carnivory showed that production of 1 is optimally induced and localized in leaves in response to capture of insect prey. As a whole, these findings reveal the clear importance of this secondary metabolite in ecological interactions as well as holding implication for future bioactivity studies on the genus. PMID:22700223

Egan, Paul A; van der Kooy, Frank



Cell-Specific Production and Antimicrobial Activity of Naphthoquinones in Roots of Lithospermum erythrorhizon  

Microsoft Academic Search

Pigmented naphthoquinone derivatives of shikonin are produced at specific times and in specific cells of Lithospermum erythrorhizon roots. Normal pigment development is limited to root hairs and root border cells in hairy roots grown on \\

Lindy A. Brigham; Paula J. Michaels; Hector E. Flores



Parameters and mechanistic studies on the oxidative ring cleavage of synthetic heterocyclic naphthoquinones by Streptomyces strains  

Microsoft Academic Search

Screening of fungal and bacterial strains allowed selection of two Streptomyces strains (S. platensis and S. cinnamonensis) that oxidatively cleave, in moderate to high yields (up to 65% in 24 h), the quinonic ring of a thiazole fused 1,4-naphthoquinone compound, INO5042, used as a model compound for a series of homologous substituted heterocyclic naphthoquinones. The respective products of these whole-cell biotransformations

Céline Fosse; Laurence Texier; Sébastien Roy; Marcel Delaforge; Sébastien Grégoire; Michel Neuwels; Robert Azerad



Antimicrobial activity of 5-hydroxy-1,4-naphthoquinone isolated from Caesalpinia sappan toward intestinal bacteria  

Microsoft Academic Search

The methanol extract of Caesalpinia sappan heartwoods was tested for the growth effects toward five intestinal microorganisms. The biologically active constituent of the C. sappan extract was characterized as 5-hydroxy-1,4-naphthoquinone (C10H6O3). The growth responses varied depending on the bacterial species and dose tested. In the test with Clostridium perfringens, 5-hydroxy-1,4-naphthoquinone produced the strong (+++) inhibition at 5 and 2mg\\/disk and

Mi-Youn Lim; Ju-Hyun Jeon; Eun-Young Jeong; Chi-Hoon Lee; Hoi-Seon Lee



Parameters determining the relative efficacy of hydroxy-naphthoquinone inhibitors of the cytochrome bc 1 complex  

Microsoft Academic Search

Hydroxy-naphthoquinones are competitive inhibitors of the cytochrome bc1 complex that bind to the ubiquinol oxidation site between cytochrome b and the iron–sulfur protein and presumably mimic a transition state in the ubiquinol oxidation reaction catalyzed by the enzyme. The parameters that affect efficacy of binding of these inhibitors to the bc1 complex are not well understood. Atovaquone®, a hydroxy-naphthoquinone, has

Jacques J. Kessl; Nikolai V. Moskalev; Gordon W. Gribble; Mohamed Nasr; Steven R. Meshnick; Bernard L. Trumpower



Antitumoral activity of new polyamine-naphthoquinone conjugates.  


Polyamine-naphthoquinone conjugates 5a-c were synthesized by nucleophilic displacement of 2-methoxy-lawsone 3a, 2-methoxylapachol 3b and 2-methoxy-nor-lapachol 3c with the polyamine N1-Boc-N5-Bn-spermidine 4. Unprotected derivatives 6a-c were synthesized to evaluate the effect of the protective Boc group on the activity of compounds 5a-c. The colorimetric MTT assay was used to evaluate their cytotoxic activity. All compounds were active against human lines of promyelocytic leukemia (HL-60), lung cancer (GLC4), Burkitt lymphoma (Daudi) and a mouse breast tumor (Ehrlich carcinoma), but only unprotected 6a-c showed activity against the human line of melanoma (MV-3). IC50 values were obtained from dose response curves by linear regression. DNA fragmentation was measured by quantification of the subG1 peak of the cell cycle. Apoptosis of HL-60 treated with 5c was dose-dependent. The amount of DNA fragmentation observed by exposure of HL-60 to 25 microM of compounds 5a-c and 6a-c is compatible with the decrease in viability induced by the drugs at this concentration. Production of ROS was measured by H2-CFDA. Kinetics of HL-60 DNA fragmentation and ROS formation by 5c indicated that production of ROS precedes cell death. In conclusion, spermidine-1,4-naphthoquinone conjugates exhibited an increase in activity compared with the natural products and induced apoptosis of tumor cell lines by a mechanism that is mediated, at least in part, by ROS production. PMID:18575741

Esteves-Souza, Andressa; Lucio, Kelly Araújo; Da Cunha, Andréa Sousa; Da Cunha Pinto, Angelo; Da Silva Lima, Edson Luiz; Camara, Celso Amorim; Vargas, Maria Domingues; Gattass, Cerli Rocha




EPA Science Inventory

Naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are the major metabolites of naphthalene that are thought to be responsible for the cytotoxicity and genotoxicity of this chemical. We measured cysteinyl adducts of these metabolites in ...


Antitumor activity of two derivatives from 2-acylamine-1, 4-naphthoquinone in mice bearing S180 tumor.  


Drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and lapachol, show excellent anticancer activity. In this study, 2-butanoylamine-1,4-naphthoquinone (1) and 2-propanoylamine-1,4-naphthoquinone (2) derivatives from 2-amine-1 ,4-naphthoquinone were synthesized, and their antitumor activity in mice bearing Sarcoma 180 tumor were examined. In addition, hematology and biochemistry analyses, as well as, histopathological and morphological analyses were performed in order to evaluate the toxicological aspects of the naphthoquinones treatment. Both naphthoquinones showed potente antitumor activity. The inhibition rates were 33.48 and 42.35% for (1) and 37.65 and 55.24% for (2) at the dose of 25 and 50 mg/kg/day, respectively. In the histopathological analysis, the naphthoquinones showed only weak toxicity. Neither enzimatic activity of transaminases (aspartate aminotransferase-AST nor alanine aminotransferase-ALT), urea level nor hematological paramenter were significantly modified after naphthoquinones treatment. These data reinforce the anticancer potential of naphthoquinones derivatives. PMID:18771085

Bezerra, Daniel Pereira; Alves, Ana Paula Negreiros Nunes; de Alencar, Nylane Maria Nunes; Mesquita, Rodney de Oliveira; Lima, Michael Will; Pessoa, Cláudia; de Moraes, Manoel Odorico; Lopes, José Norberto Callegari; Lopes, Norberto Peporine; Costa-Lotufo, Letícia Veras



Metabolic and Electrochemical Mechanisms of Dimeric Naphthoquinones Cytotoxicity in Breast Cancer Cells  

PubMed Central

Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC50 = 15 ?M. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.

Emadi, Ashkan; Le, Anne; Harwood, Cynthia J.; Stagliano, Kenneth W.; Kamangar, Farin; Ross, Ashley E.; Cooper, Charles R.; Dang, Chi V.; Karp, Judith E.; Vuica-Ross, Milena



Synthesis and preliminary pharmacological evaluation of new (+/-) 1,4-naphthoquinones structurally related to lapachol.  


Seven new 1,4-naphthoquinones structurally related to lapachol were synthesized from lawsone and oxygenated arylmercurials. These compounds can also be seen as pterocarpan derivatives where the A-ring was substituted by the 1,4-naphthoquinone nucleus. Pharmacological screening provided evidence of significant biological activities, including effects against proliferation of the MCF-7 human breast cancer cell line, against Herpes Simplex Virus type 2 infection, and against snake poison-induced myotoxicity. One derivative displaced flunitrazepam binding and showed benzodiazepine-like activity, suggesting novel neuroactive structural motifs. PMID:12057662

da Silva, Alcides J M; Buarque, Camilla D; Brito, Flávia V; Aurelian, Laure; Macedo, Luciana F; Malkas, Linda H; Hickey, Robert J; Lopes, Daniele V S; Noël, François; Murakami, Yugo L B; Silva, Noelson M V; Melo, Paulo A; Caruso, Rodrigo R B; Castro, Newton G; Costa, Paulo R R



Synthesis and properties of fused tetracyclic derivatives of 1,4-naphthoquinone thioglycosides  

Microsoft Academic Search

A series of 1,4-naphthoquinone O-acetylthioglycosides have been synthesized by the condensation of fully O-acetylated derivatives of 1-thio-d-xylose, 1-thio-L-arabinose, 1-thio-d-galactose, 1-thio-d-mannose, and 1-thiomaltose with 3-chloro-2-methoxy-1,4-naphtho-quinone. Their deacetylation with MeONa\\/MeOH proceeded with\\u000a simultaneous heterocyclization to yield linear carbohydrate-containing tetracyclic quinones. Tetracycles with trans junction of the carbohydrate and quinone rings are poorly soluble in water and organic solvents.

S. G. Polonik; V. A. Denisenko



Thiourea-catalyzed Diels-Alder reaction of a naphthoquinone monoketal dienophile  

PubMed Central

Summary A variety of organocatalysts were screened for the catalysis of the naphthoquinone monoketal Diels–Alder reaction. In this study we found that Schreiner's thiourea catalyst 10 and Jacobson's thiourea catalyst 12 facilitate the cycloaddition of the sterically hindered naphthoquinone monoketal dienophile 3 with diene 4. The use of thiourea catalysis allowed for the first time the highly selective synthesis of the exo-product 2a in up to 63% yield. In this reaction a new quaternary center was built. The so formed cycloaddition product 2a represents the ABC tricycle of beticolin 0 (1) and is also a valuable model substrate for the total synthesis of related natural products.

Kramer, Carsten S



Cytotoxicity of new n-butylamino and sulfur-containing derivatives of polyfluorinated 1,4-naphthoquinone.  


Four new n-butylamino and two sulfur-containing derivatives of polyfluoro-1,4-naphthoquinone were synthesized and their mutagenic and antioxidant properties in Salmonella cells, as well as the cytotoxicity in human myeloma (RPMI 8226), human mammary adenocarcinoma (MCF-7), mouse fibroblasts (LMTK) and primary mouse fibroblast cells (PMF) were studied. 2-n-Butylamino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1) showed efficient inhibition of the growth of the tumor cells. 2,8-Di-(n-butyl-amino)-3,5,6,7-tetrafluoro-1,4-naphthoquinone (2) had significantly less growth-inhibiting properties, while 2,6-di-(n-butylamino)-3,5,7,8-tetrafluoro-1,4-naphthoquinone (3) and 2,6,8-tri-(n-butylamino)-3,5,7-tetrafluoro-1,4-naphthoquinone (4), demonstrated very low cytotoxicity. Compounds 1 and 2 were remarkably less cytotoxic while compound 3 and 4 were not cytotoxic toward LMTK and PMF cells as compared with tumor human cell lines. Cytotoxicity of 2-(2'-methylthioethyl)amino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (5) and (2,2'-dithiodi-2)-3,5,6,7,8-pentafluoro-1,4-naphthoquinone-2-ylamino)ethan (6) toward mammalian cells was compared with that for compounds 1 and 2. PMID:19883955

Zakharova, Ol'ga A; Goryunov, Leonid I; Troshkova, Nadezhda M; Ovchinnikova, Ludmila P; Shteingarts, Vitalij D; Nevinsky, Georgy A



Selective electrochemical recognition of the ?-naphthol isomer and in situ immobilization of naphthoquinones for tunable electrocatalysis.  


Fits like a glove: Separationless and selective electrochemical oxidation of the ?-naphthol (?-NAP) isomer yields naphthoquinone species on the surface of multiwalled carbon nanotubes, which can further catalyze the electro-oxidation of NADH and hydrazine at different potentials. The ?-NAP isomer failed to show any such electro-oxidation. PMID:23471842

Swetha, Puchakayala; Kumar, Annamalai Senthil



Naphthoquinone spiroketal with allelochemical activity from the newly discovered endophytic fungus Edenia gomezpompae  

Microsoft Academic Search

Chemical investigation of the mycelium of Edenia gomezpompae, a newly discovered endophytic fungus isolated from the leaves of Callicarpa acuminata (Verbenaceae) collected from the ecological reserve El Eden, Quintana Roo, Mexico, resulted in the isolation of four naphthoquinone spiroketals, including three new compounds and palmarumycin CP2 (4). We elucidated the structures of the metabolites by extensive NMR spectroscopy studies, including

Martha L. Macías-Rubalcava; Blanca E. Hernández-Bautista; Manuel Jiménez-Estrada; María C. González; Anthony E. Glenn; Richard T. Hanlin; Simón Hernández-Ortega; Aurora Saucedo-García; Jordi M. Muria-González; Ana Luisa Anaya



Antioxidant property of polyhydroxylated naphthoquinone pigments from shells of purple sea urchin Anthocidaris crassispina  

Microsoft Academic Search

Sea urchin gonads are highly priced sushi foodstuff “Uni” in Japanese traditional food, but after removal of them the residual shells with spines are dumped as waste. However, sea urchin shells contain naphthoquinone pigments with several phenolic hydroxyl groups, which were expected to act as potent antioxidant substances by donating hydrogens. Our previous study has evaluated their antioxidant ability to

Rui Kuwahara; Hideo Hatate; Tamami Yuki; Hisashi Murata; Ryusuke Tanaka; Yoichiro Hama



Naphthoquinone spiroketal with allelochemical activity from the new endophytic fungus Edenia gomezpompae  

Technology Transfer Automated Retrieval System (TEKTRAN)

Bioassay-guided isolation from the culture of Edenia gomezpompae, a new endophytic fungus isolated from the leaves of Callicarpa acuminata (Verbenaceae) from the ecological reserve El Eden, Quintana Roo, Mexico, led to the isolation of four naphthoquinone spiroketals, including three new compounds. ...


Mutagenicity and cytotoxicity of naphthoquinones for Ames Salmonella tester strains  

SciTech Connect

The molecular mechanisms involved in quinone cytotoxicity, especially mutagenicity, are still largely unknown. In order to better understand the molecular aspects of the mechanisms of quinone mutagenicity and cytotoxicity, we examined them by using a series of 13 simple structural naphthoquinone (NQ) derivatives for 9 Ames Salmonella mutagenicity tester strains in the presence or absence of liver homogenate S9 mix from rats induced with phenobarbital and 5,6-benzoflavone. Most NQs used in this study showed mutagenicity with and/or without S9 mix. The most potent mutagenic NQ was 2,3-dichloro-1,4-NQ, with mutagenicity of 18 induced revertents/nmol/plate for strain TA104 without S9 mix. Among the strains used, TA104, which is sensitive to oxidative mutagens, was the most sensitive to the NQs, and the second most sensitive strain was TA2637, which detects bulky DNA adducts. The relationship of mutagenic potency to the one-electron reduction potential with TA104 suggested that the higher redox potential NQs were more mutagenic than the lower redox potential NQs. The cytotoxic effect of the NQs was largely dependent on the structures of their substituents. It was suggested that the higher redox potential NQs were more cytotoxic than the lower redox potential NQs for all of the strains used, in contrast to the mutagenicity of the NQs. The presence of S9 mix decreased the cytotoxic effect of the NQs, the extent of which was also largely dependent on the structures of their substituents and is in accordance with the order of the height of the one-electron reduction potentials. These results indicate that the mutagenicity of NQs in Salmonella typhimurium was due to oxidative damage produced with activated oxygen species such as hydroxy radical and superoxide anion radical, which are generated as a result of the reduction of the NQs, and to bulky NQ-DNA adducts accounting for their electrophilic property, whose contribution was largely dependent on the substituents of NQs.

Hakura, Atsushi; Mochida, Hisatoshi; Tsutsui, Yoshie; Yamatsu, Kiyomi [Eisai Co., Ltd., Tsukuba-shi (Japan)



Antitrypanosomal Activities and Cytotoxicity of Some Novel Imido-substituted 1,4-Naphthoquinone Derivatives  

PubMed Central

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 µM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 µM to 6.1 µM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).

Khraiwesh, Mozna H.; Lee, Clarence M.; Brandy, Yakini; Akinboye, Emmanuel S.; Berhe, Solomon; Gittens, Genelle; Abbas, Muneer M.; Ampy, Franklin R.; Ashraf, Mohammad



Stereoselective synthesis and cytotoxicity of a cancer chemopreventive naphthoquinone from Tabebuia avellanedae.  


Stereoselective synthesis of 1, one of biologically active naphthoquinones from a Brazilian traditional medicine Tabebuia avellanedae, was achieved by utilizing Noyori reduction as a key step. Compound 1 displayed potent cytotoxicity against several human tumor cell lines, whereas it showed lower cytotoxicity against some human normal cell lines compared with that of mitomycin. On the other hand, its enantiomer was less active toward the tumor cell lines than 1. PMID:17950604

Yamashita, Mitsuaki; Kaneko, Masafumi; Iida, Akira; Tokuda, Harukuni; Nishimura, Katsumi



A Chemical Genetic Screen for Modulators of Asymmetrical 2,2'Dimeric Naphthoquinones Cytotoxicity in Yeast  

Microsoft Academic Search

BackgroundDimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast

Ashkan Emadi; Ashley E. Ross; Kathleen M. Cowan; Yolanda M. Fortenberry; Milena Vuica-Ross; Xuewen Pan



Parameters Determining the Relative Efficacy of Hydroxy-naphthoquinone Inhibitors of the Cytochrome bc1 Complex  

PubMed Central

Summary Hydroxy-naphthoquinones are competitive inhibitors of the cytochrome bc1 complex that bind to the ubiquinol oxidation site between cytochrome b and the iron-sulfur protein and presumably mimic a transition state in the ubiquinol oxidation reaction catalyzed by the enzyme. The parameters that affect efficacy of binding of these inhibitors to the bc1 complex are not well understood. Atovaquone®, a hydroxy-naphthoquinone, has been used therapeutically to treat Pneumocystis carinii and Plasmodium infections. As the pathogens have developed resistance to this drug, it is important to understand the molecular basis of the drug resistance and to develop new drugs that can circumvent the drug resistance. We previously developed the yeast and bovine bc1 complexes as surrogates to model the interaction of atovaquone with the bc1 complexes of the target pathogens and human host. As a first step to identify new cytochrome bc1 complex inhibitors with therapeutic potential and to better understand the determinants of inhibitor binding, we have screened a library of 2-hydroxy-naphthoquinones with aromatic, cyclic, and non-cyclic alkyl side-chain substitutions at carbon-3 on the hydroxy-quinone ring. We found a group of compounds with alkyl side-chains that effectively inhibit the yeast bc1 complex. Molecular modeling of these into the crystal structure of the yeast cytochrome bc1 complex provides structural and quantitative explanations for their binding efficacy to the target enzyme. In addition we also identified a 2-hydroxy-naphthoquinone with a branched side-chain that has potential for development as an anti-fungal and anti-parasitic therapeutic.

Kessl, Jacques J.; Moskalev, Nikolai V.; Gribble, Gordon W.; Nasr, Mohamed; Meshnick, Steven R.; Trumpower, Bernard L.



Antiplasmodial activity of naphthoquinones related to lapachol and beta-lapachone.  


The in vitro antiplasmodial activity of 26 naphthoquinone derivatives related to the natural lapachol (1) and beta-lapachone (2) was tested. Ten of these derivatives are reported for the first time. The evaluation was performed on cultures of F32 strain of Plasmodium falciparum, and some derivatives displayed attractive in vitro activities (IC50 < 10 microM). Based on these results, some structure-activity relationships have been determined. PMID:17191979

Pérez-Sacau, Elisa; Estévez-Braun, Ana; Ravelo, Angel G; Gutiérrez Yapu, David; Giménez Turba, Alberto



Electron transfer in DNA duplexes containing 2-methyl-1,4-naphthoquinone  

Microsoft Academic Search

Methyl-1,4-naphthoquinone (menadione, MQ) was linked to synthetic oligonucleotides and exposed to near-UV light to generate base radical cations in DNA. This model system of electron transfer induced alkali- labile breaks at GG doublets, similar to anthraquinone and metallointercalators systems. In sharp contrast to other systems, the photolysis of MQ-DNA duplexes gave interstrand cross-links and alkali-labile breaks at bases on the

Francois Bergeron; Daniel Houde; Darel J. Hunting; J. Richard Wagner



Naphthoquinone contents of in vitro cultured plants and cell suspensions of Dionaea muscipula and Drosera species  

Microsoft Academic Search

In vitro cultured carnivorous plants were grown on a hormone-free medium. They produced the following naphthoquinones: Dionaea muscipula (plumbagin: 5.3%), Drosera rotundifolia (7-methyljuglone: 0.6%), D. binata (plumbagin: 1.4%), and D. capensis (7-methyljuglone: 0.5%). A red, slow-growing suspension culture of D. muscipula was maintained in a modified McCowns Woody Plant (McC) medium and produced plumbagin (2.59%) after 30 days growth. A

Ingrid L. I. Hook



Biosynthetic capacities of actinomycetes. 2. Juglomycin Z, a new naphthoquinone antibiotic from Streptomyces tendae.  


A new juglomycin-type antibiotic was identified by a HPLC-diode array screening technique in the culture filtrate of Streptomyces tendae Tü 901/8c. Juglomycin Z (1) differs from all other known juglomycin compounds by an additional methyl group in position 3 of the naphthoquinone ring system. Juglomycin Z is antibiotically active against Gram-positive and Gram-negative bacteria and against yeasts. PMID:7961161

Fiedler, H P; Kulik, A; Schüz, T C; Volkmann, C; Zeeck, A



Chirogenic [3 + 2]-photocycloaddition reactions of 2-substituted naphthoquinones with cyclic alkenes.  


The formal [3 + 2]-photocycloaddition of 2-hydroxy- (2a) and 2-amino-1,4-naphthoquinone (2b) to olefins was studied in various solvents aiming at a possible enantioselective reaction course. The reaction conditions were optimised for irradiation at low temperature in a nonpolar solvent employing external fluorescent lamps as irradiation sources. Best yields for the reaction of 2-hydroxy-1,4-naphthoquinone (2a) with 1-methyl-2-butene were obtained when using a large excess of the olefin (200 equiv.) in toluene as the solvent at an irradiation wavelength of ? = 419 nm. Under these conditions a variety of cyclic alkenes (cyclopentene, cyclohexene, dihydropyran, 1-methylcyclohex-1-ene) underwent the photocycloaddition in yields of 22-84%. Reactions with 2-hydroxy-1,4-naphthoquinone (2a) could be performed enantioselectively at -60 °C in toluene as the solvent employing a chiral hydrogen bonding template. The enantiomeric excess (?11%) remained low, however. Possible reasons for this lack of selectivity are discussed. PMID:21541428

Müller, Christiane; Bauer, Andreas; Bach, Thorsten



Naphthoquinones and Bioactive Compounds from Tobacco as Modulators of Neuronal Nitric Oxide Synthase Activity  

PubMed Central

Studies were conducted with extracts of several varieties of tobacco in search of neuronal nitric oxide synthase (nNOS) inhibitors which may be of value in the treatment of stroke. Current therapies do not directly exploit modulation of nNOS activity due to poor selectivity of the currently available nNOS inhibitors. The properties of a potentially novel nNOS inhibitor(s) derived from tobacco extracts, and the concentration-dependent, modulatory effects of the tobacco-derived naphthoquinone compound, 2, 3, 6-trimethyl-1, 4-naphthoquinone (TMN), on nNOS activity were investigated, using 2-methyl-1, 4-naphthoquinone (menadione) as a control. Up to 31?M, both TMN and menadione stimulated nNOS-catalyzed L-citrulline production. However, at higher concentrations of TMN (62.5-500 ?M), the stimulation was lost in a concentration-dependent manner. With TMN, the loss of stimulation did not decrease beyond the control activity. With menadione (62.5-500 ?M), the loss of stimulation surpassed that of the control (78 ± 0.01%), indicating a complete inhibition of nNOS activity. This study suggests that potential nNOS inhibitors are present in tobacco, most of which remain to be identified.

Venkatakrishnan, Priya; Gairola, C. Gary; Castagnoli, Neal; Miller, R. Timothy



Use of 1,4-naphthoquinones for control of Erwinia carotovora.  


The antimicrobial effect of 5 naphthoquinones was tested against the phytopathogenic bacteria Erwinia carotovora. Disk diffusion tests and determination of minimal inhibitory concentrations (MIC) indicate that the compound naphthazarin (NTZ) has the best antibacterial activity among the naphthoquinones tested. Studies on the mode of action indicate the effect of NTZ was bactericidal at 10 microg/mL. When cultivation was done in the presence of sodium ascorbate, the restoration of E. carotovora growth was observed with 3 microg/mL NTZ, but not when a 10 microg/mL dose was used. The incubation of NTZ with bacterial suspension of E. carotovora resulted in important changes in the absorption spectra of this naphthoquinone, indicating that a redox reaction takes place. These results may suggest that NTZ induces an increase of reactive oxygen species that are toxic to the cell. The compound NTZ was also effective in preventing E. carotovora growth on potato tubers, inhibiting the soft rot development at a concentration of 2 mg/mL. PMID:15644912

Medina, Luis F C; Stefani, Valter; Brandelli, Adriano



Probing binding determinants in center P of the cytochrome bc1 complex using novel hydroxy-naphthoquinones  

PubMed Central

Atovaquone is a substituted 2-hydroxy-naphthoquinone used therapeutically against Plasmodium falciparum (malaria) and Pneumocystis pathogens. It acts by inhibiting the cytochrome bc1 complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. As the targeted pathogens have developed resistance to this drug there is an urgent need for new alternatives. To better understand the determinants of inhibitor binding in the ubiquinol oxidation pocket of the bc1 complex we synthesized a series of hydroxy-naphthoquinones bearing a methyl group on the benzene ring that is predicted to interact with the nuclear encoded Rieske iron-sulfur protein. We have also attempted to overcome the metabolic instability of a potent cytochrome bc1 complex inhibitor, a 2-hydroxy-naphthoquinone with a branched side-chain, by fluorinating the terminal methyl group. We have tested these new 2-hydroxy-naphthoquinones against yeast and bovine cytochrome bc1 complexes to model the interaction with pathogen and human enzymes and determine parameters that affect efficacy of binding of these inhibitors. We identified a hydroxy-naphthoquinone with a trifluoromethyl function that has potential for development as an anti-fungal and anti-parasitic therapeutic.

Hughes, Louise M.; Covian, Raul; Gribble, Gordon W.; Trumpower, Bernard L.



Probing binding determinants in center P of the cytochrome bc(1) complex using novel hydroxy-naphthoquinones.  


Atovaquone is a substituted 2-hydroxy-naphthoquinone used therapeutically against Plasmodium falciparum (malaria) and Pneumocystis pathogens. It acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. As the targeted pathogens have developed resistance to this drug there is an urgent need for new alternatives. To better understand the determinants of inhibitor binding in the ubiquinol oxidation pocket of the bc(1) complex we synthesized a series of hydroxy-naphthoquinones bearing a methyl group on the benzene ring that is predicted to interact with the nuclear encoded Rieske iron-sulfur protein. We have also attempted to overcome the metabolic instability of a potent cytochrome bc(1) complex inhibitor, a 2-hydroxy-naphthoquinone with a branched side chain, by fluorinating the terminal methyl group. We have tested these new 2-hydroxy-naphthoquinones against yeast and bovine cytochrome bc(1) complexes to model the interaction with pathogen and human enzymes and determine parameters that affect efficacy of binding of these inhibitors. We identified a hydroxy-naphthoquinone with a trifluoromethyl function that has potential for development as an anti-fungal and anti-parasitic therapeutic. PMID:19660431

Hughes, Louise M; Covian, Raul; Gribble, Gordon W; Trumpower, Bernard L



Evaluation and structure-activity relationship study of acute toxicity of naphthoquinones to Photobacterium phosphoreum, Photobacterium T3B.  


The acute toxicities of five naphthoquinone compounds to Photobacterium phosphoreum were determined. We evaluated the mechanism of toxicity using the structure-activity relationship technique. The results showed that some factors, including the species of substituents, shape/size of molecule and oil-water partition coefficient (log P) played the important roles in the interaction between the naphthoquinones and the target. Among of these, the toxicities of Atovaquone and Buparvaquone were lower than the other naphthoquinones we tested because of the alkyl-substitution with the bigger volume and strong hydrophobicity. Conversely, Menadione had the highest toxicity because of the appropriate log P and shape/size of molecule resulting in the easier interaction with the target. PMID:20640400

Ding, Feng; Guo, Jing; Li, Zhen; Li, Li Ying; Zhang, Jin Yang; Zhang, Jin Hua; Lian, Jie; Song, Wen Hua; Zhu, Lin



Synthesis and Biological Evaluation of 1,4-Naphthoquinones and Quinoline-5,8-diones as Antimalarial and Schistosomicidal Agents  

PubMed Central

Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The AgII-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO3 and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of ?-hematin.

Lanfranchi, Don Antoine; Cesar-Rodo, Elena; Bertrand, Benoit; Huang, Hsin-Hung; Day, Latasha; Johann, Laure; Elhabiri, Mourad; Becker, Katja; Williams, David L.



Newbouldiaquinone and newbouldiamide: a new naphthoquinone-anthraquinone coupled pigment and a new ceramide from Newbouldia laevis.  


Newbouldiaquinone (1), a new naphthoquinone-anthraquinone coupled pigment and a new ceramide named newbouldiamide (2), have been isolated from Newbouldia laevis, besides the known compounds lapachol (3), canthic acid, oleanolic acid, 2-methyl-9,10-anthracenedione, 2-acetylfuro-1,4-naphthoquinone, 2,3-dimethoxy-1,4-benzoquinone, 2-(4-hydroxyphenyl)ethyl triacontanoate, beta-sitosterol and beta-sitosterol glucopyranoside. The structure elucidations of the isolated new compounds were performed on the basis of spectroscopic and chemical evidence. Preliminary studies showed that 1 is moderately antibacterial against Gram-positive Bacillus megaterium and that 3 has moderate herbicidal and antibacterial activities. PMID:15930769

Eyong, Kenneth Oben; Krohn, Karsten; Hussain, Hidayat; Folefoc, Gabriel Ngosong; Nkengfack, Augustin Ephram; Schulz, Barbara; Hu, Qunxiu



Comparison of the cytotoxic effect of lapachol, ?-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells  

Microsoft Academic Search

Summary  The pentacyclic 1,4-naphthoquinones 1a–d were cytotoxic (IC50???2–7 ?M) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic\\u000a cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones\\u000a 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell

Eduardo J. S. Salustiano; Chaquip D. Netto; Renata F. Fernandes; Alcides J. M. da Silva; Thiago S. Bacelar; Carolina P. Castro; Camilla D. Buarque; Raquel C. Maia; Vivian M. Rumjanek; Paulo R. R. Costa



Singlet oxygen production by pyrano and furano 1,4-naphthoquinones in non-aqueous medium.  


The influence of ring size on the photobehaviour of condensed 1,4-naphthoquinone systems, such as pyrano- and furano-derivatives (1 and 2, respectively) has been investigated. The absorption spectra for both families of naphthoquinones reveal clear differences; in the case of 2 they extend to longer wavelengths. A solvatochromic red shift in polar solvents is consistent with the ?,?* character of the S(0)? S(1) electronic transition in all cases. Theoretical (B3LYP) analysis of the HOMO and LUMO Kohn-Sham molecular orbitals of the S(0) state indicates that they are ? and ?* in nature, consistent with the experimental observation. A systematic study on the efficiency of singlet oxygen generation by these 1,4-naphthoquinones is presented, and values larger than 0.7 were found in every case. In accordance with these results, laser flash photolysis of deoxygenated acetonitrile solutions led to the formation of detectable triplet transient species with absorptions at 390 and 450 nm (1) and at 370 nm (2), with ?(ISC) close to 1. Additionally, the calculated energies for the T(1) states relative to the S(0) states at UB3LYP/6-311++G** are ca. 47 kcal mol(-1) for 1 and 43 kcal mol(-1) for 2. A comparison of the geometrical parameters for the S(0) and T(1) states reveals a marked difference with respect to the arrangement of the exocyclic phenyl ring whilst a comparison of electronic parameters revealed the change from a quinone structure to a di-dehydroquinone diradical structure. PMID:22441459

de Lucas, Nanci C; Corrêa, Rodrigo J; Garden, Simon J; Santos, Guilherme; Rodrigues, Reinaldo; Carvalho, Carlos Eduardo M; Ferreira, Sabrina B; Netto-Ferreira, José Carlos; Ferreira, Vitor F; Miro, Paula; Marin, M Luisa; Miranda, Miguel A



Crystal and molecular structure of 6- t -butyl-1,2-naphthoquinone-1-oxime  

Microsoft Academic Search

The structure of 6-t-butyl-1,2-naphthoquinone-1-oxime was determined by direct methods by the use of MoKa diffractometer data and was refined toR = 0.12. The crystals are monoclinic:a = 8.32(1),b = 6.70(1),c = 11.14(1) Å, ß = 101(1) °,Z = 2,P21\\/m. The molecule is crystallographically flat and lies in a mirror plane. Pronounced diffuse scattering on [010] oscillation photographs is caused by

J. C. A. Boeyens



The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages  

Microsoft Academic Search

The present study reports the anti-mycobacterial activity of 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol) as well as its influence on macrophage functions. Lapachol (L) did not induce apoptosis\\/necrosis of THP-1 macrophages at ?32?g\\/mL. Mycobacterium avium liquid growth was arrested by ?32?g\\/mL and intra-macrophage proliferation by ?16?g\\/mL lapachol. The main immuno-modulatory effects of lapachol observed were an up-regulation of interferon-?-receptor 1 (IFN-?R1) and major histocompatibility

Renato A. S. Oliveira; Eulalia Azevedo-Ximenes; Roberto Luzzati; Rodolfo C. Garcia



Naphthoquinone derivatives and lignans from the Paraguayan crude drug "tayï pytá" (Tabebuia heptaphylla, Bignoniaceae).  


The Paraguayan crude drug "tayï pytá" is used to treat cancer, wounds and inflammation. It consist of the bark and trunkwood of Tabebuia heptaphylla (Bignoniaceae). A phytochemical study of the crude drug gave, in addition to previously described naphthoquinones and the known lignans cycloolivil and secoisolariciresinol, three new lapachenol (lapachonone)-, two naphthofuran-, a chromone and a naphthalene derivative. The structures were elucidated by means of high field NMR spectroscopy. The biological activity of the main compound lapachol and the related alpha-lapachone as well as the lignans cycloolivil and secoisolariciresinol can explain, at least in part, the effect atributed to the crude drug in Paraguayan folk medicine. PMID:12939034

Schmeda-Hirschmann, Guillermo; Papastergiou, Fani


Naphthoquinones from Catalpa ovata and their inhibitory effects on the production of nitric oxide  

Microsoft Academic Search

Bioassay-guided fractionation of a CH2Cl2-soluble fraction of the stems of Catalpa ovata led to isolation of a new naphthoquinone, 4-hydroxy-2-(2-methoxy-3-hydroxy-3-methyl-but-1-enyl)-4-hydro-1H-naphthalen-1-one (10), together with nine known compounds, catalponol (1), catalponone (2), catalpalactone (3), ?-lapachone (4), 9-hydroxy-?-lapachone (5), 4,9-dihydroxy-?-lapachone (6), 9-methoxy-?-lapachone (7), 4-oxo-?-lapachone (8), and 9-methoxy-4-oxo-?-lapachone (9). The structures were elucidated on the basis of spectroscopic analyses. The inhibitory effects of these

Byeong Min Park; Seong Su Hong; Chul Lee; Moon Soon Lee; Shin Jung Kang; Yu Su Shin; Jae-Kyung Jung; Jin Tae Hong; Youngsoo Kim; Mi Kyeong Lee; Bang Yeon Hwang



In vitro cultures of Drosera aliciae as a source of a cytotoxic naphthoquinone: ramentaceone.  


A protocol for the in vitro propagation of Drosera aliciae to increase the yield of the naphthoquinone, ramentaceone, was developed. The highest micropropagation coefficient was obtained using half-strength Murashige-Skoog medium supplemented with 0.4 ?M 6-benzyladenine (BA). The genetic fidelity and stability of the regenerated plants was confirmed with RAPD markers. The activity of the isolated ramentaceone was determined against four human tumor cell lines: U937, HeLa, MCF-7, HCT-116 with the highest cytotoxic activity towards the leukemic U937 cell line with an IC(50) value of 3.2 ?M. PMID:21761256

Kawiak, Anna; Królicka, Aleksandra; ?ojkowska, Ewa



Effect of inducers of DT-diaphorase on the haemolytic activity and nephrotoxicity of 2-amino-1,4-naphthoquinone in rats.  


Reduction of naphthoquinones by DT-diaphorase is often described as a detoxification reaction. This is true for some naphthoquinone derivatives, such as alkyl and di-alkyl naphthoquinones, but the situation with other substances, such as 2-hydroxy-1,4-naphthoquinone, is more complex. In the present study, the effect of several substances that are known to increase tissue activities of DT-diaphorase on the toxicity of 2-amino-1,4-naphthoquinone has been investigated. Like 2-hydroxy-1,4-naphthoquinone, the 2-amino-derivative was found to cause both haemolytic anaemia and renal tubular necrosis in rats. Again like 2-hydroxy-1,4-naphthoquinone, the severity of the haemolysis induced by the 2-amino derivative was increased in animals pre-treated with inducers of DT-diaphorase, but the degree of nephrotoxicity was decreased. With these substances, therefore, DT-diaphorase both activates and detoxifies the quinone, depending on the target organ. It is not possible to generalize with regard to the effects of modulation of tissue levels of DT-diaphorase on naphthoquinone toxicity in vivo, since this may change not only the severity of the toxic effects, but also the target organ specificity. In evaluating the possible therapeutic applications of such compounds, the possibility of toxic effects upon the blood and kidney must be borne in mind. In man, renal damage by compounds such as 2-hydroxy- and 2-amino-1,4-naphthoquinone may be a particular problem, because of the low level of DT-diaphorase in human liver. PMID:16045903

Munday, Rex; Smith, Barry L; Munday, Christine M



The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages.  


The present study reports the anti-mycobacterial activity of 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol) as well as its influence on macrophage functions. Lapachol (L) did not induce apoptosis/necrosis of THP-1 macrophages at ?32 ?g/mL. Mycobacterium avium liquid growth was arrested by ?32 ?g/mL and intra-macrophage proliferation by ?16 ?g/mL lapachol. The main immuno-modulatory effects of lapachol observed were an up-regulation of interferon-?-receptor 1 (IFN-?R1) and major histocompatibility complex class II (MHCII) surface expression, and a marked inhibition of IL-10 secretion. Lapachol did not affect resting, IFN-?- or toll-like receptor 2 (TLR2)-induced levels of oxygen and nitrogen metabolism key proteins nor the TLR2-mediated secretion of TNF-?, nor induced either oxidative or endoplasmic reticulum (ER) stress. Lapachol inhibited the surface expression of the co-stimulatory molecule CD86 but not that of CD80 and CD83. The results obtained indicate that the substituted naphthoquinone lapachol exhibits an anti-mycobacterial activity that is more efficient intra- than extra-cellularly, and exerts immuno-modulatory effects some of which may enhance the capacity of the host cell to control mycobacterial growth. The immune-modulatory action of lapachol could contribute to its more efficient intra-macrophage anti-mycobacterial activity. PMID:20837170

Oliveira, Renato A S; Azevedo-Ximenes, Eulalia; Luzzati, Roberto; Garcia, Rodolfo C



Induced production of antifungal naphthoquinones in the pitchers of the carnivorous plant Nepenthes khasiana  

PubMed Central

Nepenthes spp. are carnivorous plants that have developed insect capturing traps, evolved by specific modification of the leaf tips, and are able to utilize insect degradation products as nutritional precursors. A chitin-induced antifungal ability, based on the production and secretion to the trap liquid of droserone and 5-O-methyldroserone, is described here. Such specific secretion uniquely occurred when chitin injection was used as the eliciting agent and probably reflects a certain kind of defence mechanism that has been evolved for protecting the carnivory-based provision of nutritional precursors. The pitcher liquid containing droserone and 5-O-methyldroserone at 3:1 or 4:1 molar ratio, as well as the purified naphthoquinones, exerted an antifungal effect on a wide range of plant and human fungal pathogens. When tested against Candida and Aspergillus spp., the concentrations required for achieving inhibitory and fungicidal effects were significantly lower than those causing cytotoxicity in cells of the human embryonic kidney cell line, 293T. These naturally secreted 1,4-naphthoquinone derivatives, that are assumed to act via semiquinone enhancement of free radical production, may offer a new lead to develop alternative antifungal drugs with reduced selectable pressure for potentially evolved resistance.

Eilenberg, Haviva; Pnini-Cohen, Smadar; Rahamim, Yocheved; Sionov, Edward; Segal, Esther; Carmeli, Shmuel; Zilberstein, Aviah



One-electron reduction of 2- and 6-methyl-1,4-naphthoquinone bioreductive alkylating agents  

SciTech Connect

The semiquinones, Q.-, of derivatives of 2- and 6-methyl-1,4-naphthoquinones, some incorporating leaving groups with substituents such as CH/sub 2/Br or CH/sub 2/OCONHCH/sub 3/, have been produced by radiolytic reduction of Q by (CH/sub 3/)2COH radicals. The absorption spectra and decay kinetics of Q.- were all closely similar to that produced from 2-methyl-1,4-naphthoquinone, with no evidence for unimolecular elimination of a leaving group in the semiquinone form, but immediate loss of leaving group upon two-electron reduction of Q to the hydroquinone. The redox equilibria between Q/Q.- and O2/O2.- were characterized, and reduction potentials of the couples Q/Q.- in water at pH 7.6 were calculated. The implications of these observations for the use of these compounds as bioreductive alkylating agents or as radiosensitizers with potential selective activity toward hypoxic cells are discussed.

Wilson, I.; Wardman, P.; Lin, T.S.; Sartorelli, A.C.



Stimulation of antibacterial naphthoquinones and flavonoids accumulation in carnivorous plants grown in vitro by addition of elicitors  

Microsoft Academic Search

Carnivorous plants—Dionaea muscipula and Drosera capensis contain two major groups of pharmaceutically important substances, naphthoquinones: plumbagin, ramentaceone and flavonoids: myricetin, quercetin, which are considered to be responsible, i.e. for antibacterial properties of preparations from their tissues. This study focused on increasing bactericidal activity of the extracts of in vitro grown D. muscipula and D. capensis by stimulation of secondary metabolite

A. Krolicka; A. Szpitter; E. Gilgenast; G. Romanik; M. Kaminski; E. Lojkowska



Design of anti-parasitic and anti-fungal hydroxy-naphthoquinones that are less susceptible to drug resistance  

Microsoft Academic Search

Atovaquone is a hydroxy-naphthoquinone that is used to treat parasitic and fungal infections including Plasmodium falciparum (malaria), Pneumocystis jivorecii (pneumonia) and Toxoplasma gondii (toxoplasmosis). It blocks mitochondrial oxidation of ubiquinol in these organisms by binding to the ubiquinol oxidation site of the cytochrome bc1 complex. Failure of atovaquone treatment has been linked to the appearance of mutations in the mitochondrially

Louise M. Hughes; Charlotte A. Lanteri; Michael T. O’Neil; Jacob D. Johnson; Gordon W. Gribble; Bernard L. Trumpower



Growth-Inhibitory Activities of Some 1,4-Naphthoquinones and Related Compounds on Staphylococcus Aureus and Escherichia Coli.  

National Technical Information Service (NTIS)

Growth-inhibitory activities of some or all of 98 1,4-naphthoquinones and 16 related compounds on Escherichia coli and two strains of Staphylococcus aureus were determined alone or in combination. These values, when plotted against their polarographic hal...

G. J. Leahy D. J. Currie H. L. Holmes J. R. Maltman



Synthesis and antifungal activity of terpenyl-1,4-naphthoquinone and 1,4-anthracenedione derivatives.  


The antifungal evaluation of twenty seven simple and heterocycle-fused prenyl-1,4-naphthoquinones and 1,4-anthracenediones was performed in vitro against human pathogenic yeasts (Candida spp.) and filamentous fungi (Aspergillus spp., Fusarium spp., and Trichophyton spp.). The synthetic strategy used to obtain the quinone derivatives was initially based on the Diels-Alder cycloaddition between myrcene and several p-benzoquinone derivatives, followed by cyclisation of the prenyl side chain in the case of anthracene-1,4-diones. The most promising compounds, displaying MIC values in the low ?g/mL range, were those bearing one or two chlorine atoms attached to the quinone ring. Time-kill curves determined for the most potent compounds showed their fungistatic mode of action similar to that of itraconazole. PMID:23831506

Castro, Ma Ángeles; Gamito, Ana Ma; Tangarife-Castaño, Verónica; Zapata, Bibiana; Miguel Del Corral, José Ma; Mesa-Arango, Ana C; Betancur-Galvis, Liliana; San Feliciano, Arturo



Chemically amplified resists using 1,2-naphthoquinone diazide-4-sulfonates as photoacid generators  

NASA Astrophysics Data System (ADS)

A novel positive chemically amplified resist containing partially t-butoxycarbonylmethylated poly(4-hydroxy-styrene)s and 1,2-naphthoquinone-4-sulfonates (NQ4)s was investigated. The resists are effective for a wide region of UV lights including i-line and KrF excimer laser lights. The NQ4s photodecompose to form sulfonic acids which accelerate the decomposition of t-butyl moieties of the polymers to form carboxylic acid. Only a few % of NQ4s realize the chemically amplified resists. NQ4s having electron-withdrawing groups give resists with high sensitivities which provide excellent subhalf micron patterns when exposed to either i-line light or KrF excimer laser.

Hayase, Rumiko; Onishi, Yasunobu; Niki, Hirokazu; Oyasato, Naohiko; Hayase, Shuzi



Naphthalene and Naphthoquinone: Distributions and Human Exposure in the Los Angeles Basin  

NASA Astrophysics Data System (ADS)

Naphthalene is the simplest and most abundant of the polycyclic aromatic hydrocarbons (PAHs). Naphthalene is found primarily in the gas-phase and has been detected in both outdoor and indoor samples. Evaporation from naphthalene-containing products (including gasoline), and during refining operations, are important sources of naphthalene in air. Naphthalene is also emitted during the combustion of fossil fuels and wood, and is a component of vehicle exhaust. Exposure to high concentrations of naphthalene can damage or destroy red blood cells, causing hemolytic anemia. If inhaled over a long period of time, naphthalene may cause kidney and liver damage, skin allergy and dermatitis, cataracts and retinal damage, as well as attack the central nervous system. Naphthalene has been found to cause cancer as a result of inhalation in animal tests. Naphthoquinones are photooxidation products of naphthalene and the potential health effects of exposure to these quinones are a current focus of research. We are developing and applying models that can be used to assess human exposure to naphthalene and its photooxidation products in major air basins such as California South Coast Air Basin (SoCAB). The work utilizes the Surface Meteorology and Ozone Generation (SMOG) airshed model, and the REgional Human EXposure (REHEX) model, including an analysis of individual exposure. We will present and discuss simulations of basin-wide distributions of, and human exposures to, naphthalene and naphthoquinone, with emphasis on the uncertainties in these estimates of atmospheric concentrations and human exposure. Regional modeling of pollutant sources and exposures can lead to cost-effective and optimally health-protective emission control strategies.

Lu, R.; Wu, J.; Turco, R.; Winer, A. M.; Atkinson, R.; Paulson, S.; Arey, J.; Lurmann, F.



Induction of death of leukemia cells by TW-74, a novel derivative of chloro-naphthoquinone.  


We have previously shown that a 2-chloro-1,4-naphthoquinone derivative (TW-92) induces cell death in leukemia cells. TW-92 exhibited relatively high selectivity towards primary Acute Myeloid Leukemia (AML) cells, as compared to normal mononuclear cells. In view of the selectivity of this family of naphthoquinones, novel chloroaminophenylnaphthoquinone isomers with different methyl substitutions on the phenyl ring were synthesized, and their effect on leukemia cells was tested. These compounds induced cell death in U937 human myeloid leukemia cells, which was prominent following 48 h of culture. Structure-activity relationship studies revealed that TW-74, a novel chloronaphthoquinone with a methyl group at the meta (m) position, was the most active derivative in inducing apoptosis. The mechanism underlying cell death induction by TW-74 was further investigated in U937 cells, a monocytic cell line which serves as a sensitive model of apoptosis induction. TW-74 induced rapid activation of Mitogen Activated Protein Kinases (MAPKs). It caused swelling of isolated rat liver mitochondria and an early reduction of mitochondrial membrane potential in intact cells, indicative of a direct effect on mitochondria. Apoptosis induced by TW-74 was accompanied by cytochrome C release and caspase activation. TW-74 induced down- regulation of (BCL2), an anti-apoptotic protein. Furthermore, TW-74 induced selective dose-dependent cell death in primary B-Chronic Lymphocytic Leukemia (CLL) cells. These findings demonstrate that chloronaphthoquiniones use common as well as diverse mechanisms for the induction of cell death. The data reported here warrant further studies of the utility of TW-74 in the treatment of CLL. PMID:23267144

Hallak, Maher; Thakur, Basant K; Winn, Thida; Shpilberg, Ofer; Bittner, Shmuel; Granot, Yosef; Levy, Itai; Nathan, Ilana



Naphthoquinone Derivatives Exert Their Antitrypanosomal Activity via a Multi-Target Mechanism  

PubMed Central

Background and Methodology Recently, we reported on a new class of naphthoquinone derivatives showing a promising anti-trypanosomatid profile in cell-based experiments. The lead of this series (B6, 2-phenoxy-1,4-naphthoquinone) showed an ED50 of 80 nM against Trypanosoma brucei rhodesiense, and a selectivity index of 74 with respect to mammalian cells. A multitarget profile for this compound is easily conceivable, because quinones, as natural products, serve plants as potent defense chemicals with an intrinsic multifunctional mechanism of action. To disclose such a multitarget profile of B6, we exploited a chemical proteomics approach. Principal Findings A functionalized congener of B6 was immobilized on a solid matrix and used to isolate target proteins from Trypanosoma brucei lysates. Mass analysis delivered two enzymes, i.e. glycosomal glycerol kinase and glycosomal glyceraldehyde-3-phosphate dehydrogenase, as potential molecular targets for B6. Both enzymes were recombinantly expressed and purified, and used for chemical validation. Indeed, B6 was able to inhibit both enzymes with IC50 values in the micromolar range. The multifunctional profile was further characterized in experiments using permeabilized Trypanosoma brucei cells and mitochondrial cell fractions. It turned out that B6 was also able to generate oxygen radicals, a mechanism that may additionally contribute to its observed potent trypanocidal activity. Conclusions and Significance Overall, B6 showed a multitarget mechanism of action, which provides a molecular explanation of its promising anti-trypanosomatid activity. Furthermore, the forward chemical genetics approach here applied may be viable in the molecular characterization of novel multitarget ligands.

Mazet, Muriel; Perozzo, Remo; Bergamini, Christian; Prati, Federica; Fato, Romana; Lenaz, Giorgio; Capranico, Giovanni; Brun, Reto; Bakker, Barbara M.; Michels, Paul A. M.; Scapozza, Leonardo; Bolognesi, Maria Laura; Cavalli, Andrea



In vitro activity of Brazilian medicinal plants, naturally occurring naphthoquinones and their analogues, against methicillin-resistant Staphylococcus aureus.  


Fourteen extracts from Brazilian traditional medicinal plants used to treat infectious diseases were used to look for potential antimicrobial activity against multiresistant bacteria of medical importance. Staphylococcus aureus strains were susceptible to extracts of Punica granatum and Tabebuia avellanedae. The minimum inhibitory concentrations (MICs) of the total extracts and of additional fractions of these plants were determined by employing strains of methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus, including isolates of the PFGE clone A, which is prevalent in Brazil and two ATCC reference strains. A mixture of ellagitannins isolated from P. granatum and two naphthoquinones isolated from T. avellanedae demonstrated antibacterial activity against all S. aureus strains tested. Semi-synthetic furanonaphthoquinones (FNQs) showed lower MICs than those exhibited by natural occurring naphthoquinones. The results indicate that these natural products can be effective potential candidates for the development of new strategies to treat MRSA infections. PMID:12636992

Machado, T B; Pinto, A V; Pinto, M C F R; Leal, I C R; Silva, M G; Amaral, A C F; Kuster, R M; Netto-dosSantos, K R



Newbouldiaquinone A: A naphthoquinone-anthraquinone ether coupled pigment, as a potential antimicrobial and antimalarial agent from Newbouldia laevis.  


The study of the chemical constituents of the roots of Newbouldia laevis (Bignoniaceae) has resulted in the isolation and characterization of a naphthoquinone-anthraquinone coupled pigment named newbouldiaquinone A (1) together with 14 known compounds: apigenin, chrysoeriol, newbouldiaquinone, lapachol, 2-methylanthraquinone, 2-acetylfuro-1,4-naphthoquinone, 2,3-dimethoxy-1,4-benzoquinone, oleanolic acid, canthic acid, 2-(4-hydroxyphenyl)ethyl triacontanoate, newbouldiamide, 5,7-dihydroxydehydroiso-alpha-lapachone, beta-sitosterol, and beta-sitosterol glucopyranoside. The structure elucidation of the isolated compounds was established based on spectroscopic studies, notably of the 2D NMR spectra. The antimalarial activity of compound (1) against Plasmodium falciparum in vitro shows moderate chemo suppression of parasitic growth. Its antimicrobial activity against a wide range of microorganisms was 13- and 24-fold more active against Candida gabrata and Enterobacter aerogens than the reference antibiotics nystatin and gentamycin. PMID:16442576

Eyong, Kenneth Oben; Folefoc, Gabriel Ngosong; Kuete, Victor; Beng, Veronique Penlap; Krohn, Karsten; Hussain, Hidayat; Nkengfack, Augustin Ephram; Saeftel, Michael; Sarite, Salem Ramadan; Hoerauf, Achim



An assessment of the genotoxicity of 2-hydroxy-1,4-naphthoquinone, the natural dye ingredient of Henna  

Microsoft Academic Search

2-Hydroxy-1,4-naphthoquinone (HNQ; Lawsone; CAS 83-72-7) is the principal natural dye ingredient contained in the leaves of Henna (Lawsonia inermis). Published genotoxicity studies on HNQ suggested it was a weak bacterial mutagen for Salmonella typhimurium strain TA98 or was more clearly mutagenic for strain TA 2637, both in the presence of metabolic activation. HNQ was unable to induce sex-linked recessive lethal

David Kirkland; Daniel Marzin




Technology Transfer Automated Retrieval System (TEKTRAN)

The effect of pH of the aqueous phase on the octan-1-ol / water partition coefficients (kow) of quinones was demontrated. The kow of a series of p-benzo- and p-naphthoquinones were determined using a mildly buffered aqueous phase (1 mM Hepes, pH 7.0) to correct for the pH effects on the lipophilicit...


Transition metal quinone–thiosemicarbazone complexes 3: Spectroscopic characterizations of spin-mixed iron (III) of naphthoquinone–thiosemicarbazones  

Microsoft Academic Search

An interesting series of iron (III) complexes with naphthoquinone–thiosemicarbazones are synthesized and physico-chemically characterized by elemental analysis, UV–vis, IR, EPR and magnetic susceptibility measurements. They possess a cationic octahedral [FeL2]+ species and a tetrahedral [FeCl4]? anion and exhibit unusual spin-mixed states involving high-spin and low-spin ferric centers as revealed from magnetic behavior with significant amount of exchange interactions mediated by

Rajeev C. Chikate; Subhash B. Padhye



Isolation of three antibacterial naphthoquinones from Plumbago indica roots and development of a validated quantitative HPLC analytical method.  


Three naphthoquinones, plumbagin (1), 3,3'-biplumbagin (2) and elliptinone (3), isolated from Plumbago indica roots by antibacterial bioassay-guided isolation, were used as standard markers for quantitative determination. A reversed-phase HPLC method was established for the simultaneous determination of the naphthoquinones in P. indica root extracts. The method utilised a Phenomenex® ODS column (4.6?×?150?mm, 5?µm) at 25°C with a mixture of methanol and 5% aqueous acetic acid (80?:?20 v/v) as the mobile phase at a flow rate of 0.85?mL/min, and UV detection at 260?nm. The parameters of linearity, precision, accuracy specificity and sensitivity of the method were evaluated. The recovery of the method was 98.6-100.6% with good linearity (r (2?)??0.9997) for all three naphthoquinones. A high degree of sensitivity, specificity as well as repeatability and reproducibility (R.S.D. values less than 5%) were also achieved. PMID:22010802

Kaewbumrung, Sermwut; Panichayupakaranant, Pharkphoom



Gas-phase reactivity of 2-hydroxy-1,4-naphthoquinones: a computational and mass spectrometry study of lapachol congeners.  


In order to understand the influence of alkyl side chains on the gas-phase reactivity of 1,4-naphthoquinone derivatives, some 2-hydroxy-1,4-naphthoquinone derivatives have been prepared and studied by electrospray ionization tandem mass spectrometry in combination with computational quantum chemistry calculations. Protonation and deprotonation sites were suggested on the basis of gas-phase basicity, proton affinity, gas-phase acidity (?G(acid) ), atomic charges and frontier orbital analyses. The nature of the intramolecular interaction as well as of the hydrogen bond in the systems was investigated by the atoms-in-molecules theory and the natural bond orbital analysis. The results were compared with data published for lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone). For the protonated molecules, water elimination was verified to occur at lower proportion when compared with side chain elimination, as evidenced in earlier studies on lapachol. The side chain at position C(3) was found to play important roles in the fragmentation mechanisms of these compounds. PMID:23280754

Vessecchi, Ricardo; Emery, Flávio S; Galembeck, Sérgio E; Lopes, Norberto P



Structure/antileishmanial activity relationship study of naphthoquinones and dependency of the mode of action on the substitution patterns.  


A series of naphthoquinones was tested for activity against both extracellular promastigote and intracellular amastigote Leishmania major GFP in vitro. In parallel, the compounds were evaluated for cytotoxic effects against bone marrow-derived macrophages (BMM ?) as a mammalian host cell control. Most of the compounds noticeably inhibited the growth of extracellular parasites (IC (50) 0.5 to 6?µM) and the intracellular survival of L. major GFP amastigotes (IC (50) 1 to 7?µM) when compared with the antileishmanial drug amphotericin B (IC (50) of 2.5 and 0.2?µM, respectively). In general, antiprotozoal activity and host cell cytotoxicity seemed to increase in parallel. Conspicuously, the cytotoxic effect was less pronounced on infected host cells when compared with that on noninfected cells. Concerning structure/activity relationships for the tested naphthoquinones, some interesting structural features emerged from this study. Introduction of a methyl or methoxyl group at C-2 of the parent 1,4-naphthoquinone slightly increased the antileishmanial activity against clinically relevant amastigotes, while the presence of a hydroxyl function in this position dramatically reduced the effectiveness. In contrast, hydroxylation at C-5 and dihydroxy substitution at C-5 and C-8 significantly enhanced the antiprotozoal activity. Similarly, the presence of a side chain hydroxyl group PERI to a carbonyl function as represented in the series of shikonin/alkannin derivatives increased the activity when compared with substituted analogs. Within the series of naphthoquinones tested, the dimeric mixture of vaforhizin and isovaforhizin showed the highest activity IN VITRO against the clinically relevant intracellular amastigote with an IC (50) of 1.1?µM. With IC (50) values mostly in the range of 1-3?µM, the shikonin/alkannin derivatives proved to be similarly considerably leishmanicidal. None of the compounds tested was capable to induce NO production known to play a crucial role in the host resistance against intracellular pathogens, excluding activation of microbicidal mechanisms in macrophages. The mode of action apparently depended on the substitution pattern, associated with the electrophilicity of the naphthoquinone or the efficiency of redox cycling. Conspicuously, members oxygenated in the quinone ring proved to be leishmanicidal when coincubated with glutathione, while the majority of the remaining compounds lost activity. PMID:21800278

Ali, Ahmad; Assimopoulou, Andreana Nikolaos; Papageorgiou, Vassilios Peter; Kolodziej, Herbert



Chemical reactivity studies with naphthoquinones from Tabebuia with anti-trypanosomal efficacy.  


The biological activities of the naphthoquinones lapachol and its cyclization product beta-lapachone, extracted from trees of the genus Tabebuia, have been intensively studied. Given continuity to the studies about heterocyclic derivatives obtained from the reaction of these naphtoquinones with amino-containing reagents, 22 derivatives of beta-lapachone, nor-beta-lapachone and lapachol were synthesised and their activities against trypomastigote forms of T. cruzi were evaluated. The compounds were grouped as oxazolic, imidazolic, phenoxazinic, indolic, pyranic and cyclopentenic derivatives. The variability of the new structures is based on the great electrophilicity of 1,2-quinoidal carbonyls towards reagents containing nitrogen or carbon as nucleophilic centres. In relation to the trypanocidal activity of the synthesised compounds, in view of their structural diversity, tendencies only could be verified. Among the cyclofunctionalised products the oxazolic and imidazolic derivatives showed +/- 1.5 to 34.8 times higher activity than crystal violet, the standard drug for the sterilization of stored blood. These results corroborate the tendency of trypanocidal activity in imidazolic skeletons, and indicate that this moiety could be used as a guide for architectural delineation of molecules with potential value for the chemotherapy of Chagas disease. PMID:11190779

Pinto, C N; Dantas, A P; De Moura, K C; Emery, F S; Polequevitch, P F; Pinto, M C; de Castro, S L; Pinto, A V



Synthesis and evaluation of bioactive naphthoquinones from the Brazilian medicinal plant, Tabebuia avellanedae.  


A series of naphthoquinones based on the naphtho[2,3-b]furan-4,9-dione skeleton such as (-)-5-hydroxy-2-(1'-hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (1) and its positional isomer, (-)-8-hydroxy-2-(1'-hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (2), which are secondary metabolites found in the inner bark of Tabebuia avellanedae, were stereoselectively synthesized and their biological activities were evaluated in conjunction with those of their corresponding enantiomers. Compound 1 exhibited potent antiproliferative effect against several human tumor cell lines, but its effect against some human normal cell lines was much lower than that of mitomycin. On the other hand, its enantiomer (R)-1 was less active toward the above tumor cell lines than 1. The antiproliferative effect of 2 against all tumor cell lines was significantly reduced. These results indicated the presence of the phenolic hydroxy group at C-5 is of great important for increasing antiproliferative effect. In addition, 1 also showed higher cancer chemopreventive activity than 2, while there were no significant differences between 1 and 2 in antimicrobial activity. Both compounds displayed modest antifungal and antibacterial activity (gram-positive bacteria), whereas they were inactive against gram-negative bacteria. PMID:19674905

Yamashita, Mitsuaki; Kaneko, Masafumi; Tokuda, Harukuni; Nishimura, Katsumi; Kumeda, Yuko; Iida, Akira



Inhibition of Nox-4 activity by plumbagin, a plant-derived bioactive naphthoquinone.  


NAD(P)H oxidase contributes to the pathogenesis of cancer and cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy and heart failure. Plumbagin, a plant-derived naphthoquinone, has been shown to exert anticarcinogenic and anti-atherosclerosis effects in animals. However, the molecular mechanisms underlying these effects remain unknown. It is possible that the beneficial effect of plumbagin is due to the inhibition of NAD(P)H oxidase. Human embryonic kidney 293 (HEK293) and brain tumour LN229 cells express mainly Nox-4, a renal NAD(P)H oxidase. We have examined the effect of plumbagin on Nox-4 activity in HEK293 and LN229 cells using lucigenin-dependent chemiluminescence assay. Plumbagin inhibited the activity of Nox-4 in a time- and dose-dependent manner in HEK293 and LN229 cells. Production of superoxide in HEK293 cells was inhibited by diphenyleneiodonium (DPI), a NAD(P)H oxidase inhibitor. The superoxide production in HEK293 cells was NADPH- and NADH-dependent indicating that the superoxide was generated by a NAD(P)H oxidase in HEK293 cells, but not by the redox-cycling of lucigenin. Furthermore, plumbagin inhibited the superoxide production in Nox-4 transfected COS-7 cells. These results indicated that plumbagin directly interacted with Nox-4 and inhibited its activity. PMID:15638999

Ding, Yaxian; Chen, Zi-Jiang; Liu, Shiguo; Che, Danian; Vetter, Michael; Chang, Chung-Ho




PubMed Central

Chagas disease, caused by Trypanosoma cruzi, is a wide spread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD50 = 2.5 ?M) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD50 = 130 ?M). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days post-infection, when compared to control group (infected, untreated). We also observed a 2-fold decrease in the parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi.

Ramos, Enrique I.; Garza, Kristine M.; Krauth-Siegel, R. L.; Bader, Julia; Martinez, Luiz E.; Maldonado, Rosa A.



A Chemical Genetic Screen for Modulators of Asymmetrical 2,2?-Dimeric Naphthoquinones Cytotoxicity in Yeast  

PubMed Central

Background Dimeric naphthoquinones (BiQ) were originally synthesized as a new class of HIV integrase inhibitors but have shown integrase-independent cytotoxicity in acute lymphoblastic leukemia cell lines suggesting their use as potential anti-neoplastic agents. The mechanism of this cytotoxicity is unknown. In order to gain insight into the mode of action of binaphthoquinones we performed a systematic high-throughput screen in a yeast isogenic deletion mutant array for enhanced or suppressed growth in the presence of binaphthoquinones. Methodology/Principal findings Exposure of wild type yeast strains to various BiQs demonstrated inhibition of yeast growth with IC50s in the µM range. Drug sensitivity and resistance screens were performed by exposing arrays of a haploid yeast deletion mutant library to BiQs at concentrations near their IC50. Sensitivity screens identified yeast with deletions affecting mitochondrial function and cellular respiration as having increased sensitivity to BiQs. Corresponding to this, wild type yeast grown in the absence of a fermentable carbon source were particularly sensitive to BiQs, and treatment with BiQs was shown to disrupt the mitochondrial membrane potential and lead to the generation of reactive oxygen species (ROS). Furthermore, baseline ROS production in BiQ sensitive mutant strains was increased compared to wild type and could be further augmented by the presence of BiQ. Screens for resistance to BiQ action identified the mitochondrial external NAD(P)H dehydrogenase, NDE1, as critical to BiQ toxicity and over-expression of this gene resulted in increased ROS production and increased sensitivity of wild type yeast to BiQ. Conclusions/Significance In yeast, binaphthoquinone cytotoxicity is likely mediated through NAD(P)H:quonine oxidoreductases leading to ROS production and dysfunctional mitochondria. Further studies are required to validate this mechanism in mammalian cells.

Emadi, Ashkan; Ross, Ashley E.; Cowan, Kathleen M.; Fortenberry, Yolanda M.; Vuica-Ross, Milena



Trypanosoma cruzi: insights into naphthoquinone effects on growth and proteinase activity.  


In this study we compared the effects of naphthoquinones (?-lapachone, ?-lapachone, nor-?-lapachone and Epoxy-?-lap) on growth of Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed ?-lapachone and Epoxy-?-lap with a high trypanocidal activity in contrast to ?-lapachone and nor-?-lapachone whereas Epoxy-?-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. ?-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-?-lap inhibited the T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and ?-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-?-lap showed no important interactions. Overall, our results infer that ?-lapachone and Epoxy-?-lap compounds may inhibit T. cruzi epimastigotes growth by affecting T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds. PMID:20647011

Bourguignon, Saulo C; Cavalcanti, Danielle F B; de Souza, Alessandra M T; Castro, Helena C; Rodrigues, Carlos R; Albuquerque, Magaly G; Santos, Dilvani O; da Silva, Gabriel Gomes; da Silva, Fernando C; Ferreira, Vitor F; de Pinho, Rosa T; Alves, Carlos R



Hydroxyl radical generation mechanism during the redox cycling process of 1,4-naphthoquinone.  


Airborne quinones contribute to adverse health effects of ambient particles probably because of their ability to generate hydroxyl radicals (·OH) via redox cycling, but the mechanisms remain unclear. We examined the chemical mechanisms through which 1,4-naphthoquinone (1,4-NQ) induced ·OH, and the redox interactions between 1,4-NQ and ascorbate acid (AscH(2)). First, ·OH formation by 1,4-NQ was observed in cellular and acellular systems, and was enhanced by AscH(2). AscH(2) also exacerbated the cytotoxicity of 1,4-NQ in Ana-1 macrophages, at least partially due to enhanced ·OH generation. The detailed mechanism was studied in an AscH(2)/H(2)O(2) physiological system. The existence of a cyclic 1,4-NQ process was shown by detecting the corresponding semiquinone radical (NSQ·-) and hydroquinone (NQH(2)). 1,4-NQ was reduced primarily to NSQ·- by O2·- (which was from AscH(2) reacting with H(2)O(2)), not by AscH(2) as normally thought. At lower doses, 1,4-NQ consumed O2·- to suppress ·OH; however, at higher doses, 1,4-NQ presented a positive association with ·OH. The reaction of NSQ·- with H(2)O(2) to release ·OH was another important channel for OH radical formation except for Haber-Weiss reaction. As a reaction precursor for O2·-, the enhanced ·OH response to 1,4-NQ by AscH(2) was indirect. Reducing substrates were necessary to sustain the redox cycling of 1,4-NQ, leading to more ·OH and a deleterious end point. PMID:22288565

Shang, Yu; Chen, Chenyong; Li, Yi; Zhao, Jincai; Zhu, Tong



Differential cellular responses to protein adducts of naphthoquinone and monocrotaline pyrrole.  


Protein-xenobiotic adducts are byproducts of xenobiotic metabolism. While there is a correlation between protein adduction and target organ toxicity, a cause and effect relationship is not often clear. Naphthoquinone (NQ) and monocrotaline pyrrole (MCTP) are two pneumotoxic electrophiles that form covalent adducts with a similar select group of proteins rich in reactive thiols. In this study, we treated human pulmonary artery endothelial cells (HPAEC) with NQ, MCTP, or preformed NQ or MCTP adducts to the protein galectin-1 (gal-1) and examined indicators of reactive oxygen species (ROS) oxidative injury, markers of apoptosis (caspase-3 and annexin V), and gene responses of cellular stress. ROS production was assayed fluorescently using CM-H(2)DCFDA. NQ adducts to gal-1 (NQ-gal) produced 183% more intracellular ROS than gal-1 alone (p < 0.0001). Caspase-3 activity and annexin V staining of phosphatidylserine were used to assess apoptotic activity in treated cells. HPAEC exposed to MCTP-gal had increases in both caspase-3 activation and membrane translocation of annexin V relative to gal-1 alone (p < 0.0001). Direct application of NQ produced significantly more ROS and induced significant caspase-3 activation, whereas MCTP did not. Human bronchial epithelial cells were also exposed to MCTP-gal and found to have significant increases in both caspase-3 activation and annexin V staining in comparison to that of gal-1 (p < 0.05). Western blot analysis showed that both NQ and MCTP significantly induced the Nrf2 mediated stress response pathway despite differences in ROS generation. ER stress was not induced by either adducts or parent compounds as seen by quantitative RT-PCR, but HOX-1 expression was significantly induced by NQ-gal and MCTP alone. Electrophile adduction to gal-1 produces different cytotoxic effects specific to each reactive intermediate. PMID:20695460

Nakayama Wong, Lynn S; Lamé, Michael W; Jones, A Daniel; Wilson, Dennis W



Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells.  


The pentacyclic 1,4-naphthoquinones 1a-d were cytotoxic (IC(50) approximately 2-7 microM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell lines were highly insensitive to lapachol (2) and alpha-lapachone (3). Mitomycin-C inhibited cell proliferation at concentrations as low as 0.5 microM. The low toxicity against lymphocytes activated by phytohemagglutinin shows that these compounds are selective for the cancer cells studied. Previous data suggest that these compounds (1a-d) can be bioactivated in situ by reduction followed by rearrangement leading to enones, which are powerful alkylating agents. In contrast, lapachol (2) and beta-lapachone (3), which cannot be bioactivated by reduction, showed little activity against the same cell lines. PMID:19255723

Salustiano, Eduardo J S; Netto, Chaquip D; Fernandes, Renata F; da Silva, Alcides J M; Bacelar, Thiago S; Castro, Carolina P; Buarque, Camilla D; Maia, Raquel C; Rumjanek, Vivian M; Costa, Paulo R R



Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease.  


Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, ?-lapachone and its ?-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones. PMID:21110810

Salas, Cristian O; Faúndez, Mario; Morello, Antonio; Maya, Juan Diego; Tapia, Ricardo A



Interaction of 2,3-dichloro-1,4-naphthoquinone with n-butylamine in halocarbon solvents.  


The rapid interaction between 2,3-dichloro-1,4-naphthoquinone (DClNQ) and n-butylamine results in the formation of 2N(n-butylamino)-3-chloro-1,4-naphthoquinone as the final product. The reaction is found to proceed through the initial formation of charge-transfer (CT) complex as an intermediate. The final product of the reaction has been isolated and characterized using FTIR, H1 and C13 NMR spectroscopy, mass spectrometry, and elemental analysis. The rate of formation of product has been measured as a function of time in different halocarbon solvents, viz., chloroform, dichloromethane and 1:1 (v/v) mixture of two solvents. The pseudo first order and second order rate constants at various temperatures for the transformation process were evaluated from the absorbance time data. The activation parameters (E(a), DeltaS#, DeltaH#, and DeltaG#) were obtained from temperature dependence of rate constants. The influence of dielectric constant on the properties of reaction was discussed and the probable course of reaction is presented. PMID:15863041

Neelgund, Gururaj M; Budni, M L



Studies on photoinduced H-atom and electron transfer reactions of o-naphthoquinones by laser flash photolysis.  


The quenching of the triplets of 1,2-naphthoquinone (NQ) and 1,2-naphthoquinone-4-sulfonic acid sodium salt (NQS) by various electron and H-atom donors was investigated by laser flash photolysis measurement in acetonitrile and benzene. The results showed that the reactivities and configurations of 3NQ* (3NQS*) are governed by solvent polarity. All the quenching rate constants (kq) measured in benzene are larger than those in acetonitrile. The SO3Na substituent at the C-4 position of NQS makes 3NQS* more reactive than 3NQ* in electron/H-atom transfer reactions. Large differences of kq values were discovered in H-atom transfer reactions for alcohols and phenols, which can be explained by different H-abstraction mechanisms. Detection of radical cations of amines/anilines in time-resolved transient absorption spectra confirms an electron transfer mechanism. Triplets are identified as precursors of formed radical anions of NQ and NQS in photoinduced reactions. The dependence of electron transfer rate constants on the free energy changes (DeltaG) was treated by using the Rehm-Weller equation. For the four anilines with different substituents on the para or meta position of amidocyanogen, good correlation between log kq values with Hammett sigma constants testifies the correctness of empirical Hammett equation. Charge density distributions, adiabatic ionization/affinity potentials and redox potentials of NQ (NQS) and some quenchers were studied by quantum chemistry calculation. PMID:16759119

Pan, Yang; Fu, Yao; Liu, Shaoxiong; Yu, Haizhu; Gao, Yuhe; Guo, Qingxiang; Yu, Shuqin



Evaluation of selected benzoquinones, naphthoquinones, and anthraquinones as replacements for phylloquinone in the A sub 1 acceptor site of the photosystem I reaction center  

SciTech Connect

Selected substituted 1,4-benzoquinones, 1,4-naphthoquinones, and 9,10-anthraquinones were investigated as possible replacement quinones in spinach photosystem I (PSI) preparations that had been depleted of endogenous phylloquinone by extraction with hexane/methanol. As a criterion for successful biochemical reconstitution, the restoration of electron transfer was determined by measuring P-430 turnover at room temperature from flash-induced absorbance transients. Restoration of complete electron transfer between A{sub 0}{sup {minus}} and P-430 (terminal iron-sulfur centers, F{sub A}F{sub B}) was demonstrated by using phylloquinone, 2-methyl-3-decyl-1,4-naphthoquinone, 2-methyl-3-(isoprenyl){sub 2}-1,4-naphthoquinone, and 2-methyl-3-(isoprenyl){sub 4}-1,4-naphthoquinone. All other quinones tested did not restore P-430 turnover but acted as electron acceptors and oxidized A{sub 0}{sup {minus}}. It is concluded that the specificity of the replacement quinone for interaction with the primary acceptor, A{sub 0}{sup {minus}}, is low but additional structural constraints are required for the quinone occupying the A{sub 1} site to donate to the iron-sulfur center, F{sub x}. It is suggested that the 3-phytyl side chain of phylloquinone and the 3-alkyl tails of the three naphthoquinones that restored P-430 turnover may be required for interaction with a hydrophobic domain of the A{sub 1} site in the PSI core to promote electron transfer to F{sub x} and then to F{sub A}F{sub B}.

Biggins, J. (Brown Univ., Providence, RI (USA))



The Effect of 5OH-1,4-Naphthoquinone on Norway Spruce Seeds during Germination 1  

PubMed Central

The effect of 5-OH-1,4-naphthoquinone (5OH-NQ), a known inhibitor of germination and growth and an inducer of oxidative stress, on seeds from Norway spruce (Picea abies) during germination was studied. 5OH-NQ was activated by homogenate from seeds to reactive species that reduce oxygen to superoxide radicals in vitro. Increasing concentrations of 5OH-NQ increased lipid peroxidation during this activation. Small effects of 5OH-NQ on germination of seeds were observed at concentrations up to 200 ?m. However, higher concentrations, e.g. 500 and 1000 ?m, exerted more pronounced effects on seeds. These results suggest that the effect of 5OH-NQ was a delay rather than an inhibition of germination. However, the effect of 5OH-NQ on postgerminative growth was more potent than that on germination, and higher concentrations inhibited growth >97%. These results suggest that the seeds have a very effective defense system against quinone and reactive oxygen species, since the small effects of 5OH-NQ on germination and postgermination at concentrations up to 200 ?m can be explained by the formation of a metabolite of 5OH-NQ that is not as reactive with oxygen as the original quinone. The 5OH-NQ metabolite collected during germination experiments showed differences in its absorption spectrum in comparison with 5OH-NQ, which suggest changes in structure. This metabolite was reduced by quinone reductase, but reduction of oxygen to superoxide radicals was not detected during its activation with homogenate from seeds. This metabolite may arise via a conjugation reaction, since the addition of 500 ?m uridine 5?-diphosphoglucuronic acid or 3?-phosphoadenosine-5?-phosphosulfate to the incubation mixture during activation of this metabolite by homogenate from seeds in vitro inhibited reduction of oxygen to superoxide radicals by 50 and 64%, respectively. The constitutive levels of superoxide dismutase and catalase were sufficient to prevent oxygen toxicity during activation of 5OH-NQ, since these enzymes were not induced when the seeds were treated with 200 ?m 5OH-NQ.

Segura-Aguilar, Juan; Hakman, Inger; Rydstrom, Jan



Griseusins F and G, Spiro-Naphthoquinones from a Tin Mine Tailings-Derived Alkalophilic Nocardiopsis Species.  


Griseusins F (1) and G (2), two 2a-hydro-8a-(2-oxopropyl)-substituted spiro-naphthoquinones with a previously undescribed C(23) polyketide skeleton, were isolated from a Yunnan tin mine tailings-derived alkalophilic actinomycete, Nocardiopsis sp. YIM DT266. Their complete structure assignments with the absolute stereochemistry were elucidated by spectroscopic data, X-ray crystal diffraction, calculation of optical rotation, and CD spectroscopic analysis. Compounds 1 and 2 exhibited strong cytotoxicity (IC(50) 0.37-0.82 ?M) and antibacterial activity (MIC 0.80-1.65 ?g/mL) against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) in vitro. PMID:23095059

Ding, Zhang-Gui; Zhao, Jiang-Yuan; Li, Ming-Gang; Huang, Rong; Li, Qing-Ming; Cui, Xiao-Long; Zhu, Hua-Jie; Wen, Meng-Liang



Synthesis using microwave irradiation and antibacterial evaluation of new N,O-acetals and N,S-acetals derived from 2-amino-1,4-naphthoquinones.  


This paper describes a novel series of N,O-acetals and N,S-acetals (7a-o) derived from 2-amino-1,4-naphthoquinones that were synthesized and evaluated as potential antimicrobial agents. These compounds were obtained in good yields using microwave irradiation, and several of them showed promising antibacterial profiles. Three of our biologically active 2-amino-1,4-naphthoquinone N,O-acetals and N,S-acetals tested against hospital bacterial strains were identified as potential lead compounds. Characterization of all compounds was performed using one-dimensional NMR techniques ((1)H, (13)C-APT), IR spectra, elemental analyses and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). PMID:23474905

Jordão, Alessandro K; Novais, Juliana; Leal, Bruno; Escobar, Ana C; dos Santos, Helvécio M; Castro, Helena C; Ferreira, Vitor F



1,2Naphthoquinone4-sulphonic acid sodium salt (NQS) as an analytical reagent for the determination pharmaceutical amine by spectrophotometry  

Microsoft Academic Search

Several papers have been presented in recent years regarding the field of application of 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS) as chromogenic reagent for the determination of pharmaceutical amines using spectrophotometry. In this review article, various spectrophotometric methods using NQS as a labeling reagent for determination of pharmaceutical amines are presented. The application of these methods for the determination of drugs

Abdalla Ahmed Elbashir; Abir Abdalla Ahmed; Shazalia M. Ali Ahmed; Hassan Y. Aboul-Enein



1,2Naphthoquinone4Sulphonic Acid Sodium Salt (NQS) as an Analytical Reagent for the Determination of Pharmaceutical Amine by Spectrophotometry  

Microsoft Academic Search

Abstract: Several papers have been presented in recent years regarding the field of application of 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS) as a chromogenic reagent for the determination of pharmaceutical amines using spectrophotometry. In this review article, various spectrophotometric methods using NQS as a labeling reagent for determination of pharmaceutical amines are presented. The application of these methods for the determination

Abdalla Ahmed Elbashir; Abir Abdalla Ahmed; Shazalia M. Ali Ahmed; Hassan Y. Aboul-Enein



High activity in selective catalytic oxidation of naphthol to 2-hydroxy-1,4-naphthoquinone by molecular oxygen under air pressure over recycled iron porphyrin catalysts  

Microsoft Academic Search

Naphthol is selectively converted into 2-hydroxy-1,4-naphthoquinone (HNQ) by relatively cheap and clean oxidant of molecular oxygen under air pressure in an alkaline solution over iron porphyrin catalysts. E.g. Fe–porphyrin (TMOPPFeCl) catalyst shows high activity (62%) and selectivity (100%) for the oxidation of naphthol to HNQ by O2 under air-pressure at 45 °C in alkaline media, where a recycle of the

Yan Yan; En-Hua Kang; Ke-Er Yang; Shan-Ling Tong; Chi-Guang Fang; Si-Jie Liu; Feng-Shou Xiao



Using of liquid chromatography coupled with diode array detector for determination of naphthoquinones in plants and for investigation of influence of pH of cultivation medium on content of plumbagin in Dionaea muscipula.  


The interest of many investigators in naphthoquinones is due to their broad-range of biological actions from phytotoxic to fungicidal. The main aim of this work was to investigate the influence of different pH values of cultivation medium on naphthoquinone content in Dionaea muscipula. For this purpose, we optimized the simultaneous analysis of the most commonly occurring naphthoquinones (1,4-naphthoquinone, lawsone, juglone and plumbagin) by high performance liquid chromatography coupled with diode array detector (HPLC-DAD). The most suitable chromatographic conditions were as follows: mobile phase: 0.1 mol l-1 acetic acid:methanol in ratio of 33:67 (%, v/v), flow rate: 0.75 ml min-1 and temperature: 42 degrees C. Moreover, we looked for the most suitable technique for preparation of plant samples (D. muscipula, Juglans regia, Paulownia tomentosa, Impatience glandulifera, Impatience parviflora, Drosera rotundifolia, Drosera spathulata and Drosera capensis) due to their consequent analysis by HPLC-DAD. It clearly follows from the results obtained that sonication were the most suitable technique for preparation of J. regia plants. We also checked the recoveries of the determined naphthoquinones, which were from 96 to 104%. Finally, we investigated the changes in content of plumbagin in D. muscipula plants according to different pH of cultivation medium. The content increased with increasing pH up to 5 and, then, changed gradually. The lower content of plumbagin at lower pH values was of interest to us. Therefore, we determined the content of this naphthoquinone in the cultivation medium, what has not been studied before. We discovered that the lower tissue content of plumbagin was due to secretion of this naphthoquinone into the cultivation medium. PMID:16765109

Babula, Petr; Mikelova, Radka; Adam, Vojtech; Kizek, Rene; Havel, Ladislav; Sladky, Zdenek



Spectrophotometric determination of ampicillin sodium in pharmaceutical products using sodium 1,2-naphthoquinone-4-sulfonic as the chromogentic reagent  

NASA Astrophysics Data System (ADS)

Spectrophotometric determination of ampicillin sodium is described. The ampicillin sodium reacts with sodium 1,2-naphthoquinone-4-sulfonic in pH 9.00 buffer solution to form a salmon pink compound, and its maximum absorption wavelength is at 463 nm, ?463=1.14×10 4. The absorbance of ampicillin sodium from 2.0-80 ?g ml -1 obeys Beer's law. The linear regression equation of the calibration graph is C=40.24 A-2.603, with a linear regression correlation coefficient is 0.9997, the detection limit is 1.5 ?g ml -1, recovery is from 97.23 to 104.5%. Effects of pH, surfactant, organic solvents, and foreign ions on the determination of ampicillin sodium have been examined. This method is rapid and simple, and can be used for the determination of ampicillin sodium in the injection solution of ampicillin sodium. The results obtained by this method agreed with those by the official method (HPLC).

Xu, Lixiao; Wang, Huaiyou; Xiao, Yan



Determination of lapachol in the presence of other naphthoquinones using 3MPA-CdTe quantum dots fluorescent probe.  


3MPA-CdTe QDs in aqueous dispersion was used as a fluorescent probe for the determination of lapachol, a natural naphthoquinone found in plants of the Bignoniaceae family genus Tabebuia. Working QDs dispersions (4.5×10(-8) mol L(-1) of QDs) was prepared in aqueous media containing Tris-HCl buffer pH 7.4 and methanol (10% in volume). The excitation was made at 380 nm with signal measurement at 540 nm. To establish a relationship between fluorescence (corrected to inner filter effect) and concentration of lapachol, a Stern-Volmer model was used. The linear range obtained was from 1.0×10(-5) to 1.0×10(-4) mol L(-1). The limit of detection (x(b)-3s(b)) was 8.0×10(-6) mol L(-1). The 3MPA-CdTe QDs probe was tested in the determination of lapachol in urine, previously cleansed in an acrylic polymer. The average recovery was satisfactory. PMID:22591798

Aucélio, Ricardo Q; Peréz-Cordovés, Ana I; Xavier Lima, Juliano L; Ferreira, Aurélio Baird B; Esteva Guas, Ana M; da Silva, Andrea R



1,2-Naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea  

SciTech Connect

1,2-Naphthoquinone (1,2-NQ) has recently been identified as an environmental quinone in diesel exhaust particles (DEP) and atmospheric PM{sub 2.5}. We have found that this quinone is capable of causing a concentration-dependent contraction of tracheal smooth muscle in guinea pigs with EC{sub 5} value of 18.7 {mu}M. The contraction required extracellular calcium and was suppressed by L-type calcium channel blockers nifedipine and diltiazem. It was found that 1,2-NQ activated phospholipase A2 (PLA2)/lipoxygenase (LO)/vanilloid receptor (VR1) signaling. Additionally, 1,2-NQ was capable of transactivating protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR) in guinea pig trachea, suggesting that phosphorylation of PTKs contributes to 1,2-NQ-induced tracheal contraction. Consistent with this notion, this action was blocked by the PTKs inhibitor genistein and the EGFR antagonist PD153035, indicating that contraction was, at least in part, attributable to PTKs phosphorylation that activates VR1, resulting in increased intracellular calcium content in the smooth muscle cells.

Kikuno, Shota [Master's Program in Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 (Japan); Taguchi, Keiko [Department of Environmental Medicine, Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 (Japan); Iwamoto, Noriko [Department of Environmental Medicine, Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 (Japan); Yamano, Shigeru [Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180 (Japan); Cho, Arthur K. [Southern California Particle Center and Supersite, Institute of the Environment, University of California, Los Angeles, Los Angeles, CA 90095 (United States); Froines, John R. [Southern California Particle Center and Supersite, Institute of the Environment, University of California, Los Angeles, Los Angeles, CA 90095 (United States); Kumagai, Yoshito [Department of Environmental Medicine, Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 (Japan) and Southern California Particle Center and Supersite, Institute of the Environment, University of California, Los Angeles, Los Angeles, CA 90095 (United States)]. E-mail:



New 2-aryl-1,4-naphthoquinone-1-oxime methyl ether compound induces microtubule depolymerization and subsequent apoptosis.  


In this study, we describe the antitumor activity of QO-1, one of the new 2-aryl-1,4-naphthoquinone-1-oxime methyl ether derivatives. QO-1 is a derivative of macarpine, a natural occurring product from Rutaceae plant. It could potently inhibit cell growth when tested on 19 cancer cell lines. To investigate its mechanism, two cell lines (HeLa and MCF-7) sensitive to QO-1 were selected. Based on flow cytometry, it was found to induce G(2)/M-phase arrest. Moreover, it could cause microtubule depolymerization both in vitro and in vivo. On the other hand, QO-1 activated spindle assembly checkpoint (SAC) proteins. Expression of Bub1, one of the SAC, was gradually increased, reaching a peak after 16 - 20 h, and then gradually decreased. Instead, QO-1 increased the sub-G(1) population, which suggested a cell death population. Actually, expression of Bcl-2 family proteins and activation of caspase-3/7 were evidences of apoptosis. Consistent with these results, cells with DNA fragmentation and multinucleated cells were increased time-dependently after QO-1 exposure. In conclusion, QO-1 has promising antitumor effects via microtubule depolymerization. PMID:22447301

Sato, Hiromi; Yamada, Ryota; Yanagihara, Midori; Okuzawa, Hiroko; Iwata, Hiroki; Kurosawa, Ayako; Ichinomiya, Saki; Suzuki, Rina; Okabe, Hiroyuki; Yano, Tomohiro; Kumamoto, Takuya; Suzuki, Noriyuki; Ishikawa, Tsutomu; Ueno, Koichi



Novel spectrophotometric method for determination of some macrolide antibiotics in pharmaceutical formulations using 1,2-naphthoquinone-4-sulphonate  

NASA Astrophysics Data System (ADS)

New, simple and rapid spectrophotometric method has been developed and validated for the assay of two macrolide drugs, azithromycin (AZT) and erythromycin (ERY) in pure and pharmaceutical formulations. The proposed method was based on the reaction of AZT and ERY with sodium 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline medium at 25 °C to form an orange-colored product of maximum absorption peak at 452 nm. All variables were studied to optimize the reaction conditions and the reaction mechanism was postulated. Beer's law was obeyed in the concentration range 1.5-33.0 and 0.92-8.0 ?g mL-1 with limit of detection values of 0.026 and 0.063 ?g mL-1 for AZT and ERY, respectively. The calculated molar absorptivity values are 4.3 × 104 and 12.3 × 104 L mol-1 cm-1 for AZT and ERY, respectively. The proposed methods were successfully applied to the determination of AZT and ERY in formulations and the results tallied well with the label claim. The results were statistically compared with those of an official method by applying the Student's t-test and F-test. No interference was observed from the concomitant substances normally added to preparations.

Ashour, Safwan; Bayram, Roula



Effects of juglone (5-hydroxy-1,4-naphthoquinone) on midgut morphology and glutathione status in Saturniid moth larvae.  


Actias luna and Callosamia promethea larvae were fed birch foliage supplemented with juglone (5-hydroxy-1,4-naphthoquinone) to determine whether juglone causes oxidative stress in midguts of these species. Juglone is a substituent of walnut foliage. A. luna, but not C. promethea, thrives on walnut foliage, as well as birch foliage supplemented with juglone. After 2 and 3 days on juglone-containing diets, midgut samples from these animals were compared histologically and were analyzed for GSH and GSSG content. C. promethea, but not A. luna, midguts revealed partial loss of epithelial structure. In contrast, GSH and GSSG did not change significantly in either species. In a separate experiment, live midgut explants from each species were cultured for 4 h in 0, 0.05, and 0.25% juglone. In juglone-treated explants, GSSG increased 2.1 and 5.6-fold, respectively, for A. luna, and 1.6 and 2.7-fold, respectively, for C. promethea. There was also a small dose-dependent decrease in GSH in C. promethea, but not A. luna. Although histology indicates that the midgut is a target of juglone toxicity in C. promethea, GSH analyses from either species do not support the expectation that changes in GSH/GSSG explain differences in susceptibility to juglone toxicity. PMID:9827067

Thiboldeaux, R L; Lindroth, R L; Tracy, J W



Determination of lapachol in the presence of other naphthoquinones using 3MPA-CdTe quantum dots fluorescent probe  

NASA Astrophysics Data System (ADS)

3MPA-CdTe QDs in aqueous dispersion was used as a fluorescent probe for the determination of lapachol, a natural naphthoquinone found in plants of the Bignoniaceae family genus Tabebuia. Working QDs dispersions (4.5 × 10-8 mol L-1 of QDs) was prepared in aqueous media containing Tris-HCl buffer pH 7.4 and methanol (10% in volume). The excitation was made at 380 nm with signal measurement at 540 nm. To establish a relationship between fluorescence (corrected to inner filter effect) and concentration of lapachol, a Stern-Volmer model was used. The linear range obtained was from 1.0 × 10-5 to 1.0 × 10-4 mol L-1. The limit of detection (xb - 3 sb) was 8.0 × 10-6 mol L-1. The 3MPA-CdTe QDs probe was tested in the determination of lapachol in urine, previously cleansed in an acrylic polymer. The average recovery was satisfactory.

Aucélio, Ricardo Q.; Peréz-Cordovés, Ana I.; Xavier Lima, Juliano L.; Ferreira, Aurélio Baird B.; Esteva Guas, Ana M.; da Silva, Andrea R.


Novel spectrophotometric method for determination of some macrolide antibiotics in pharmaceutical formulations using 1,2-naphthoquinone-4-sulphonate.  


New, simple and rapid spectrophotometric method has been developed and validated for the assay of two macrolide drugs, azithromycin (AZT) and erythromycin (ERY) in pure and pharmaceutical formulations. The proposed method was based on the reaction of AZT and ERY with sodium 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline medium at 25 °C to form an orange-colored product of maximum absorption peak at 452 nm. All variables were studied to optimize the reaction conditions and the reaction mechanism was postulated. Beer's law was obeyed in the concentration range 1.5-33.0 and 0.92-8.0 ?g mL(-1) with limit of detection values of 0.026 and 0.063 ?g mL(-1) for AZT and ERY, respectively. The calculated molar absorptivity values are 4.3 × 10(4) and 12.3 × 10(4) L mol(-1) cm(-1) for AZT and ERY, respectively. The proposed methods were successfully applied to the determination of AZT and ERY in formulations and the results tallied well with the label claim. The results were statistically compared with those of an official method by applying the Student's t-test and F-test. No interference was observed from the concomitant substances normally added to preparations. PMID:23041925

Ashour, Safwan; Bayram, Roula



Addition of thiols to o-quinone methide: new 2-hydroxy-3-phenylsulfanylmethyl[1,4]naphthoquinones and their activity against the human malaria parasite Plasmodium falciparum (3D7).  


A series of 36 new phenylsulfanylmethyl[1,4]naphthoquinones (7-42) were synthesized by a three-component reaction that involves lawsone, the appropriate aldehyde and thiols with variable substitution patterns. These reactions involve the in situ generation of o-quinone methides (o-QM) via Knoevenagel condensation and 1,4-nucleophilic addition under conventional heating or microwave irradiation. The new naphthoquinones obtained by this methodology were shown to have moderate to good in vitro antimalarial activity against Plasmodium falciparum (3D7). PMID:23202850

Sharma, Abhinay; Santos, Isabela O; Gaur, Pratibha; Ferreira, Vitor F; Garcia, Celia R S; da Rocha, David R



Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes.  


Several chlorido and amino Pt(2+) complexes of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases HL exhibiting moderate to high cytotoxicity against cancer cell lines were studied in order to investigate their modes of DNA binding, in vitro DNA strand breaks, mechanism of topoisomerase (Topo I) inhibition and cellular accumulation. DNA model base studies have shown that complex 1a [Pt(HL1)Cl(2)] was capable of binding covalently to 9-ethylguanine (9-EtG) and 5'-GMP. (1)H NMR and mass spectrometry studies have shown that both chlorides were substituted by 9-EtG ligands, whereas 5'-GMP was able to replace only one chlorido ligand, due to steric hindrance. The chlorido Pt(2+) complexes [Pt(HL)Cl(2)] highly accumulate in prostate (PC-3) and melanoma (MDA-MB-435) cell lines, being able to induce DNA strand breaks in vitro and inhibit Topo I by a catalytic mode. On the other hand, the free 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones HL and the amino Pt(2+) complexes [Pt(L(-))(NH(3))(2)]NO(3) neither cause DNA strand breakage nor exhibit strong DNA interaction, nevertheless the latter were also found to be catalytic inhibitors of Topo I at 100?M. Thus, coordination of the Mannich bases HL to the "PtCl(2)" fragment substantially affects the chemical and biophysical properties of the pro-ligands, leading to an improvement of their DNA binding properties and generating compounds that cleave DNA and catalytically inhibit Topo I. Finally, the high cytotoxicity exhibited by the free (uncomplexed) 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones might be associated with their decomposition in solution, which is not observed for the Pt(2+) complexes. PMID:23186648

Neves, Amanda P; Pereira, Michelle X G; Peterson, Erica J; Kipping, Ralph; Vargas, Maria D; Silva-Jr, Floriano P; Carneiro, J Walkimar M; Farrell, Nicholas P



NP-313, 2-acetylamino-3-chloro-1,4-naphthoquinone, a novel antithrombotic agent with dual inhibition of thromboxane A2 synthesis and calcium entry  

PubMed Central

BACKGROUND AND PURPOSE 1,4-Naphthoquinones exhibit antiplatelet activity both in vivo and in vitro. In the present study, we investigated the antiplatelet effect of a novel naphthoquinone derivative NP-313, 2-acetylamino-3-chloro-1,4-naphthoquinone and its mechanism of action. EXPERIMENTAL APPROACH We measured platelet aggregation, Ca2+ mobilization, thromboxane B2 formation and P-selectin expression and examined several enzymatic activities. Furthermore, we used the irradiated mesenteric venules in fluorescein sodium–treated mice to monitor the antithrombotic effect of NP-313 in vivo. KEY RESULTS NP-313 concentration-dependently inhibited human platelet aggregation induced by collagen, arachidonic acid, thapsigargin, thrombin and A23187. NP-313 also inhibited P-selectin expression, thromboxane B2 formation and [Ca2+]i elevation in platelets stimulated by thrombin and collagen. NP-313 at 10 µM inhibited cyclooxygenase, thromboxane A2 synthase, and protein kinase C?, whereas it did not affect phospholipase A2 or phospholipase C activity. In the presence of indomethacin and an adenosine 5-diphosphate scavenger, NP-313 concentration-dependently inhibited thrombin- and A23187-induced [Ca2+]i increase through its inhibitory effects on Ca2+ influx, rather than blocking Ca2+ release from intracellular stores. NP-313 also inhibited thapsigargin-mediated Ca2+ influx through store-operated calcium channel but had no effect on Ca2+ influx through store-independent calcium channel evoked by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol. Nevertheless, it had little effect on cyclic AMP and cyclic GMP levels. Also, intravenously administered NP-313 dose-dependently inhibited the thrombus occlusion of the irradiated mesenteric vessels of fluorescein-pretreated mice. CONCLUSIONS AND IMPLICATIONS Taken together, these results indicate that NP-313 exerts its antithrombotic activity through dual inhibition of thromboxane A2 synthesis and Ca2+ influx through SOCC.

Kuo, Heng-Lan; Lien, Jin-Cherng; Chang, Chien-Hsin; Chung, Ching-Hu; Kuo, Sheng-Chu; Hsu, Chun-Chieh; Peng, Hui-Chin; Huang, Tur-Fu



Structural simplification of bioactive natural products with multicomponent synthesis. 4. 4H-pyrano-[2,3-b]naphthoquinones with anticancer activity.  


4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses. PMID:22819765

Magedov, Igor V; Kireev, Artem S; Jenkins, Aaron R; Evdokimov, Nikolai M; Lima, Dustin T; Tongwa, Paul; Altig, Jeff; Steelant, Wim F A; Van slambrouck, Severine; Antipin, Mikhail Yu; Kornienko, Alexander



Restoration of active transport of solutes and oxidative phosphorylation by naphthoquinones in irradiated membrane vesicles from Mycobacterium phlei  

PubMed Central

Irradiation of the inverted membrane vesicles of Mycobacterium phlei with light at 360 nm inactivated the natural menaquinone [MK9(II-H)] and resulted in a loss of substrate oxidation, pH gradient, membrane potential, active transport of proline or calcium ions, and oxidative phosphorylation. Restoration of the protonmotive force and active transport occurred on addition of naphthoquinones such as vitamin K1, menadione, or lapachol to the irradiated membrane vesicles. However, coupled phosphorylation was restored only by vitamin K1. Menadione and lapachol did not act as uncoupling agents. The magnitude of the pH gradient and membrane potential in the quinone-restored system was a reflection of the rate of oxidation and was correlated with the rate of uptake of proline or Ca2+. These results are consistent with the chemosmotic hypothesis proposed for the energy transducing mechanism for active transport and further demonstrate that the complete respiratory chain is not required to drive active transport. In contrast, the data suggest that in addition to the driving force (protonmotive force) necessary to establish oxidative phosphorylation, a specific spatial orientation of the respiratory components, such as the naphthaquinones, is essential for the utilization of the proton gradient or membrane potential or both. Bypass of electrons from the respiratory chain with menadione may explain the inability of this quinone to restore oxidative phosphorylation; however, lapachol restores oxidation by the same electron transport pathway as the natural menaquinone but fails to restore phosphorylation. Because all three quinones restore the protonmotive force, other factors that are discussed must be considered in understanding the mechanism of oxidative phosphorylation.

Lee, Soon-Ho; Sutherland, Thomas O.; Deves, Rosa; Brodie, Arnold F.



Biological evaluation of 3-acyl-2-arylamino-1,4-naphthoquinones as inhibitors of Hsp90 chaperoning function.  


Hsp90 is a chaperone that plays a key function in cancer cells by stabilizing proteins responsible of cell growth and survival. Disruption of the Hsp90 chaperone machinery leads to the proteasomal degradation of its client proteins. Hsp90 appears then as an attractive target for the development of new anticancer molecules. We have shown that ascorbate- driven menadione-redox cycling inhibits Hsp90 activity by provoking an N-terminal cleavage of the protein, inducing the degradation of several of its client proteins. Since the mechanism involves an oxidative stress, we explored the effect of a series of diverse donor-acceptor 3-acyl-2-phenylamino 1,4-naphthoquinones on Hsp90 integrity, in the presence of ascorbate. Results show that quinone-derivatives that bear two electroactive groups (namely quinone and nitro) exhibit the highest inhibitory activity (Hsp90 cleavage and cell death). The biological activity of the series mainly relies on their redox capacity and their lipophilicity, which both modulate the ability of these compounds to induce a cytotoxic effect in K562 cells. As observed with other redox cycling quinones, the protein cleavage is blocked in the presence of N-terminal Hsp90 inhibitors suggesting that the availability or occupancy of nucleotide binding site in the N-terminal pocket of Hsp90 plays a critical role. In addition the survival of cancer cells and their metabolic and redox homeostasis were strongly impaired by the presence of ascorbate. Since these effects were similar to that obtained by ascorbate/menadione and they were blocked by the antioxidant N-acetylcyteine (NAC), it appears that oxidative stress is a major component of this cytotoxicity. PMID:23167798

Ríos, David; Benites, Julio; Valderrama, Jaime A; Farias, Mirelle; Pedrosa, Rozangela C; Verrax, Julien; Buc Calderon, Pedro



Novel spectrophotometric method for determination of cinacalcet hydrochloride in its tablets via derivatization with 1,2-naphthoquinone-4-sulphonate  

PubMed Central

This study represents the first report on the development of a novel spectrophotometric method for determination of cinacalcet hydrochloride (CIN) in its tablet dosage forms. Studies were carried out to investigate the reaction between CIN and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 8.5), an orange red-colored product exhibiting maximum absorption peak (?max) at 490 nm was produced. The stoichiometry and kinetic of the reaction were investigated and the reaction mechanism was postulated. This color-developing reaction was employed in the development of a simple and rapid visible-spectrophotometric method for determination of CIN in its tablets. Under the optimized reaction conditions, Beer's law correlating the absorbance with CIN concentration was obeyed in the range of 3 - 100 ?g/ml with good correlation coefficient (0.9993). The molar absorptivity (?) was 4.2 × 105 l/mol/cm. The limits of detection and quantification were 1.9 and 5.7 ?g/ml, respectively. The precision of the method was satisfactory; the values of relative standard deviations (RSD) did not exceed 2%. No interference was observed from the excipients that are present in the tablets. The proposed method was applied successfully for the determination of CIN in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.80 - 102.23 ± 1.27 - 1.62%. The results were compared favorably with those of a reference pre-validated method. The method is practical and valuable in terms of its routine application in quality control laboratories.



Novel spectrophotometric method for determination of cinacalcet hydrochloride in its tablets via derivatization with 1,2-naphthoquinone-4-sulphonate.  


This study represents the first report on the development of a novel spectrophotometric method for determination of cinacalcet hydrochloride (CIN) in its tablet dosage forms. Studies were carried out to investigate the reaction between CIN and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 8.5), an orange red-colored product exhibiting maximum absorption peak (?max) at 490 nm was produced. The stoichiometry and kinetic of the reaction were investigated and the reaction mechanism was postulated. This color-developing reaction was employed in the development of a simple and rapid visible-spectrophotometric method for determination of CIN in its tablets. Under the optimized reaction conditions, Beer's law correlating the absorbance with CIN concentration was obeyed in the range of 3 - 100 ?g/ml with good correlation coefficient (0.9993). The molar absorptivity (?) was 4.2 × 105 l/mol/cm. The limits of detection and quantification were 1.9 and 5.7 ?g/ml, respectively. The precision of the method was satisfactory; the values of relative standard deviations (RSD) did not exceed 2%. No interference was observed from the excipients that are present in the tablets. The proposed method was applied successfully for the determination of CIN in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.80 - 102.23 ± 1.27 - 1.62%. The results were compared favorably with those of a reference pre-validated method. The method is practical and valuable in terms of its routine application in quality control laboratories. PMID:22305461

Darwish, Ibrahim A; Al-Shehri, Mona M; El-Gendy, Manal A



Mechanism of inhibition of the ATPase domain of human topoisomerase II? by 1,4-benzoquinone, 1,2-naphthoquinone, 1,4-naphthoquinone, and 9,10-phenanthroquinone.  


The inhibition of human topoisomerase II? (Hu-TopoII?), a major enzyme involved in maintaining DNA topology, repair, and chromosome condensation/decondensation results in loss of genomic integrity. In the present study, the inhibition of ATPase domain of Hu-TopoII? as a possible mechanism of genotoxicity of 1,4-benzoquinone (BQ), hydroquinone (HQ), naphthoquinone (1,2-NQ and 1,4-NQ), and 9,10-phenanthroquinone (9,10-PQ) was investigated. In silico modeling predicted that 1,4-BQ, 1,2-NQ, 1,4-NQ, and 9,10-PQ could interact with Ser-148, Ser-149, Asn-150, and Asn-91 residues of the ATPase domain of Hu-TopoII?. Biochemical inhibition assays with the purified ATPase domain of Hu-TopoII? revealed that 1,4-BQ is the most potent inhibitor followed by 1,4-NQ > 1,2-NQ > 9,10-PQ > HQ. Ligand-binding studies using isothermal titration calorimetry revealed that 1,4-BQ, HQ, 1,4-NQ, 1,2-NQ, and 9,10-PQ enter into four sequentially binding site models inside the domain. 1,4-BQ exhibited the strongest binding, followed by 1,4-NQ > 1,2-NQ > 9,10-PQ > HQ, as revealed by their average K(d) values. The cellular fate of such inhibition was further evidenced by an increase in the number of Hu-TopoII?-DNA cleavage complexes in the human lung epithelial cells (BEAS-2B) using trapped in agarose DNA immunostaining (TARDIS) assay, which utilizes antibody specific for Hu-TopoII?. Furthermore, the increase in ?-H2A.X levels quantitated by flow cytometry and visualized by immunofluorescence microscopy illustrated that accumulation of DNA double-strand breaks inside the cells can be attributed to the inhibition of Hu-TopoII?. These findings collectively suggest that 1,4-BQ, 1,2-NQ, 1,4-NQ, and 9,10-PQ inhibit the ATPase domain and potentially result in Hu-TopoII?-mediated clastogenic and leukemogenic events. PMID:22218491

Gurbani, Deepak; Kukshal, Vandna; Laubenthal, Julian; Kumar, Ashutosh; Pandey, Alok; Tripathi, Sarita; Arora, Ashish; Jain, Swatantra K; Ramachandran, Ravishankar; Anderson, Diana; Dhawan, Alok



An assessment of the genotoxicity of 2-hydroxy-1,4-naphthoquinone, the natural dye ingredient of Henna.  


2-Hydroxy-1,4-naphthoquinone (HNQ; Lawsone; CAS 83-72-7) is the principal natural dye ingredient contained in the leaves of Henna (Lawsonia inermis). Published genotoxicity studies on HNQ suggested it was a weak bacterial mutagen for Salmonella typhimurium strain TA98 or was more clearly mutagenic for strain TA 2637, both in the presence of metabolic activation. HNQ was unable to induce sex-linked recessive lethal mutations in Drosophila melanogaster. However, a small increase in micronucleus frequency was reported in the bone marrow of mice at a single mid-range dose level, 24h after intraperitoneal injection. In view of the wide use of Henna hair dyes it was deemed necessary to conduct a thorough investigation, under Good Laboratory Practice conditions, of the genotoxicity of HNQ. HNQ was non-mutagenic in bacterial (Ames test) or mammalian (V79 hprt) assays. It was borderline positive in a mouse lymphoma tk mutation assay and a chromosome aberration test (CHO cells), results that may reflect a similar clastogenic mechanism. Negative in vivo genotoxicity results were noted in the rat hepatocyte in vivo/in vitro UDS test, in peripheral lymphocytes (chromosome aberrations) of rats receiving repeated oral doses of HNQ at the MTD for 28 days, and in mouse and hamster bone marrow chromosome aberration tests. However small, but statistically significant increases in the incidence of bone marrow micronuclei were observed in two out of five tests at 72 h after dosing, but not at 24 or 48 h. There was evidence of haematotoxicity at 72 h, which may have been enhanced by the vehicle (DMSO) used in the positive tests. As erythropoiesis and administration of haematotoxic agents are known to induce small increases in the frequency of bone marrow micronuclei, typically at delayed sampling times, the data suggest that the positive 72 h response produced by HNQ is consistent with stimulation of haematopoiesis subsequent to haematological toxicity of HNQ, and not due to a DNA-reactive mechanism. Overall, the weight of evidence suggests that Henna and HNQ pose no genotoxic risk to the consumer. PMID:12787822

Kirkland, David; Marzin, Daniel



Validated spectrophotometric method for the determination, spectroscopic characterization and thermal structural analysis of duloxetine with 1,2-naphthoquinone-4-sulphonate  

NASA Astrophysics Data System (ADS)

A novel, selective, sensitive and simple spectrophotometric method was developed and validated for the determination of the antidepressant duloxetine hydrochloride in pharmaceutical preparation. The method was based on the reaction of duloxetine hydrochloride with 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline media to yield orange colored product. The formation of this complex was also confirmed by UV-visible, FTIR, 1H NMR, Mass spectra techniques and thermal analysis. This method was validated for various parameters according to ICH guidelines. Beer's law is obeyed in a range of 5.0-60 ?g/mL at the maximum absorption wavelength of 480 nm. The detection limit is 0.99 ?g/mL and the recovery rate is in a range of 98.10-99.57%. The proposed methods was validated and applied to the determination of duloxetine hydrochloride in pharmaceutical preparation. The results were statistically analyzed and compared to those of a reference UV spectrophotometric method.

Ulu, Sevgi Tatar; Elmali, Fikriye Tuncel



Micelles catalyzed chemoselective synthesis 'in water' and biological evaluation of oxygen containing hetero-1,4-naphthoquinones as potential antifungal agents.  


Various oxygen containing 1,4-naphthoquinone derivatives have been synthesized chemoselectively by an economical, viable green methodology approach using water as solvent with or without surfactants such as Triton X-100, SDS, LD (laundry detergent), and TBAB, a phase transfer catalyst and evaluated for their in vitro antifungal and antibacterial activity. The antifungal profile of 3, 4a, 4b, and 6 indicated that compounds 3a, 3b, 4b, 6a, and 6c have potent antifungal activity compared to clinically prevalent antifungal drugs Fluconazole and Amphotericin-B against Sporothrix schenckii, Trichophyton mentagraphytes, and Candida parapsilosis and compound 3b has been found to be a lead antifungal agent for further study. PMID:21930375

Tandon, Vishnu K; Maurya, Hardesh K; Mishra, Nripendra N; Shukla, Praveen K



A novel and efficient synthesis of diverse dihydronaphtho[1,2-b]furans using the ceric ammonium nitrate-catalyzed formal [3 + 2] cycloaddition of 1,4-naphthoquinones to olefins and its application to furomollugin.  


A novel approach was developed for the synthesis of diverse dihydronaphtho[1,2-b]furans from 1,4-naphthoquinones and olefins in the presence of ceric ammonium nitrate. This reaction provides a rapid route for the synthesis of a variety of dihydronaphtho[1,2-b]furans and naphtho[1,2-b]furans bearing different substituents. This methodology was also used to synthesize the biologically important natural product furomollugin in only 2 steps. PMID:23963248

Xia, Likai; Lee, Yong Rok



Effect of l-phenylalanine on PAL activity and production of naphthoquinone pigments in suspension cultures of Arnebia euchroma (Royle) Johnst.  


The effects of l-phenylalanine (PHE) on cell growth and production of shikonin and its derivatives, acetylshikonin (ACS) and isobutyrylshikonin (IBS), in suspension cultures of Arnebia euchroma were examined. Supplementing media using PHE have been successfully utilized to enhance shikonin production in cell cultures of other species of Boraginaceae. l-Phenylalanine, the key compound in the phenylpropanoid pathway, is converted by phenylalanine ammonia lyase (PAL) to trans-cinnamic acid, which is the precursor of p-hydroxybenzoic acid (PHB). Coupling of PHB and geranyl pyrophosphate (derived from mevalonate pathway) by p-hydroxybenzoate-m-geranyltransferase leads later to biosynthesis of shikonins. The addition of 0.01 or 0.1 mM PHE to the culture medium stimulated cell proliferation, where the highest observed increase in fresh cell biomass (measured as a ratio of final weight to initial weight) was 12-fold, in contrast to an eightfold increase in control cultures. Whereas, growth media supplemented with 1 mM PHE markedly reduced the rate of cell growth (to only twofold). Precursor feeding had detrimental effects on both ACS and IBS production in all PHE-supplemented media. The highest total content (intracellular + extracellular) of the investigated red pigments (9.5 mg per flask) was detected in the control culture without PHE. ACS was the major component of the naphthoquinone fraction determined in cells and post-culture media. Shikonin itself was found only in the post-culture media from cultures supplemented with 0.01 or 0.1 mM PHE. Increases in PAL activity corresponded well with the accumulation of investigated naphthoquinones in control culture. However, peak PAL activity did not directly correlate with maximum production of shikonin derivatives. Cytotoxicity of extracts, prepared from the cells cultivated in the presence of PHE or in control cultures, was tested on three cancer cell lines: HL-60, HeLa, and MCF-7. The extracts prepared from the untreated control cultures proved to be the most potent against the examined cancer cell lines. The mean inhibitory concentration values were 0.3, 13, and 8 ?g ml(-1) for the HL-60, HeLa, and MCF-7 cells, respectively. PMID:23049233

Syk?owska-Baranek, Katarzyna; Pietrosiuk, Agnieszka; Naliwajski, Marcin R; Kawiak, Anna; Jeziorek, Ma?gorzata; Wyderska, Sylwia; Lojkowska, Ewa; Chinou, Ioanna



In vitro and in vivo Leishmanicidal activity of 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol).  


This study aims to evaluate the in vitro and in vivo leishmanicidal activity of lapachol, a naphthoquinone found in the seeds and heartwood of certain tropical plants, and to compare its efficacy with a reference drug, sodium stibogluconate (Pentostam(R)). These compounds (0.0125-4.0 mg/mL) were evaluated in vitro against intracellular amastigotes of Leishmania (Viannia) braziliensis (LVb), then tested in an animal model (hamster) to try to reproduce the leishmanicidal activity. In vitro, lapachol exhibited an anti-amastigote effect, whereas in vivo it did not prevent the development of LVb-induced lesions at an oral dose of 300 mg/kg/day for 42 days. Pentostam(R) demonstrated a significant anti-amastigote effect in vitro for LVb and apparent clinical cure in vivo (60 mg/kg/day). However, it could not completely eradicate parasites from the tissues of infected animals. The observation that lapachol exerts leishmanicidal activity in vitro without offering significant protection against LVb-infected lesions in hamsters suggests that lapachol in vivo might possibly inhibit the microbicidal functioning of macrophages. Alternatively, it might be transformed into an inactive metabolite(s) or neutralized, losing its leishmanicidal activity. It is also possible that an optimal and sustained plasma level of the drug could not be achieved at the dose used in this study. PMID:11180522

Teixeira, M J; de Almeida, Y M; Viana, J R; Holanda Filha, J G; Rodrigues, T P; Prata, J R; Coêlho, I C; Rao, V S; Pompeu, M M



Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: Electrochemical studies on the effects of the quinoidal moiety.  


In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8?M. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6?M for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent. PMID:24074878

Diogo, Emilay B T; Dias, Gleiston G; Rodrigues, Bernardo L; Guimarães, Tiago T; Valença, Wagner O; Camara, Celso A; de Oliveira, Ronaldo N; da Silva, Mauro G; Ferreira, Vitor F; de Paiva, Yen Galdino; Goulart, Marilia O F; Menna-Barreto, Rubem F S; de Castro, Solange L; da Silva Júnior, Eufrânio N



A dedicated thioesterase of the Hotdog-fold family is required for the biosynthesis of the naphthoquinone ring of vitamin K1  

PubMed Central

Phylloquinone (vitamin K1) is a bipartite molecule that consists of a naphthoquinone ring attached to a phytyl side chain. The coupling of these 2 moieties depends on the hydrolysis of the CoA thioester of 1,4-dihydroxy-2-naphthoate (DHNA), which forms the naphthalenoid backbone. It is not known whether such a hydrolysis is enzymatic or chemical. In this study, comparative genomic analyses identified orthologous genes of unknown function that in most species of cyanobacteria cluster with predicted phylloquinone biosynthetic genes. The encoded approximately 16-kDa proteins display homology with some Hotdog domain-containing CoA thioesterases that are involved in the catabolism of 4-hydroxybenzoyl-CoA and gentisyl-CoA (2,5-dihydroxybenzoyl-CoA) in certain soil-dwelling bacteria. The Synechocystis ortholog, encoded by gene slr0204, was expressed as a recombinant protein and was found to form DHNA as reaction product. Unlike its homologs in the Hotdog domain family, Slr0204 showed strict substrate specificity. The Synechocystis slr0204 knockout was devoid of DHNA-CoA thioesterease activity and accumulated DHNA-CoA. As a result, knockout cells contained 13-fold less phylloquinone than their wild-type counterparts and displayed the typical photosensitivity to high light associated to phylloquinone deficiency in cyanobacteria.

Widhalm, Joshua R.; van Oostende, Chloe; Furt, Fabienne; Basset, Gilles J. C.



Copper(II)-Catalyzed Sequential C,N-Difunctionalization of 1,4-Naphthoquinone for the Synthesis of Benzo[f]indole-4,9-diones under Base-Free Condition.  


An efficient synthesis of benzo[f]indole-4,9-diones has been achieved by copper(II)-catalyzed naphthoquinone sequential C,N-difunctionalization reactions with ?-enaminones. New C-C and C-N bonds are easily formed in the reaction course. Copper(II) salt plays a dual role as Lewis acid and oxidative catalyst, and O2 acts as the terminal oxidant. The advantage of this reaction is the high atom economy with broad substrate scope and excellent yields. The reaction can be scaled up to using at least grams of substrates. PMID:24070011

Sun, Jin-Wei; Wang, Xiang-Shan; Liu, Yun



Kinetics of jack bean urease inhibition by 2,3-dichloro-1,4-naphthoquinone. Elucidation of the mechanism: redox cycling and sulfhydryl arylation.  


The inhibition of jack bean urease by 2,3-dichloro-1,4-naphthoquinone (DCNQ) was studied at ambient temperature in 20 mM phosphate buffer, pH 7.8. The process was investigated by incubation procedure in the absence of substrate. It was found that DCNQ acted as a time- and concentration-dependent inactivator of urease. The time course of the reaction displayed a biphasic mode. Each phase followed a pseudo-first-order kinetics, however the inactivation rate at the first phase was significantly faster than at the next one. The biphasity indicated the complex mechanism of DCNQ action on urease. Quinones action on proteins has been elucidated as at least two processes: direct arylation of essential protein thiols and/or indirect oxidation of essential thiols by reactive oxygen species (ROS) realising during quinone reduction to semiquinones. The next evidence of the studied mechanism was provided by the reactivation experiment that showed the participation of reversible and irreversible processes in the inactivation. The application of dithiothreitol (DTT) into DCNQ blocked-urease solution resulted in an effective enzyme activity regain which quickly returned to 70 +/- 10%. The irreversible inactivation of urease was attributed to DCNQ arylation of thiol residues in the protein. On the other hand, it was assumed that the reversible inactivation was a result of the action of ROS such as H(2)O(2). Presence of H(2)O(2) in the incubation system was proved by an experiment with the use of catalase. The enzyme by the elimination of H(2)O(2) decreased DCNQ inactivating influence on urease. The comparison of participation of the fast and slow phase in the inactivation with the percentage of the process reversibility was assumed that the fast period was a result of the arylation mechanism while the slow phase was related to the oxidative influence of H(2)O(2). PMID:19621983

Zaborska, Wies?awa; Kot, Miros?awa; Bala, Agnieszka



The antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain.  


Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are "subversive substrates." These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates. PMID:23439633

Ehrhardt, Katharina; Davioud-Charvet, Elisabeth; Ke, Hangjun; Vaidya, Akhil B; Lanzer, Michael; Deponte, Marcel



The Antimalarial Activities of Methylene Blue and the 1,4-Naphthoquinone 3-[4-(Trifluoromethyl)Benzyl]-Menadione Are Not Due to Inhibition of the Mitochondrial Electron Transport Chain  

PubMed Central

Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are “subversive substrates.” These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates.

Ehrhardt, Katharina; Ke, Hangjun; Vaidya, Akhil B.; Lanzer, Michael



Antimalarial naphthoquinones from Nepenthes thorelii.  


Roots of Nepenthes thorelii yielded plumbagin, 2-methylnaphthazarin, octadecyl caffeate, isoshinanolone, and droserone. In addition, seven derivatives were prepared from plumbagin. Each of these natural and semisynthetic compounds was evaluated for in vitro antimalarial potential. PMID:9581522

Likhitwitayawuid, K; Kaewamatawong, R; Ruangrungsi, N; Krungkrai, J



LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells.  


Despite the relevant therapeutic progresses obtained with imatinib, clinical resistance to this drug has emerged and reemerged after cytogenetic remission in a group of patients with chronic myeloid leukemia (CML). Therefore, novel treatment strategies are needed. In this study, we evaluated the anti-CML activity and mechanisms of action of LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]. LQB-118 treatment resulted in an important reduction of cell viability in cell lines derived from CML, both the vincristine-sensitive K562 cell line, and the resistant K562-Lucena (a cell line overexpressing P-glycoprotein). In agreement with these results, the induction of caspase-3 activation by this compound indicated that a significant rate of apoptosis was taking place. In these cell lines, apoptosis induced by LQB-118 was accompanied by a reduction of P-glycoprotein, survivin, and XIAP expression. Moreover, this effect was not restricted to cell lines as LQB-118 produced significant apoptosis rate in cells from CML patients exhibiting multifactorial drug resistance phenotype such as P-glycoprotein, MRP1 and p53 overexpression. The data suggest that LQB-118 has a potent anti-CML activity that can overcome multifactorial drug resistance mechanisms, making this compound a promising new anti-CML agent. PMID:20499132

Maia, Raquel C; Vasconcelos, Flavia C; de Sá Bacelar, Thiago; Salustiano, Eduardo J; da Silva, Luis Felipe R; Pereira, Débora L; Moellman-Coelho, Arthur; Netto, Chaquip D; da Silva, Alcides J; Rumjanek, Vivian M; Costa, Paulo R R



Identification of a novel gene cluster participating in menaquinone (vitamin K2) biosynthesis. Cloning and sequence determination of the 2-heptaprenyl-1,4-naphthoquinone methyltransferase gene of Bacillus stearothermophilus.  


We recently described the isolation and sequence analysis of a DNA region containing the genes of Bacillus stearothermophilus heptaprenyl diphosphate synthase, which catalyzes the synthesis of the prenyl side chain of menaquinone-7 of this bacterium. Sequence analyses revealed the presence of three open reading frames (ORFs), designated as ORF-1, ORF-2, and ORF-3, and the structural genes of the heptaprenyl diphosphate synthase were proved to consist of ORF-1 (heps-1) and ORF-3 (heps-2) (Koike-Takeshita, A., Koyama, T., Obata, S., and Ogura, K. (1995) J. Biol. Chem. 270, 18396-18400). The predicted amino acid sequence of ORF-2 (234 amino acids) contains a methyltransferase consensus sequence and shows a 22% identity with UbiG of Escherichia coli, which catalyzes S-adenosyl-L-methionine-dependent methylation of 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone. These pieces of information led us to identify the ORF-2 gene product. The cell-free homogenate of the transformant of E. coli with an expression vector of ORF-2 catalyzed the incorporation of S-adenosyl-L-methionine into menaquinone-8, indicating that ORF-2 encodes 2-heptaprenyl-1,4-naphthoquinone methyltransferase, which participates in the terminal step of the menaquinone biosynthesis. Thus it is concluded that the ORF-1, ORF-2, and ORF-3 genes, designated heps-1, menG, and heps-2, respectively, form another cluster involved in menaquinone biosynthesis in addition to the cluster of menB, menC, menD, and menE already identified in the Bacillus subtilis and E. coli chromosomes. PMID:9139683

Koike-Takeshita, A; Koyama, T; Ogura, K



Effects of ethanolic extract and naphthoquinones obtained from the bulbs of Cipura paludosa on short-term and long-term memory: involvement of adenosine A? and A?A receptors.  


Previous studies from our group have indicated important biological properties of the ethanolic extract and isolated compounds from the bulbs of Cipura paludosa (Iridaceae), a native plant widely distributed in northern Brazil, including antioxidant, neuroprotective and anti-nociceptive activities. In the present study, the effects of the ethanolic extract and its two naphthoquinones (eleutherine and isoeleutherine) on the short- and long-term memory of adult rodents were assessed in social recognition and inhibitory avoidance tasks. Acute pre-training oral administration of the ethanolic extract improved the short-term social memory in rats as well as facilitated the step-down inhibitory avoidance short- and long-term memory in mice. Moreover, the co-administration of 'non-effective' doses of the extract of Cipura paludosa and the adenosine receptor antagonists caffeine (non-selective), DPCPX (adenosine A1 receptor antagonist) and ZM241385 (adenosine A2A receptor antagonist) improved the social recognition memory of rats. In the inhibitory avoidance task, the co-administration of sub-effective doses of the extract with caffeine or ZM241385, but not with DPCPX, improved the short- and long-term memory of mice. Finally, the acute oral administration of eleutherine and isoeleutherine facilitated the inhibitory avoidance short- and long-term memory in mice. These results demonstrate for the first time the cognitive-enhancing properties of the extract and isolated compounds from the bulbs of Cipura paludosa in rodents and suggest a possible involvement of adenosine A1 and A2A receptors in these effects. PMID:23057724

Lucena, Greice M R S; Matheus, Filipe C; Ferreira, Vania M; Tessele, Priscila B; Azevedo, Mariangela S; Cechinel-Filho, Valdir; Prediger, Rui D



Chemistry and hair dyes application of dihydroxy derivatives of anthraquinone and naphthoquinone  

Microsoft Academic Search

Leucoquinizarin reacted with butylamine to give 1-butylamino-4-hydroxyanthraquinone and 1,4-bis(butylamino)anthraquinone. Their structures were elucidated and the reaction mechanism was discussed from the kinetic studies. Quinizarin reacted with butylamine to give 2-butylaminoquinizarin selectively, even in the presence of sodium dithionite. Under a nitrogen atmosphere, quinizarin was butylaminated to give 1-butylamino-4-hydroxyanthraquinone and\\/or 1,4-bis(butylamino)anthraquinone, even in the absence of sodium dithionite. Effects of sodium

Masashi Yoshida



Semisynthesis and antitumoral activity of 2-acetylfuranonaphthoquinone and other naphthoquinone derivatives from lapachol.  


Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), beta-lapachone (10) and dehydro-beta-lapachone diacetate (11) showed 100% inhibition at 25 microg/ml. All the tested samples showed dose-dependent activity. PMID:18829316

Eyong, Kenneth O; Kumar, Ponminor S; Kuete, Victor; Folefoc, Gabriel N; Nkengfack, Ephriam A; Baskaran, Sundarababu



Molecularly imprinted polymers for the isolation of bioactive naphthoquinones from plant extracts.  


Molecularly Imprinted Polymers (MIPs) targeting shikonin, a potent antioxidant and wound healing agent, have been prepared using methacrylic acid (MAA) and 2-diethylaminoethyl methacrylate (DEAEMA) as functional monomers. An investigation of solution association between shikonin and both acidic and basic functional monomers by UV-vis titrations, suggested stronger affinity towards the basic functionality. Strong inhibition of the co-polymerisation reaction of such basic monomers was observed, but was overcome by reduction of the amount of template used during polymer synthesis. Polymer morphology was severely impacted by the template's radical scavenging behaviour as demonstrated by solid state NMR spectroscopy measurements. HPLC evaluation of the final materials in polar conditions revealed limited imprinting effects and selectivity, with the MAA polymers exhibiting marginally better performance. During application of the polymers as MI-SPE sorbents in non-polar solvents it was found that the DEAEMA based polymer was more selective towards shikonin compared to the MAA counterpart, while shikonin recoveries of up to 72% were achieved from hexane solutions of a commercial sample of shikonin, hexane extract of Alkanna tinctoria roots and a commercial pharmaceutical ointment. PMID:24075017

Tsermentseli, Stella K; Manesiotis, Panagiotis; Assimopoulou, Andreana N; Papageorgiou, Vassilios P



Naphthalene and Naphthoquinone: Distributions and Human Exposure in the Los Angeles Basin  

Microsoft Academic Search

Naphthalene is the simplest and most abundant of the polycyclic aromatic hydrocarbons (PAHs). Naphthalene is found primarily in the gas-phase and has been detected in both outdoor and indoor samples. Evaporation from naphthalene-containing products (including gasoline), and during refining operations, are important sources of naphthalene in air. Naphthalene is also emitted during the combustion of fossil fuels and wood, and

R. Lu; J. Wu; R. Turco; A. M. Winer; R. Atkinson; S. Paulson; J. Arey; F. Lurmann



Induced production of antifungal naphthoquinones in the pitchers of the carnivorous plant Nepenthes khasiana  

Microsoft Academic Search

Nepenthes spp. are carnivorous plants that have developed insect capturing traps, evolved by specific modification of the leaf tips, and are able to utilize insect degradation products as nutritional precursors. A chitin-induced antifungal ability, based on the production and secretion to the trap liquid of droserone and 5-O-methyldroserone, is described here. Such specific secretion uniquely occurred when chitin injection was

Haviva Eilenberg; Smadar Pnini-Cohen; Yocheved Rahamim; Edward Sionov; Esther Segal; Shmuel Carmeli; Aviah Zilberstein



Naphthoquinones from Onosma paniculata Induce Cell-Cycle Arrest and Apoptosis in Melanoma Cells  

PubMed Central

Activity-guided fractionation of a petroleum ether-soluble extract of the roots of Onosma paniculata, which has been shown to affect the cell cycle and to induce apoptosis in melanoma cells, led to the isolation of several shikonin derivatives, namely, ?-hydroxyisovalerylshikonin (1), acetylshikonin (2), dimethylacrylshikonin (3), and a mixture of ?-methylbutyrylshikonin and isovalerylshikonin (4+5). All compounds exhibited strong cytotoxicity against eight cancer cell lines and MRC-5 lung fibroblasts, with 3 found to possess the most potent cytotoxicity toward four melanoma cell lines (SBcl2, WM35, WM9, and WM164). Furthermore, 3 and the mixture of 4+5 were found to interfere with cell-cycle progression in these cell lines and led to an increasing number of cells in the subG1 region as well as to caspase-3/7 activation, indicating apoptotic cell death.



Presence of peroxyradicals in cigarette smoke and the scavenging effect of shikonin, a naphthoquinone pigment.  


Using a new method having been developed for the purpose of quantitative determination for peroxyradicals, the presence of peroxyradicals was proved in cigarette smoke. In brief, peroxyradicals in cigarette smoke were measured by ESR spectrometry coupled to non-reductive scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH). As a result, peroxyradicals were found to be major reactive oxygen species (ROS) since the concentration of peroxyradicals recovered from cigarette smoke was much higher than that of any of other ROS (superoxide and hydroxyl radical) and nitric oxide. Furthermore, several antioxidants (ascorbic acid, reduced glutathione, epigallocatechin gallate, shikonin) were examined for scavenging activity against peroxyradicals in the cigarette smoke. Among them shikonin alone exerted the scavenging activity, suggesting that shikonin is promising antioxidant for cigarette filters because of its effectiveness against broad range of ROS including peroxyradicals, heat resistance, nonvolatility and high affinity to the filter. PMID:15997138

Nishizawa, Masahiro; Kohno, Masahiro; Nishimura, Minemitsu; Kitagawa, Akio; Niwano, Yoshimi



Isolation and chemopreventive evaluation of novel naphthoquinone compounds from Alkanna tinctoria.  


Botanically derived natural products have recently become an attractive source of new chemotherapeutic agents. To explore active anticolorectal cancer compounds, we carried out phytochemical studies on Alkanna tinctoria and isolated eight quinone compounds. Using different spectral methods, compounds were identified as alkannin (1), acetylalkannin (2), angelylalkannin (3), 5-methoxyangenylalkannin (4), dimethylacryl alkannin (5), arnebifuranone (6), alkanfuranol (7), and alkandiol (8). Compounds 4, 7, and 8 are novel compounds. The structures of the three novel compounds were elucidated on the basis of extensive spectroscopic evidence including high-resolution mass spectrometry and nuclear magnetic resonance spectra. The antiproliferative effects of these eight compounds on HCT-116 and SW-480 human colorectal cancer cells were determined using the MTS method. Cell cycle and apoptosis were determined using flow cytometry. Enzymatic activities of caspases were determined using a colorimetric assay, and interactions of compound 4 and caspase 9 were explored by docking analysis. Among the eight compounds, alkannin (1), angelylalkannin (3), and 5-methoxyangenylalkannin (4) showed strong antiproliferative effects, whereas compound 4 showed the most potent effects. Compound 4 arrested cancer cells in the S and G2/M phases, and significantly induced cell apoptosis. The apoptotic effects of compound 4 were supported by caspase assay and docking analysis. The structural-functional relationship assay suggested that to increase anticancer potential, future modifications on alkannin (1) should focus on the hydroxyl groups at C-5 and C-8. PMID:24025561

Tung, Nguyen Huu; Du, Guang-Jian; Yuan, Chun-Su; Shoyama, Yukihiro; Wang, Chong-Zhi



Study on the Introduction of Two Different Substituents, an Amino and a Thio-group, on 1,4-Naphthoquinones  

Microsoft Academic Search

Many quinones are biologically active and beneficial for a variety of medicinal purposes including anticancers. One such example is vitamin K, which could function as an antitumor agent, in addition to its well-known role in blood clotting. This biological activity is ascribed to its modification of the cysteine residue in the active site of tyrosine phosphatase, inhibiting the cell growth

Liliana Castelblanco



Tabebuia avellanedae naphthoquinones: activity against methicillin-resistant staphylococcal strains, cytotoxic activity and in vivo dermal irritability analysis  

Microsoft Academic Search

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococcus infections are a worldwide concern. Currently, these isolates have also shown resistance to vancomycin, the last therapy used in these cases. It has been observed that quinones and other related compounds exhibit antibacterial activity. This study evaluated the antibacterial activity, toxicity and in vivo dermal irritability of lapachol extracted from Tabebuia avellanedae

Eliezer Menezes Pereira; Thelma de Barros Machado; Ivana Correa Ramos Leal; Desyreé Murta Jesus; Clarissa Rosa de Almeida Damaso; Antonio Ventura Pinto; Marcia Giambiagi-deMarval; Ricardo Machado Kuster; Kátia Regina Netto dos Santos



Plumbagin, a Naturally Occurring Naphthoquinone: Its Isolation, Spectrophotometric Determination in Roots, Stems, and Leaves in Plumbago Europaea L  

Microsoft Academic Search

A new method for isolation and spectrophotometric determination of plumbagin is presented. Plumbagin was isolated by thin layer chromatography (TLC) and column chromatography (CC) techniques, as an orange tinged yellow long crystalline substances. Plumbagin exhibits two absrop-tion maxima at 410 and 510 nm. Stability of the color, pKa value, and the effect of pH were studied. Beer's law is obeyed

Mohammed A. Al-Nuri; Mohammed A. Hannoun; Nidal A. Zatar; Maher A. Abu-Eid; Waheed J. Al-Jondi; Ahmad I. Hussein; Mohammed S. Ali-Shtayeh



Potent and specific bactericidal effect of juglone (5-hydroxy-1,4-naphthoquinone) on the fire blight pathogen Erwinia amylovora.  


A screening of plant quinones for inhibiting effects on the bacterial fire blight pathogen Erwinia amylovora was performed. The most active compound, juglone from walnuts, has a potent and specific bactericidal effect on E. amylovora and minimal inhibitory concentrations of only 2.5-10 ?M, with stronger effects at lower, but still physiological, pH values. In vitro tests with juglone and inoculated flowers of apple (Malus domestica) showed an efficacy of 67% in preventing infection. In two years of field tests juglone had variable degrees of efficacy ranging from 40 to 82%, seemingly due to environmental conditions. A phytotoxic reaction to juglone, which is known for its allelopathic effect on plants, was restricted to browning of petals; later fruit russeting was not observed. Juglone is a promising candidate for the development of a new environmentally friendly plant protectant to replace the antibiotic streptomycin currently used in fire blight control. PMID:23163769

Fischer, Thilo Christopher; Gosch, Christian; Mirbeth, Beate; Gselmann, Markus; Thallmair, Veronika; Stich, Karl



Plumbagin, a Medicinal Plant-Derived Naphthoquinone, Is a Novel Inhibitor of the Growth and Invasion of Hormone-Refractory Prostate Cancer  

Microsoft Academic Search

Prostate cancer (PCa) is the second leading cause of cancer- related deaths in men. Hormone-refractory invasive PCa is the end stage and accounts for the majority of PCa patient deaths. We present here that plumbagin (PL), a quinoid constituent isolated from the root of the medicinal plant Plumbago zeylanica L., may be a potential novel agent in the control of

Moammir H. Aziz; Nancy E. Dreckschmidt; Ajit K. Verma



Cis-4A,5,8,8A-Tetrahydro-6,7-di-(Bromomethyl) Naphthoquinone from 2,3-di-(Bromomethyl)-1,3-Butadiene.  

National Technical Information Service (NTIS)

3,4-di-(bromomethyl)-2,5-dihydrothiophene-1,1-dioxide was prepared and then decomposed by heating to yield 2,3-di-(bromomethyl)-1,3-butadiene (I). This diene was very sensitive to light and polymerized readily. Polymerization also occurs in most solvents ...

G. B. Butler R. M. Ottenbrite



Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone refractory prostate cancer  

PubMed Central

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men. Hormone refractory invasive PCa is the end stage and accounts for the majority of PCa patient deaths. We present here that plumbagin (PL), a quinoid constituent isolated from the root of the medicinal plant Plumbago zeylanica L, may be a potential novel agent in the control of hormone refractory PCa. Specific observations are the findings that PL inhibited PCa cell invasion and selectively induced apoptosis in PCa cells but not in immortalized non-tumorigenic prostate epithelial RWPE-1 cells. Also, intraperitoneal administration of PL (2mg/kg body weight), beginning 3 days after ectopic implantation of hormone refractory DU145 PCa cells, delayed tumor growth by 3 weeks and reduced both tumor weight and volume by 90%. Discontinuation of PL treatment in PL- treated mice, for as long as 4 weeks did not result in progression of tumor growth. PL, at concentrations as low as 5 ?M, inhibited both in cultured PCa cells and DU145 xenografts the expression of: 1) PKC?, PI3K, pAKT, pJAK-2 and pStat3; 2) the DNA-binding activity of transcription factors AP-1, NFkB, and Stat3 and 3) Bcl-xL, cdc25A and COX-2 expression. The results indicate for the first time, using both in vitro and in vivo preclinical models, that PL inhibits the growth and invasion of PCa. PL inhibits multiple molecular targets including PKC?, a predictive biomarker of PCa aggressiveness. PL may be a novel agent for therapy of hormone refractory PCa.

Aziz, Moammir H.; Dreckschmidt, Nancy E.; Verma, Ajit K.



1,3-Azoles from ortho-naphthoquinones: synthesis of aryl substituted imidazoles and oxazoles and their potent activity against Mycobacterium tuberculosis.  


Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 ?g/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes. PMID:23000294

Moura, Kelly C G; Carneiro, Paula F; Pinto, Maria do Carmo F R; da Silva, José A; Malta, Valéria R S; de Simone, Carlos A; Dias, Gleiston G; Jardim, Guilherme A M; Cantos, Jéssica; Coelho, Tatiane S; da Silva, Pedro E Almeida; da Silva, Eufrânio N



Evidence of Polymorphism on the Antitrypanosomal Naphthoquinone (4E)-2-(1H-Pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one  

PubMed Central

The aim of this study was to characterize the solid state properties of (4E)-2-(1H-pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one (BiPNQ), a compound with a significant inhibitory activity against Trypanosoma cruzi, the etiological agent of Chagas disease (American trypanosomiasis). Methods used included Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD), Hot Stage, and Confocal Microscopy. Two BiPNQ samples were obtained by crystallization from absolute methanol and 2-propanol-water that exhibited different thermal behaviours, PXRD patterns, and FTIR spectra, indicating the existence of an anhydrous form (BiPNQ-I) and a solvate (BIPNQ-s), which on heating desolvated leading to the anhydrous modification BiPNQ-I. It was determined that FTIR, DSC, and PXRD are useful techniques for the characterization and identification of the crystalline modifications of BiPNQ.

Sperandeo, Norma R.; Faudone, Sonia N.



Spectrophotometric and spectrofluorimetric studies on the selective sensing of fluoride ions by Co(II) and Ni(II) complexes of naphthoquinone derivative possessing enhanced H-bonding property.  


A novel colorimetric chemosensor based on aminonaphthoquinone (L) bearing an N-H receptor unit directly attached to quinone signaling unit has been designed, synthesized and demonstrated. The ligand showed a highly selective colorimetric response to fluoride ions based on H-bond formation with the receptor unit. The binding constants of the L and its square planar [Co(L)Cl(2)]·3H(2)O and [Ni(L)Cl(2)]·4H(2)O complexes, computed using fluorescent enhancement data, were found to be 0.6, 1.5 and 0.9×10(8)M(-1), respectively, indicating enhancement of H-bond donor ability of the receptor unit, as a result of complexation with metal ions, towards fluoride ion sensing. Also, these sensors had high selectivity for fluoride ion detection over other common anions, such as Cl(-), Br(-), I(-), AcO(-), NO(3)(-), H(2)PO(4)(-) and CN(-) in acetonitrile. PMID:22820046

Madhupriya, Selvaraj; Elango, Kuppanagounder P



Mechanism of antifeedant activity of plumbagin, a compound concerning the chemical defense in carnivorous plant  

Microsoft Academic Search

Dionaea muscipula Ellis accumulates a large amount of plumbagin (1), which operates as an antifeedant against predators. Content of 1 reached 0.5% weight of the fresh trap lobes. It was found that other carnivorous plants also accumulated similar naphthoquinone-type strong antifeedant. Thus, naphthoquinone analogs are widely used as an antifeedant among the carnivorous plants. By using several analogs of 1,

Takashi Tokunaga; Noboru Takada; Minoru Ueda



A new method for sodium sulfide removal from an aqueous solution and application to industrial wastewater and sludge  

Microsoft Academic Search

The catalyst activities for Na2S oxidation in aqueous solution were examined for various materials such as activated carbon, carbon black, ferric salts, hydroquinone, 1,4-naphthoquinone-2-sulfonic acid sodium salt, 1,4-naphthoquinone, and their mixed systems.

Yasuo Ueno; Alan Williams; F. E. Murray



Cytotoxicity of new polyfluorinated 1,4-naphtoquinones with diverse substituents in the quinone moiety.  


Fluorinated derivatives of 1,4-naphthoquinones are highly potent inhibitors of Cdc25A and Cdc25B phosphatases and growth of tumor cells. Eight new derivatives of polyfluoro-1,4-naphthoquinone were synthesized and their cytotoxicity in human myeloma, human mammary adenocarcinoma, mouse fibroblasts and primary mouse fibroblast cells as well as their mutagenic and antioxidant properties in a Salmonella tester strain were studied. The efficiency of suppressing the growth of two lines of tumor cells decreased in the order: 2-(2-hydroxy-ethylamino)-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (1), 2,3-dimethoxy-5,6,7,8-tetrafluoro-1,4-naphthoquinone (2), 2-[2-hydroxyethyl(methyl)amino]-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (3), 2-morpholino-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (4), 2-[bis-(2-hydroxyethyl)amino]-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (5), 2-[(2-hydroxy)ethylsulfanyl)]-5,6,7,8-tetrafluoro-1,4-naphthoquinone (6), 2-methoxy-3,5,6,7,8-pentafluoro-1,4-naphthoquinone (7), and 1,4-dioxo-3-(1-pyridinio)-1,4-dihydro-5,6,7,8-tetrafluoronaphthalene-2-olate (8). Taking into account these data together with the better cytotoxic effect against cancer cells as compared with normal mammalian cells, protecting of bacterial cells from spontaneous and H(2)O(2)-dependent mutagenesis, and lower general toxicity of the compounds towards different cells, one can propose that compounds 3-5 may be considered as useful potential inhibitors of growth of tumor cells. PMID:21134760

Zakharova, Ol'ga D; Ovchinnikova, Ludmila P; Goryunov, Leonid I; Troshkova, Nadezhda M; Shteingarts, Vitalij D; Nevinsky, Georgy A



'Schistosoma mansoni' Chemoprophylaxis with Dietary Lapachol.  

National Technical Information Service (NTIS)

Lapachol (2-hydroxy-3(3-methyl-2-butenyl)-1,4-naphthoquinone) suspended in mineral oil and Freund's incomplete adjuvant administered by gavage to mice to reduce schistosoma mansoni cercarial penetration and worm burdens.

F. G. Austin



The Chemistry of Plant and Animal Dyes.  

ERIC Educational Resources Information Center

|Provides a brief history of natural dyes. Chemical formulas are provided for flavonoids, luteolin, genistein, brazilin, tannins, terpenes, naphthoquinone, anthraquinone, and dyes with an alkaloid structure. Also discusses chemical background of different dye processes. (CS)|

Sequin-Frey, Margareta




PubMed Central

In the title compound, C18H18ClNO4, the imide group with its two alkyl substituents is approximately perpendicular to the plane of the naphtho­quinone ring system [dihedral angle = 78.5?(1)°]. Further, the imide carbonyl groups are oriented in an anti sense. In the crystal, the substituted naphtho­quinone rings form ?–? stacks in the a-axis direction [perpendicular centroid–centroid distance = 3.209?(2)?Å and slippage = 4.401?Å].

Butcher, Ray J.; Berhe, Solomon; Anderson, Alan J.; Bakare, Oladapo



Fluoride salts-alcohols-alumina as reagents for nucleophilic substitution of chlorine atoms for alkoxy groups in 2,3-dichlorosubstituted juglones, naphthazarines, and quinizarines  

Microsoft Academic Search

Direct displacement of chlorine atoms by alkoxy groups in 2,3-dichlorosubstituted juglones (5-hydroxy-1,4-naphthoquinones), naphthazarines (5,8-dihydroxy-1,4-naphthoquinones), and quinizarines (1,4-dihydroxy-9,10-anthraquinones) is generally ineffective, however high yields are obtained when methanol or cellosolves activated by fluoride anion are used as nucleophiles and the reaction goes in the presence of alumina.

Victor Ph. Anufriev; Vyacheslav L. Novikov



CIDEP and kinetics of 1,4-naphthosemiquinone radicals during photoreduction  

NASA Astrophysics Data System (ADS)

Light modulated CIDEP experiments and T1 measurements were performed on solutions of 1,4-naphthoquinone. Solvents were 2-propanol and 2-butanol and temperatures -4 and -21°C. Experiments with different concentrations of 1,4-naphthoquinone provided strong evidence for secondary polarization in 2-propanol. For 2-butanol the evidence was less convincing. The temperature dependence of the chemical decay rate constant confirmed the termination reaction as a diffusion controlled process. The experimental data for the initial polarization displayed no hyperfine dependency. They were readily accounted for the microscopic theory for the triplet mechanism considering the uncertaintly in the parameters characterizing the triplet state of 1,4-naphthoquinone. The experimental values for the radical pair polarization showed some scatter. However, their average values were found in satisfactory agreement with those calculated from the microscopic theory for bimolecular termination between 1,4-naphthosemiquinone radicals.

Frydkjaer, S.; Muus, L. T.



Metabolism of naphthalene by Cunninghamella elegans.  

PubMed Central

Cunninghamella elegans grown on Sabouraud dextrose broth in the presence of naphthalene produced six metabolites. Each product was isolated and identified by conventional chemical techniques. The major metabolites were 1-naphthol (67.9%) and 4-hydroxy-1-tetralone (16.7%). Minor products isolated were 1,4-naphthoquinone (2.8%), 1,2-naphthoquinone (0.2%), 2-naphthol (6.3%), and trans-1,2-dihydroxy-1,2-dihydronaphthalene (5.3%). C. elegans oxidized both 1-naphthol and 1,4-naphthoquinone to 4-hydroxy-1-tetralone. The results suggest that C. elegans oxidizes naphthalene by a sequence of reactions similar to those reported for the mammalian metabolism of this hydrocarbon.

Cerniglia, C E; Gibson, D T



The chemical mechanism of action of glucose oxidase from Aspergillus niger  

Microsoft Academic Search

Glucose oxidase from Aspergillus niger (EC is able to catalyze the oxidation of -D-glucose with p-benzoquinone, methyl-1,4-benzoquinone, 1,2-naphthoquinone, 1,2-naphthoquinone-4-sulfonic acid, potassium ferricyanide, phenazine methosulfate, and 2,6-dichloroindophenol. In this work, the steady-state kinetic parameters, V\\u000a1\\/K\\u000a\\u000aB\\u000a, for reactions of these substrates were collected from pH 2.5–8. Further, the molecular models of the enzyme's active site were constructed for

Gerd Wohlfahrt; Svetlana Trivi?; Jasmina Zeremski; Draginja Peri?in; Vladimir Leskovac




PubMed Central

In the title compound, C19H10ClNO4, the dihedral angle between the naphtho­quinone and coumarin rings is 48.99?(6)°. In the crystal, mol­ecules are linked by strong N—H?O hydrogen bonds into chains with graph-set motif C(6) along [101]. The packing also features ?–? stacking inter­actions between naphtho­quinone and coumarin rings [centroid-to-centroid distances = 3.7679?(12) and 3.6180?(13)?Å].

Sousa, Mikaelly O. B.; Silveira, Gleiciani Q.; Gomez, Javier A. G.



A fungitoxic principle from the leaves of lawsonia inermis lam.  


During antifungal screening of higher plants, the leaves of Lawsonia inermis were found to exhibit strong fungitoxicity. On chemical investigation, the antifungal factor was found to be 2-hydroxy-1,4-naphthoquinone (Lawsone). The minimum effective dose against test organism was found to be 1000 ppm. Lawsone was found to exhibit fungicidal activity, wide fungitoxic spectrum and nonphytotoxicity. PMID:620734

Tripathi, R D; Srivastava, H S; Dixit, S N



Cytotoxicity of lawsone and cytoprotective activity of antioxidants in catalase mutant Escherichia coli  

Microsoft Academic Search

Lawsone is an active naphthoquinone derivative isolated from henna (Lawsonia inermis L.), a widely used hair dye. Previous study on the toxicity of lawsone remains unclear since the involvement of oxidative stress and the kind of ROS (reactive oxygen species) involved have not been fully resolved yet. This present study reports the cytotoxic effects of lawsone and henna. We carried

Rani Sauriasari; Da-Hong Wang; Yoko Takemura; Ken Tsutsui; Noriyoshi Masuoka; Kuniaki Sano; Masako Horita; Bing-Ling Wang; Keiki Ogino



A fungitoxic principle from the leaves of Lawsonia inermis Lam  

Microsoft Academic Search

Summary During antifungal screening of higher plants, the leaves ofLawsonia inermis were found to exhibit strong fungitoxicity. On chemical investigation, the antifungal factor was found to be 2-hydroxy-1,4-naphthoquinone (Lawsone). The minimum effective dose against test organism was found to be 1000 ppm. Lawsone was found to exhibit fungicidal activity, wide fungitoxic spectrum and nonphytotoxicity.

R. D. Tripathi; H. S. Srivastava; S. N. Dixit



Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata.  

PubMed Central

Microbial transformation of lapachol, a naturally occurring naphthoquinone, was carried out by Curvularia lunata (NRRL 2178). The fungus brings about oxidative cyclization of the substrate to dehydro-alpha-lapachone, which was isolated and characterized by nuclear magnetic resonance and mass spectral analyses; its structure was verified by chemical synthesis. The metabolite is a naturally occurring chromene possessing antibacterial and antitumor activities.

Otten, S; Rosazza, J P



Phosphonium lipocations as antiparasitic agents  

PubMed Central

Phosphonium lipocations were synthesized and evaluated for inhibition of the development of Plasmodium falciparum and Trypanosoma cruzi, etiological agents of malaria and Chagas disease, respectively. Optimal phthalimides and 1,4-naphthoquinone-based lipocations were active in vitro at mid-high nM concentrations against P. falciparum and low ?M concentrations against T. cruzi.

Long, Timothy E.; Lu, Xiao; Galizzi, Melina; Docampo, Roberto; Gut, Jiri; Rosenthal, Philip J.



Comparison of the cytotoxic activities of naturally occurring hydroxyanthraquinones and hydroxynaphthoquinones  

Microsoft Academic Search

Seven hydroxyanthraquinone derivatives, 1–7, were isolated from the root of Rheum palmatum (Polygonaceae). Two propionated anthraquinone derivatives, 8 and 9, were synthesized. Four hydroxynaphthoquinone derivatives, 13, 14, 16 and 21, were isolated from the root of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae) and also three naphthoquinone derivatives, 19, 22 and 23, were isolated from the root of Macrotomia euchroma (Royle)

Xing-Ri Cui; Maiko Tsukada; Nao Suzuki; Takeshi Shimamura; Li Gao; Jyunichi Koyanagi; Fusao Komada; Setsuo Saito




PubMed Central

In the title compound, C17H12ClNO2, the naphtho­quinone system is essentially planar [maximum deviation = 0.078?(2)?Å] and makes a dihedral angle of 52.38?(7)° with the benzene ring. The crystal structure features N—H?O inter­actions.

Gao, Li-Jiu; Liu, Yun



Characterization of the quinone reductase activity of the ferric reductase B protein from Paracoccus denitrificans.  


The ferric reductase B (FerB) protein of Paracoccus denitrificans exhibits activity of an NAD(P)H: Fe(III) chelate, chromate and quinone oxidoreductase. Sequence analysis places FerB in a family of soluble flavin-containing quinone reductases. The enzyme reduces a range of quinone substrates, including derivatives of 1,4-benzoquinone and 1,2- and 1,4-naphthoquinone, via a ping-pong kinetic mechanism. Dicoumarol and Cibacron Blue 3GA are competitive inhibitors of NADH oxidation. In the case of benzoquinones, FerB apparently acts through a two-electron transfer process, whereas in the case of naphthoquinones, one-electron reduction takes place resulting in the formation of semiquinone radicals. A ferB mutant strain exhibited an increased resistance to 1,4-naphthoquinone, attributable to the absence of the FerB-mediated redox cycling. The ferB promoter displayed a high basal activity throughout the growth of P. denitrificans, which could not be further enhanced by addition of different types of naphthoquinones. This indicates that the ferB gene is expressed constitutively. PMID:19138657

Sedlácek, Vojtech; van Spanning, Rob J M; Kucera, Igor



Synthetic lapachol derivatives relax guinea-pig ileum by blockade of the voltage-gated calcium channels.  


The present study was designed to further evaluate a possible spasmolytic activity of synthetic lapachol derivatives, norlapachol, alpha-norlapachone, beta-norlapachone and hydro-hydroxy-norlapachol (HH-norlapachol), on guinea-pig ileum. In guinea-pig ileum, except for norlapachol, all naphthoquinones inhibited the phasic contractions induced by carbachol or histamine. Even when the ileum was pre-contracted with KCl, carbachol or histamine, all naphthoquinones induced relaxation, suggesting that these naphthoquinones could be acting on the voltage-gated calcium channels (Ca(V)). As the tonic component this contraction is maintained mainly by the opening of the Ca(V), we hypothesized that these naphthoquinones might be acting on these channels. This hypothesis was confirmed by the observation that norlapachol (pD'2 = 4.99), alpha-norlapachone (pD'2 = 4.49), beta-norlapachone (pD'2 = 6.33), and HH-norlapachol (pD'2 = 4.53) antagonized the contractions induced by CaCl2 in depolarizing medium nominally without Ca2+. As beta-norlapachone was the most potent we decided to continue the study of its action mechanism. The fact that this naphthoquinone has inhibited the tonic contractions induced by S-(-)-Bay K8644 [EC50 = (1.6 +/- 0.30) x 10(-5) M] suggests that the Ca2+ channel involved belongs to the type L (Ca(V)1.2). In addition, in the functional level, the spasmolytic effect of beta-norlapachone does not involve participation of free radicals, since its curve of relaxation was unchanged in the presence of glutathione, an antioxidant agent. PMID:21138067

Cavalcante, Fabiana de A; Monteiro, Fabio de S; Martins, Italo Rossi R; Barbosa, Ticiano P; Camara, Celso de A; Pinto, Angelo C; Vargas, Maria D; da Silva, Bagnólia A


Monoarylhydrazones of alpha-lapachone: synthesis, chemical properties and antineoplastic activity.  


The biological activities of the naphthoquinones lapachol, extracted from trees of the genus Tabebuia and its cyclization products alpha and beta-lapachone, have been intensively studied. Giving continuity to the research about new derivatives obtained from the reaction of these naphthoquinones with amino-containing reagents, a series of arylhydrazones of alpha-lapachone was synthesized and their antineoplastic activity was evaluated. This new structure is based on the great electrophilicity of 1,4-quinoidal carbonyl groups towards reagents containing nitrogen as nucleophilic centers, such as arylhydrazines. The products were assayed by the National Cancer Institute (NCI, USA) and their binding to DNA, redox properties and QSAR studies were also determined. PMID:14609278

Renou, S G; Asís, S E; Abasolo, M I; Bekerman, D G; Bruno, A M



Toxicological assessment of beta-lapachone on organs from pregnant and non-pregnant rats.  


Naphthoquinones have been studied extensively due to their activity as topoisomerase inhibitors. These enzymes are critical to DNA replication in cells. beta-Lapachone (beta-lap) is an o-naphthoquinone chemically obtained from lapachol. This work results in a toxicological evaluation of beta-lap in Wistar rats observing the following parameters: teratology, histology, hematology and serum biochemistry. The data demonstrate teratogenic action at the doses used, as well as hematological alterations in the total leukocytes, monocytes and segmented. The biochemical data demonstrated an increase in gamma glutamyl transferase, alkaline phosphatase and glutamate pyruvate transaminase levels. Histological study showed significant alterations in the spleen, however, the liver and kidney did not present significant alterations. PMID:19197915

de Almeida, Edvaldo Rodrigues; Lucena, Flávia Raquel Santos; Silva, Camilla Vila Nova Soares; da Silva Costa-Junior, Wilson; Cavalcanti, Jouse Bezerra; Couto, Gerald Bosco Lindoso; da Silva, Luiz Lúcio Soares; da Mota, Diógenes Luís; da Silveira, Alex Benício; de Sousa Filho, Samuel Daniel; da Silva, Aldo Cezar Passilongo



Mixed complexes of uranyl with oximes  

SciTech Connect

According to the authors, a distinguishing feature of hydroxylamine and its N-derivatives as ligands in the coordination chemistry of uranyl is their bidentate-cyclic coordination through the nitrogen and oxygen atoms, with the formation of a strong three-membered metallocycle. On the example of 1.2-naphthoquinone-2-oximate- and 1,2-naphthoquinone-1oximato-ligands, bidentate-cyclic coordination of the deprotonated oxime group of the ligands by uranyl with the formation of a threemembered ''hydroxylaminate'' ring was confirmed. The results of experiments presented here confirm the authors' concept of the relationship of the coordination-chemical behavior of hydroxylamines and oximes toward the uranyl ions.

Shelokov, R.N.; Ashurov, Z.R.; Beirakhov, A.G.; Mikhailov, Yu.N.; Orlova, I.M.



Extraction of Bioactive Compounds From Leaves of lawsonia Inermis by Green Pressurized Fluids  

Microsoft Academic Search

Supercritical carbon dioxide and microwave-assisted hydrothermal methods were investigated for extraction of bioactive components of leaves of Lawsonia inermis (henna), a world renowned source of natural hair dye component called lawsone (2-hydroxy-1,4-naphthoquinone). Results showed that the use of supercritical carbon dioxide was selective to extraction of non-polar compounds such as essential oils, and recovery of lawsone was low. However, using

Tayyebeh Haleh Zohourian; Armando T. Quitain; Mitsuru Sasaki; Motonobu Goto



Quinone reduction by Rhodothermus marinus succinate:menaquinone oxidoreductase is not stimulated by the membrane potential  

Microsoft Academic Search

Succinate:quinone oxidoreductase (SQR), a di-haem enzyme purified from Rhodothermus marinus, reveals an HQNO-sensitive succinate:quinone oxidoreductase activity with several menaquinone analogues as electron acceptors that decreases with lowering the redox midpoint potential of the quinones. A turnover with the low-potential 2,3-dimethyl-1,4-naphthoquinone that is the closest analogue of menaquinone, although low, can be detected in liposome-reconstituted SQR. Reduction of the quinone is

Andreia S. Fernandes; Alexander A. Konstantinov; Miguel Teixeira; Manuela M.. Pereira



A new rapid multicomponent domino heteroannulation of heterocyclic ketene aminals: solvent-free regioselective synthesis of functionalized benzo[g]imidazo[1,2-a]quinolinediones.  


A highly efficient and straightforward three-component cascade reaction was developed to synthesize benzo[g]imidazo[1,2-a]quinolinedione derivatives from heterocyclic ketene aminals (HKAs), aldehydes, and 2-hydroxy-1,4-naphthoquinone (HNQ) via Et(3)N-catalyzed tandem [3 + 2 + 1] annulation under solvent-free conditions. The reactions were very mild, convenient and highly regioselective to form new fused tetracyclic target molecules. PMID:23224037

Wen, Li-Rong; Sun, Qi-Chang; Zhang, Hai-Liang; Li, Ming



Synthesis and solid state absorption spectra of some aminonaphthoquinone dyes  

Microsoft Academic Search

The 2,6- and 4,8-bisarylamino-1,5-naphthoquinone derivatives 3b-d and 6a-e were synthesized by the amination of naphthazarin (1) and naphthazarin intermediate (4), respectively. Their chromophoric systems were evaluated by the PPP MO method, and their absorption spectra in solution and the solid state were investigated to evaluate the intermolecular ?-? interactions of the dye molecules in the solid state. In the case

Jae Hong Kim; Masaru Matsuoka; Koushi Fukunishi



Antitumor and anticarcinogenic actions of Cpd 5: a new class of protein phosphatase inhibitor  

Microsoft Academic Search

Dual specificity phosphatases (DSP) play an important role in control of the cell cycle and signal transduction. We have synthesized a new class of DSP inhibitors. Cpd 5 or (2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone) is one of the most potent of these. It inhibits DSPs of cells in culture and induces tyrosine phosphorylation of various DSP substrates, including the Cdc25 target Cdks and it

Siddhartha Kar; Meifang Wang; Craig S. Wilcox; Brian I. Carr


New polyaromatic metabolites from a marine-derived fungus Penicillium sp.  


Herqueiazole (1), herqueioxazole (2), and herqueidiketal (3), polyaromatic metabolites with a novel skeletal class, were isolated from the marine-derived fungus Penicillium sp. Based on the combined spectroscopic analyses, the structures of 1 and 2 were determined to be the first examples of pyrrole- and oxazole-containing phenalenone compounds, respectively, whereas 3 possessed a novel skeleton with a highly oxidized naphthoquinone moiety. Compound 3 exhibited moderate cytotoxicity and significant inhibitory activity against sortase A. PMID:23431962

Julianti, Elin; Lee, Jung-Ho; Liao, Lijuan; Park, Wanki; Park, Sunghyouk; Oh, Dong-Chan; Oh, Ki-Bong; Shin, Jongheon



Determination of gabapentin in human plasma and urine by high-performance liquid chromatography with UV–vis detection  

Microsoft Academic Search

A simple and reliable high-performance liquid chromatographic (HPLC) method with UV–vis detection has been developed and validated for the determination of gabapentin (GBP) in human plasma and urine. The clean up of the sample was carried out by solid-phase extraction with C18-cartridge. After the clean up procedure, the samples were pre-column derivatizated with 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS). A chromatographic

Olcay Sagirli; Sevil Müge Çetin; Arma?an Önal



Larvicidal activity of Cybistax antisyphilitica against Aedes aegypti larvae.  


The larvicidal activity against Aedes aegypti larvae of a stem wood hexane extract of Cybistax antisyphilitica was evaluated. Bioassay-guided fractionation of the crude extract, monitored by larvicidal assay, led to the isolation of a natural quinone identified as 2-hydroxy-3-(3-methyl-2-butenyl)-1.4-naphthoquinone (lapachol). This compound was quite potent against A. aegypti larvae (LC50 26.3 microg/ml). PMID:16229968

Rodrigues, A M S; de Paula, J E; Roblot, F; Fournet, A; Espíndola, L S



Molluscicidal activity of synthetic lapachol amino and hydrogenated derivatives.  


A series of new amino derivatives and a new partially hydrogenated derivative of the natural naphthoquinone lapachol were assayed for molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, and a 3.1 microg/mL value for the most potent derivative of the series. The toxicity is in agreement with the decrease of polar character of the tested compounds. PMID:15582464

Silva, Tania M S; Camara, Celso A; Barbosa, Ticiano P; Soares, André Z; da Cunha, Luciana C; Pinto, Angelo C; Vargas, Maria D



Synthesis and pharmacological activity of diterpenylnaphthoquinone derivatives.  


New diterpenylquinones, combining a diterpene diacid and a naphthoquinone, were prepared from junicedric acid and lapachol. The new derivatives were assessed as gastroprotective agents by the HCl-EtOH-induced gastric lesions model in mice as well as for basal cytotoxicity on the following human cell lines: Normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). Several of the new compounds were significantly active as antiulcer agents and showed selective cytotoxicity against AGS cells. PMID:21996716

Pertino, Mariano Walter; Theoduloz, Cristina; Palenzuela, Jose Antonio; Afonso, Maria del Mar; Yesilada, Erdem; Monsalve, Francisco; González, Paulo; Droguett, Daniel; Schmeda-Hirschmann, Guillermo



A Colour Reaction of Vitamin E with Vitamin K and Cysteine  

Microsoft Academic Search

A FEW crystals of vitamin K (2-hydroxy-3-methyl-1,4-naphthoquinone) and of cysteine (chorhydrate) are added to a solution containing 7-20 µgm.\\/ml. of vitamin E (sodium phosphate of alpha-tocopherol). The solution is heated up to boiling point. About one minute after boiling the solution takes a blue tint. The intensity of colour is proportional to the content of vitamin E and increases during

Eduardo Cruz-Coke



Naphtho[1,2- b]furan-4,5-dione inactivates EGFR and PI3K\\/Akt signaling pathways in human lung adenocarcinoma A549 cells  

Microsoft Academic Search

AimsNaphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti-carcinogenic effect. This study was performed to elucidate whether EGFR and PI3K signaling pathways are involved in NFD-induced apoptosis of human lung adenocarcinoma A549 cells.

Jung-Chen Su; Kuei-Li Lin; Ching-Ming Chien; Chih-Hua Tseng; Yeh-Long Chen; Long-Sen Chang; Shinne-Ren Lin



Role of sugar in controlling reaction pathways: A study with thymine and thymidine  

Microsoft Academic Search

Magnetic field effect in conjunction with laser flash photolysis have been used for studying interactions of 9,10-anthraquinone and 2-methyl 1,4-naphthoquinone (menadione) with a DNA base, thymine (Thy) and its nucleoside, thymidine (dThd). Irrespective of medium Thy has been found to support both electron transfer (ET) and hydrogen abstraction with the quinones while dThd has exhibited a complete reluctance towards ET.

Adity Bose; Achintya K. Sarkar; Samita Basu



Administration of rosemary essential oil enhances resistance of rat hepatocytes against DNA-damaging oxidative agents  

Microsoft Academic Search

The aim of this paper was to evaluate the potential DNA-protective effects of rosemary essential oil-supplementation on rat hepatocytes damaged with three different genotoxins attacking DNA by oxidative stress. Hydrogen peroxide (H2O2) reacts by the generation of hydroxyl radicals, visible light-excited methylene blue forms oxidative DNA lesions via singlet oxygen and 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induces oxidative stress by participation in redox

Eva Horváthová; Darina Slame?ová; Jana Navarová



Linear free energy relationships for polyhalogenated alkane transformation by electron-transfer mediators in model aqueous systems  

Microsoft Academic Search

Linear free energy relationships (LFERs) based on Marcus theory were generated for transformation of Câ- and Câ-polyhalogenated alkanes (PHAs or R-X, where X = H, F, Cl, Br) in model aqueous systems containing bulk reductants and the electron-transfer mediators iron porphyrin or mercaptojuglone (5-hydroxy-2-mercapto-1,4-naphthoquinone). The model systems are representative of common natural environments where iron species and natural organic matter

Judith A. Perlinger; Raghuraman Venkatapathy; James F. Harrison



03219A, a new ?(8,9)-pregnene isolated from Streptomyces sp. SCSIO 03219 obtained from a South China Sea sediment.  


03219A (1), a new pregnene steroid possessing a rare ?(8,9)-double bond in the skeleton, together with the known naphthoquinone antibiotic (+)-cryptosporin (2) have been isolated from the fermentation broth of Streptomyces sp. SCSIO 03219, which was isolated from a marine sediment collected in the South China Sea. The structure of 03219A was elucidated using a combination of NMR, MS and X-ray crystallographic methods. PMID:23549354

Zhang, Yun; Zhou, Xiao; Huang, Hongbo; Tian, Xinpeng; Song, Yongxiang; Zhang, Si; Ju, Jianhua



Genetic engineering of shikonin biosynthesis hairy root cultures of Lithospermum erythrorhizon transformed with the bacterial ubiC gene  

Microsoft Academic Search

The biosynthetic pathway to 4-hydroxybenzoate (4HB), a precursor of the naphthoquinone pigment shikonin, was modified in Lithospermum erythrorhizon hairy root cultures by introduction of the bacterial gene ubiC. This gene of Escherichia coli encodes chorismate pyruvate-lyase (CPL), an enzyme that converts chorismate into 4HB and is not normally present in plants. The ubiC gene was fused to the sequence for

Susanne Sommer; Annegret Köhle; Kazufumi Yazaki; Koichiro Shimomura; Andreas Bechthold; Lutz Heide



The specific functions of menaquinone and demethylmenaquinone in anaerobic respiration with fumarate, dimethylsulfoxide, trimethylamine N-oxide and nitrate by Escherichia coli  

Microsoft Academic Search

The respiratory activities of E. coli with H2 as donor and with nitrate, fumarate, dimethylsulfoxide (DMSO) or trimethylamine N-oxide (TMAO) as acceptor were measured using the membrane fraction of quinone deficient strains. The specific activities of the membrane fraction lacking naphthoquinones with fumarate, DMSO or TMAO amounted to ?2% of those measured with the membrane fraction of the wild-type strain.

U. Wissenbach; A. Kröger; G. Unden



The metal carbonyl promoted rearrangement of aryl-cyclopropenes. II. Approaches towards a model system of dynemicin A  

SciTech Connect

The ability of 3-vinyl- or 3-phenylcyclopropenes to undergo metal carbonyl promoted rearrangement with CO insertion to yield phenol or naphthol derivatives led to investigations using 3-naphthylcyclopropenes with the goal of producing material containing an anthracene carbon framework. Rearrangement of 1-methyl-3-(1,4-dimethoxynaphth-2-yl)cyclopropene, however, only gave material containing the phenanthrene framework. It is the goal of Part I of this thesis to modify a naphthylcyclopropene so that the metal carbonyl induced rearrangement will yield material containing an anthracene framework. A working hypothesis was put forth that focused on the electronic stabilization of certain aromatic intermediates to explain phenanthrene vs. anthracene formation. Semi-empirical calculations performed on model systems to estimate thermodynamic properties supported the hypothesis. Two naphthoquinone derivatives were prepared based on the hypothesis. In the first case, the cyclopropene substituent is arranged in the 2-position of a naphthoquinone-1,4-bisketal; in the second case, the cyclpropene is at C-2 in a 1,4-naphthoquinone. In both cases, the alkene unit (C-2/C-4) is less aromatic' than an alkene unit in a naphthalene ring, and the expected rearrangement can give only the anthraquinone skeleton. Investigations with the bisketal were unsucessful; attempted rearrangement at low temperatures gave only recovered starting material and experiments at higher temperatures polymerized the sensitive cyclopropene. Investigations with the 1,4-naphthoquinone proved modestly successful. Metal carbonyl catalyzed rearrangement with CO insertion to yield anthraquinone was observed. Additionally, low temperature conditions were developed that may prove useful in future work.

Cohen, D.H.



Antidermatophyte and antimelanogenesis compound from Eleutherine americana grown in Indonesia  

Microsoft Academic Search

An active compound from the bulb of Eleutherine americana L. Merr. (Iridaceae) collected from East Kalimantan, Indonesia, was tested for its antidermatophyte and antimelanogenesis\\u000a activity. Antifungal assay-directed fractionation of the n-hexane-soluble fraction of the methanolic extract of the bulb of E. americana led to the isolation of 1 as an active compound. The compound was identified as the naphthoquinone eleutherin

Irawan Wijaya Kusuma; Enos Tangke Arung; Enih Rosamah; Sri Purwatiningsih; Harlinda Kuspradini; Syafrizal; Juli Astuti; Yong-Ung Kim; Kuniyoshi Shimizu



Characterization of the redox components of transplasma membrane electron transport system from Leishmania donovani promastigotes  

Microsoft Academic Search

An investigation has been made of the points of coupling of four nonpermeable electron acceptors e.g., ?-lipoic acid (ALA), 5,5?-dithiobis (2-nitroaniline-N-sulphonic acid) (DTNS), 1,2-naphthoquinone-4-sulphonic acid (NQSA) and ferricyanide which are mainly reduced via an interaction with the redox sites present in the plasma membrane of Leishmania donovani promastigotes. ALA, DTNS, NQSA and ferricyanide reduction and part of O2 reduction is

Tanmoy Bera; Kuruba Lakshman; Debiprasad Ghanteswari; Sabita Pal; Dharmalingam Sudhahar; Nihar Ranjan Bhuyan; Pradeep Das



Regioselective synthesis of 6-aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-7,8-diones as potent antitumoral agents.  


Three-component coupling of aldehyde, 2-hydroxy-1,4-naphthoquinone and 3-amino-1,2,4-triazole has been achieved using a catalytic amount of sulfamic acid under solvent free conditions to produce a novel series of 6-aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-7,8-dione derivatives in good yields and with high regioselectivity. These compounds are found to exhibit potent antitumoral properties. PMID:23871222

Wu, Liqiang; Zhang, Chong; Li, Weilin



Mechanisms for naphthalene removal during electrolytic aeration  

Microsoft Academic Search

Batch tests were performed to investigate chemical and physical processes that may result during electrolytic aeration of a contaminated aquifer using naphthalene as a model contaminant. Naphthalene degradation of 58–66% took place electrolytically and occurred at the same rates at a pH of 4 and 7. 1,4-naphthoquinone was identified as a product of the electrolysis. Stripping due to gases produced

Ramesh K. Goel; Joseph R. V. Flora; John Ferry



Anodic oxidation of 2-naphthol at boron-doped diamond electrodes  

Microsoft Academic Search

The anodic oxidation of 2-naphthol in acid media was investigated at a synthetic boron-doped diamond thin film electrode (BDD) using cyclic voltammetry and bulk electrolysis. The results have shown that in the potential region, where the supporting electrolyte is stable, reactions involving simple electron transfer, such as oxidation of 2-naphthol to naphthoxy radical and 1,4-naphthoquinone occur. Polymeric materials, which lead

M. Panizza; P. A. Michaud; G. Cerisola; Ch. Comninellis



Effects of butylated hydroxyanisole and dicoumarol on the toxicity of menadione to rats  

Microsoft Academic Search

The enzyme DT-diaphorase catalyses the 2-electron reduction of quinones. This reaction may facilitate the detoxification of such compounds, since the hydroquinone so formed can be converted into non-toxic conjugates. There is evidence for the involvement of DT-diaphorase in the detoxification of menadione (2-methyl-1,4-naphthoquinone) in a wide range of cells and tissues in vitro, but no information is available on the

Rex Munday; Barry L Smith; Christine M Munday



The role of ancillary ligands and of electron poor alkenes and alkynes in stabilizing Pd(0) derivatives: A comparative study  

Microsoft Academic Search

The peculiar characteristics of the ligand neocuproine (2,9-dimethylphenanthroline) allow a number of exchange equilibrium studies between the low valence complex [Pd(?2-nq)(Neocup)] (nq=naphthoquinone; Neocup=neocuproine) and several alkenes and alkynes. A new order of stability which compares differently unsaturated molecules was established. An overview of the factors governing the stability of palladium(0) alkene and alkyne derivatives as a function of the steric

Luciano Canovese; Fabiano Visentin; Claudio Santo; Alessandro Dolmella



Bioactive Constituents of Brazilian Red Propolis  

PubMed Central

In a new propolis type, red Brazilian propolis, 14 compounds were identified (six of them new for propolis), among them simple phenolics, triterepenoids, isoflavonoids, prenylated benzophenones and a naphthoquinone epoxide (isolated for the first time from a natural source). Three of the major components demonstrated significant antimicrobial activity, and two (obtained as inseparable mixture) possessed radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH).

Trusheva, Boryana; Popova, Milena; Bankova, Vassya; Simova, Svetlana; Marcucci, Maria Cristina; Miorin, Patricia Laguna; da Rocha Pasin, Flavia; Tsvetkova, Iva



Lysosomal release of Cathepsin D precedes relocation of Cytochrome C and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress  

Microsoft Academic Search

Apoptosis was induced in human foreskin fibroblasts by the redox-cycling quinone naphthazarin (5,8-dihydroxy-1,4-naphthoquinone). Most of the cells displayed ultrastructure typical of apoptosis after 8 h of exposure to naphthazarin. Apoptosis was inhibited in fibroblasts pretreated with the cathepsin D inhibitor pepstatin A. Immunofluorescence analysis of the intracellular distribution of cathepsin D revealed a distinct granular pattern in control cells, whereas

Karin Roberg; Uno Johansson; Karin Öllinger



Bodipy derivatives as organic triplet photosensitizers for aerobic photoorganocatalytic oxidative coupling of amines and photooxidation of dihydroxylnaphthalenes.  


We used iodo-Bodipy derivatives that show strong absorption of visible light and long-lived triplet excited states as organic catalysts for photoredox catalytic organic reactions. Conventionally most of the photocatalysts are based on the off-the-shelf compounds, usually showing weak absorption in the visible region and short triplet excited state lifetimes. Herein, the organic catalysts are used for two photocatalyzed reactions mediated by singlet oxygen ((1)O2), that is, the aerobic oxidative coupling of amines and the photooxidation of dihydroxylnaphthalenes, which is coupled to the subsequent addition of amines to the naphthoquinones, via C-H functionalization of 1,4-naphthoquinone, to produce N-aryl-2-amino-1,4-naphthoquinones (one-pot reaction), which are anticancer and antibiotic reagents. The photoreactions were substantially accelerated with these new iodo-Bodipy organic photocatalysts compared to that catalyzed with the conventional Ru(II)/Ir(III) complexes, which show weak absorption in the visible region and short-lived triplet excited states. Our results will inspire the design and application of new organic triplet photosensitizers that show strong absorption of visible light and long-lived triplet excited state and the application of these catalysts in photoredox catalytic organic reactions. PMID:23668289

Huang, Ling; Zhao, Jianzhang; Guo, Song; Zhang, Caishun; Ma, Jie



Direct photooxidation and xanthene-sensitized oxidation of naphthols: quantum yields and mechanism.  


The photoinduced oxidation of 1-naphthol to 1,4-naphthoquinone and of 5-hydroxy-1-naphthol to 5-hydroxy-1,4-naphthoquinone was studied by steady-state and time-resolved techniques. The direct photooxidation of naphthols in methanol or water takes place by reaction of the naphoxyl radical ((•)ONaph) with the superoxide ion radical (O(2)(•-)), the latter of which results from the reaction of the solvated electron with oxygen after photoionization. The sensitized oxidation takes place by energy transfer from the xanthene triplet state to oxygen. From the two oxygen atoms, which are consumed, one is incorporated into the naphthol molecule giving naphthoquinone and the second gives rise to water. The effects of eosin, erythrosin, and rose bengal in aqueous solution, pH, and the oxygen and naphthol concentrations were studied. The quantum yield of the photosensitized transformation was determined, which increases with the naphthol concentration and is largest at pH > 10. The quantum yield of oxygen uptake is similar. The pathway involving singlet molecular oxygen is suggested to operate for the three sensitizers. The alternative pathway via electron transfer from the naphthol to the xanthene triplet state and subsequent reaction of (•)ONaph with O(2)(•-), the latter of which is formed by scavenging of the xanthene radical anion by oxygen, does also contribute. PMID:21162586

Oelgemöller, Michael; Mattay, Jochen; Görner, Helmut



Cytotoxic and antimicrobial constituents of the bark of Diospyros maritima collected in two geographical locations in Indonesia.  


Bioactivity-directed fractionation of extracts of two Diospyros maritima bark samples from Indonesia,one collected at sea level in a beach forest in Java and the other collected at a slight elevation away from the sea shore on the island of Lombok, yielded a diverse set of secondary metabolites. The naphthoquinone plumbagin (1), although found in extracts of both specimens, constituted a much larger percentage of the former sample, which also yielded a series of plumbagin dimers, maritinone (2), chitranone (3), and zeylanone (4). The latter sample yielded a new naphthoquinone derivative, (4S)-shinanolone (5), and a new natural product coumarin, 7,8-dimethoxy-6-hydroxycoumarin (6), along with three other analogues of plumbagin, 2-methoxy-7-methyljuglone (7), 3-methoxy-7-methyljuglone (8), and 7-methyljuglone (9). The structures of compounds 5 and 6 were elaborated by physical, spectral, and chemical methods. All of the isolates were evaluated in both cytotoxicity and antimicrobial assays, and structure-activity relationships of these naphthoquinones are proposed. Plumbagin (1) and maritinone (2) were evaluated also for in vivo antitumor activity in the hollow fiber assay, but both were found to be inactive. PMID:15270571

Gu, Jian-Qiao; Graf, Tyler N; Lee, Dongho; Chai, Hee-Byung; Mi, Qiuwen; Kardono, Leonardus B S; Setyowati, Fransisca M; Ismail, Rachman; Riswan, Soedarsono; Farnsworth, Norman R; Cordell, Geoffrey A; Pezzuto, John M; Swanson, Steven M; Kroll, David J; Falkinham, Joseph O; Wall, Monroe E; Wani, Mansukh C; Kinghorn, A Douglas; Oberlies, Nicholas H



Determination of glucosamine and carisoprodol in pharmaceutical formulations by LC with pre-column derivatization and UV detection.  


A simple and reliable precolumn derivatization liquid chromatography method with ultraviolet detection has been developed and validated for the analysis of glucosamine (GS) in various dietary supplement formulations and raw materials. Additionally, the proposed method was used for analysis of carisoprodol (CR) found in ternary mixture with paracetamol (PR) and caffeine (CF). The linearity ranges were 1-100 ?g/mL for GS, 1-150 ?g/mL for CR, PR and CF. Derivatization was used with 1,2-naphthoquinone-4-sulphonic acid sodium salt in the presence of borate buffer. Chromatographic separation of GS-naphthoquinone derivative was achieved by using a mixture of acetonitrile and water (pH 7.3 adjusted with 0.1 M NaOH) in the ratio 10:90, v/v and flow-rate of 1.0 mL/min. UV detection was carried out at 280 nm. For PR, CF, and CR-naphthoquinone derivative, the chromatographic separation was achieved by using mixture of acetonitrile and 20 mM KH(2)PO(4) (pH 3.0 adjusted with phosphoric acid) in the ratio 20:80, v/v and flow-rate of 1.0 mL/min. UV detection was carried out at 275 nm. The limits of detection were 37.2, 35.9, 30.4 and 40.0 ng/mL for GS, CR, PR and CF, respectively. PMID:22362883

Hadad, Ghada M; Abdel-Salam, Randa A; Emara, Samy



Novel rearranged abietane diterpenoids from the roots of Salvia sahendica.  


Two naphthoquinone diterpenoids, 1 and 2, one tricyclic, and one tetracyclic rearranged abietane ('4,5-seco-10,5-friedo-abietane') diterpenoids, 3 and 4, respectively, together with horminone (5) have been isolated from the roots of Salvia sahendica. Compounds 2 and 3 are new, and the 13C-NMR assignment for compound 4 was modified using ' Heteronuclear Multiple-Bond Correlation' (HMBC) spectroscopic data. The structures of the compounds have been established by using different spectral data including 1D- and 2D-NMR, IR, UV, and MS. The elemental composition for the major peaks of 3 and 4 were determined by ' High-Resolution Electron Impact Mass Spectrometry' (HR-EI-MS). The relative configurations of the new compounds were determined by 1H-NMR and 'Rotating-Frame NOES' (ROESY) spectroscopy. Compounds 1, 2, and 5 showed antifungal activities when tested on Blakeslea trispora. Lapachol, a prelynated naphthoquinone, was used as a positive control. The biological activities of the related naphthoquinones and abietane diterpenoids were discussed. PMID:17193322

Jassbi, Amir Reza; Mehrdad, Morteza; Eghtesadi, Farrokh; Ebrahimi, Samad Nejad; Baldwin, Ian T



Preliminary evaluation of the human relevance of respiratory tumors observed in rodents exposed to naphthalene.  


Inhalation bioassays in mice and rats exposed to naphthalene (NA) show incidences of lung and nasal cancer, respectively. This paper describes a preliminary mode of action (MOA)/human relevance (HR) framework for NA. Species differences in both carcinogenic and cytotoxic responses between the rodent and human have been noted based on qualitative and quantitative differences in metabolism. Some occur at the initial oxidation of NA in the rat through CYP2F, versus CYP2A13 metabolism in the human respiratory system and which results in a difference in the specific naphthoquinone formed. Normally, subsequent reactive metabolites are then conjugated through glutathione, but high dose exposures, as in the rat bioassay, result in glutathione depletion, and the availability of 1,2-naphthoquinone for other conjugation. In the rat nose, it is proposed that a naphthoquinone imine is formed via a species and site-specific aryl amidase acting on an amino acid conjugate of the quinone. Such a quinone imine is believed to be the active agent in Alachlor and phenacetin, resulting in the same profile of respiratory tumors in the rat as NA. Based on the MOA and the limited epidemiological data indicating no human evidence of nasal or lung tumor risk, the carcinogenic response observed in rats does not appear relevant to the human. PMID:22342949

Piccirillo, Vincent J; Bird, Michael G; Lewis, R Jeffrey; Bover, W James



Effects of ethanol on the hematotoxicity of twelve pharmaceutical and environmental agents  

SciTech Connect

The ability of ethanol (5%) to potentiate the oxidant stressor effects of twelve well-know hematoxic agents was investigated in vitro using human erythrocytes. Human whole blood was incubated with one of the following agents with and without ethanol for one hour at 37/sup 0/C: o-aminophenol (0.5 mM); p-benzoquinone (4.0 mM); butyl nitrite (1.0 mM); p-hydroxyacetophenone (3.0 mM); hydroxylamine (0.5 mM); O,N-dimethylhydroxylamine (7.0 mM); 1,2-naphthoquinone (0.4 mM); 1,4-naphthoquinone (0.5 mM); p-phenylenediamine (5.0 mM); phenylhydrazine (1.0 mM); potassium nitrite (1.0 mM) and primaquine (8.0 mM). Methemoglobin (METHB) and reduced glutathione (GSH) levels were subsequently measured. Synergistic increases in METHB levels occurred for primaquine, 1,2-naphthoquinone and p-phenylenediamine incubated with ethanol.

Calabrese, E.J.; Tilli, F.; Horton, H.M.; Stoddard, A.



Use of quinones in brain-tumor therapy: preliminary results of preclinical laboratory investigations  

SciTech Connect

Failure of current chemotherapeutic agents of effectively treat human brain tumors has prompted the search for alternative regimens based on the inherent metabolic pathways of target cells. One way to accomplish this goal would be to design drugs in an inactive form, which upon entry into the cell would be transformed to a toxic metabolite by a naturally occurring pathway. One such pathway may be the reductive activation of naphthoquinones with one or two side chains capable of alkylation, such as 2,3-dibromomethyl-1,4-naphthoquinone (DBNQ). This reductive activation can be catalyzed by the flavoprotein DT-diaphorase (NAD(P)H:quinone oxidoreductase). The authors have found that both rat 9L and some human brain-tumor cell lines contain very high levels of this enzyme and that halogenated dimethyl naphthoquinones, such as DBNQ, are highly toxic to these cells in vitro. Moreover, they have found that the cytotoxic effects of DBNQ on human tumor and murine bone marrow stem cells can be prevented or lessened by pretreatment of the cells with dicoumarol, a potent inhibitor of DT-diaphorase. Since dicoumarol does not cross the blood-brain barrier, the potential exists for human brain tumors to be destroyed with halogenated dimethylquinones and for peripheral host toxicity to be prevented by coadministration of dicoumarol.

Berger, M.S.; Talcott, R.E.; Rosenblum, M.L.; Silva, M.; AliOsman, F.; Smith, M.T.



Development and validation of the first assay method coupling liquid chromatography with chemiluminescence for the simultaneous determination of menadione and its thioether conjugates in rat plasma.  


Menadione (2-methyl-1,4-naphthoquinone, MQ), a component of multivitamin drugs with antihemorrhagic, antineoplastic, and antimalarial activity, is frequently used to investigate quinone-induced cytotoxicity. The formation of MQ conjugates with glutathione (GSH) by Michael addition and subsequent biotransformation to yield N-acetyl-l-cysteine conjugates is believed to be an important detoxification process. However, the resulting conjugates, 2-methyl-3-(glutathione-S-yl)-1,4-naphthoquinone (MQ-GS) and 2-methyl-3-(N-acetyl-l-cysteine-S-yl)-1,4-naphthoquinone (MQ-NAC), retain the ability to redox cycle and to arylate cellular nucleophiles. Although the nephrotoxicity and hepatotoxicity of MQ-thiol conjugates have been reported in vitro, methods for their determination in vivo have yet to be published. Herein, a highly sensitive, simple, and selective HPLC-chemiluminescence (HPLC-CL) coupled method is reported, allowing for the first time the simultaneous determination of MQ, MQ-GS, and MQ-NAC in rat plasma after MQ administration. Our method exploits the unique redox characteristics of MQ, MQ-GS, and MQ-NAC to react with dithiothreitol (DTT) to liberate reactive oxygen species (ROS) which are detected by a CL assay using luminol as a CL probe. To verify the proposed mechanism, MQ-GS and MQ-NAC were synthetically prepared. Specimen preparation involved solid-phase extraction on an Oasis HLB cartridge followed by isocratic elution on an ODS column. No interference from endogenous substances was detected. Linearity was observed in the range of 5-120 nM for MQ-GS and MQ-NAC and 10-240 nM for MQ, with detection limits (S/N of 3) of 1.4, 0.8, and 128 fmol for MQ-GS, MQ-NAC, and MQ, respectively. The application of our method reported here is the first to extensively study the stability and reversibility of thiol-quinones. PMID:23905771

Elgawish, Mohamed Saleh; Shimomai, Chikako; Kishikawa, Naoya; Ohyama, Kaname; Wada, Mitsuhiro; Kuroda, Naotaka



Magnetic Field Effect: An Efficient Tool To Investigate The Mechanism Of Reactions Using Laser Flash Photolysis Technique  

SciTech Connect

Magnetic field effect combined with laser flash photolysis technique have been used to study the mechanism of interactions between two drug-like quinone molecules, Menadione (1,4-naphthoquinone, MQ) and 9, 10 Anthraquinone (AQ) with one of the DNA bases, Adenine in homogeneous acetonitrile/water and heterogeneous micellar media. A switchover in reaction mode from electron transfer to hydrogen abstraction is observed with MQ on changing the solvent from acetonitrile/water to micelle; whereas, AQ retains its mode of interaction towards Adenine as electron transfer in both the media due to its bulky structure compared to MQ.

Basu, Samita; Bose, Adity; Dey, Debarati [Chemical Sciences Division, S aha Institute of Nuclear Physics, 1/AF, Bidhannagar, Kolkata--700 064 (India)



Anticancer Activities of Six Selected Natural Compounds of Some Cameroonian Medicinal Plants  

Microsoft Academic Search

BackgroundNatural products are well recognized as sources of drugs in several human ailments. In the present work, we carried out a preliminary screening of six natural compounds, xanthone V1 (1); 2-acetylfuro-1,4-naphthoquinone (2); physcion (3); bisvismiaquinone (4); vismiaquinone (5); 1,8-dihydroxy-3-geranyloxy-6-methylanthraquinone (6) against MiaPaCa-2 pancreatic and CCRF-CEM leukemia cells and their multidrug-resistant subline, CEM\\/ADR5000. Compounds 1 and 2 were then tested in

Victor Kuete; Hippolyte K. Wabo; Kenneth O. Eyong; Michel T. Feussi; Benjamin Wiench; Benjamin Krusche; Pierre Tane; Gabriel N. Folefoc; Thomas Efferth



Thermal and physical properties of flame-retardant epoxy resins containing 2-(6-oxido-6 H-dibenz? c, e??1,2?oxaphosphorin-6-yl)-1,4-naphthalenediol and cured with dicyanate ester  

Microsoft Academic Search

2-(6-oxido-6H-dibenz(c,e)(1,2)oxaphosphorin-6-yl)-1,4-naphthalenediol (DOPONQ) was prepared by the addition reaction of 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) with 1,4-naphthoquinone. The phosphorus-containing diol (DOPONQ) was used as a reactive flame retardant by an advancement reaction with the diglycidyl ether of bisphenol-A epoxy (DGEBA) resin at various stoichiometric ratios. DOPONQ-containing advanced epoxy was separately cured with various dicyanate esters to form flame-retardant epoxy\\/cyanate ester systems. The effect of

Tsung-Han Ho; Hann-Jang Hwang; Jeng-Yueh Shieh; Ming-Chin Chung



Triterpenoids from the roots of Pterospermum heterophyllum Hance  

Microsoft Academic Search

Two new triterpenoids taraxer-14-ene-1?,3?-diol (1) and 3?-hydroxytaraxer-14-ene-1-one (2), together with the known triterpenes taraxerol (3), betulin (4), betulinic acid (5), sumaresinolic acid (6), and 5-hydroxy-2-methoxy-1,4-naphthoquinone (7), 5,7-dihydroxy-6,8-dimethylchromone (8), ?-monpalmitin (9), palmitic acid (10), 6?-hydroxystigmast-4-en-3-one (11), ?-sitostero1 (12), have been isolated from the petroleum ether fraction of the ethanolic extract of Pterospermum heterophyllum. Their structures were established by spectroscopic methods including

Shuai Li; Yan Shi; Xiao-Ya Shang; Bao-Song Cui; Yi Yuan; Xiao-Guang Chen; Yong-Chun Yang; Jian-Gong Shi



Electrochemical study of oxygen interaction with lapachol and its radical anions.  


Cyclovoltammetric studies were performed with lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone], in the absence and presence of oxygen, which aimed to investigate possible oxygen interaction with lapachol and its radical anion. The obtained results clearly indicate the consumption of the semiquinone anion-radicals by oxygen in an EC type reaction, generating the deprotonated form of lapachol and HOO*. The observed generation of reactive oxygen species (ROS) after electron transfer can be related to the mechanism of biological action of lapachol. PMID:12699823

Goulart, Marília O F; Falkowski, Piotr; Ossowski, Tadeusz; Liwo, Adam



Inhibitory effects of lapachol derivatives on epstein-barr virus activation.  


Sixteen derivatives (2-17) synthesized from the naphthoquinone lapachol (1), were tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), as a test for potential cancer chemopreventive agents. They exhibited a variety of inhibitory activities from very high to moderate, which allow us to suggest structure-activity relationships. Ten of these derivatives are reported for the first time, their structures being thoroughly determined by spectroscopic methods. PMID:12538012

Sacau, Elisa Pérez; Estévez-Braun, Ana; Ravelo, Angel G; Ferro, Esteban A; Tokuda, Harunkuni; Mukainaka, Teruo; Nishino, Hoyoku



Microwave-assisted rapid cyclization of lapachol, a main constituent of Heterophragma adenophyllum.  


Cyclization reactions of lapachol (1) isolated from Heterophragma adenophyllum have been studied under microwave irradiation under different conditions using alumina (acidic, basic and neutral)/silica gel/montmorillonite (KSF and K-10) as solid support along with neat reaction using 2-3 drops of DMF giving naturally occurring dehydro-alpha-lapachone (2), alpha-lapachone (3), beta-lapachone (4) depending upon the nature of support and irradiation time. A novel naphthoquinone derivative adenophyllone (5) can be synthesized from lapachol using DMF under microwaves. PMID:16496478

Singh, P; Natani, K; Jain, S; Arya, K; Dandia, A



Colorimetric microbial viability assay based on reduction of water-soluble tetrazolium salts for antimicrobial susceptibility testing and screening of antimicrobial substances  

Microsoft Academic Search

The applicability of a colorimetric microbial viability assay based on reduction of a tetrazolium salt {2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt [WST-8]} via 2-methyl-1,4-naphthoquinone (2-methyl-1,4-NQ) as an electron mediator for determining the susceptibility of various bacteria to antibiotics and screening antimicrobial substances was investigated. The measurement conditions, which include the effects of the concentration of 2-methyl-1,4-NQ, were optimized for proliferation assays of gram-negative

Tadayuki Tsukatani; Tomoko Higuchi; Hikaru Suenaga; Tetsuyuki Akao; Munetaka Ishiyama; Takatoshi Ezoe; Kiyoshi Matsumoto



Naphtho[1,2- b]furan-4,5-dione induces apoptosis of oral squamous cell carcinoma: Involvement of EGF receptor\\/PI3K\\/Akt signaling pathway  

Microsoft Academic Search

Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exerts an anti-tumor effect. This study was performed to elucidate whether the epidermal growth factor (EGF) receptor and phosphatidylinositol-3-kinase (PI3K) signaling pathways are involved in NFD-induced apoptosis of oral squamous cell carcinoma (OSCC). Immunoblot showed that NFD suppressed the phosphorylation of EGF receptor and activation of PI3K\\/Akt, downstream

Ching-Ming Chien; Kuei-Li Lin; Jung-Chen Su; Pei-Wen Chuang; Chih-Hua Tseng; Yeh-Long Chen; Long-Sen Chang; Shinne-Ren Lin



Secondary metabolites from the stems of Engelhardia roxburghiana and their antitubercular activities.  


Bioassay-guided fractionation of stems of Engelhardia roxburghiana led to isolation of: four diarylheptanoids, engelheptanoxides A-D (1-4); two cyclic diarylheptanoids, engelhardiols A (5) and B (6); one naphthoquinone dimer, engelharquinonol (7); and one 1-tetralone, (4S)-4,6-dihydroxy-1-tetralone (8), along with 24 known compounds (9-32). The structures of 1-8 were by spectroscopic analysis. Compounds 5, 6, 13, 22, and 23 showed antitubercular activity against Mycobacterium tuberculosis H(37)Rv with MIC values of 72.7, 62.1, 9.1, 15.3, and 70.1?M, respectively. PMID:22818359

Wu, Ho-Chen; Cheng, Ming-Jen; Peng, Chien-Fang; Yang, Shyh-Chyun; Chang, Hsun-Shuo; Lin, Chu-Hung; Wang, Chyi-Jia; Chen, Ih-Sheng



Discovery, total synthesis, HRV 3C-protease inhibitory activity, and structure-activity relationships of 2-methoxystypandrone and its analogues.  


2-Methoxystypandrone, a naphthoquinone, was isolated from a Chinese herb Polygonum cuspidatum by bioassay guided fractionation using HRV 3C-protease assay. It showed an IC(50) value of 4.6 microM and is moderately selective. A new 10-step, total synthesis of 2-methoxystypandrone was accomplished in 45% overall yield using a Diels-Alder approach. Several analogues of this compound were prepared. Isolation, synthesis and HRV 3C-protease structure-activity relationships of these compounds have been described. PMID:11720861

Singh, S B; Graham, P L; Reamer, R A; Cordingley, M G



Malvone A, a phytoalexin found in Malva sylvestris (family Malvaceae).  


The isolation and structure of a phytoalexin, malvone A (2-methyl-3-methoxy-5,6-dihydroxy-1,4-naphthoquinone) is reported. Malvone A formation is induced in Malva sylvestris L. by the plant pathogen Verticillium dahliae. In a turbimetric assay for toxicity to V. dahliae, it had an ED50 value of 24 microg/ml. The structure of malvone A was determined by MS and NMR spectroscopy, and by X-ray crystallographic analysis. The X-ray analysis showed water molecules were located in channels that run along the a-axis. PMID:16996095

Veshkurova, Olga; Golubenko, Zamira; Pshenichnov, Egor; Arzanova, Irina; Uzbekov, Vyacheslav; Sultanova, Elvira; Salikhov, Shavkat; Williams, Howard J; Reibenspies, Joseph H; Puckhaber, Lorraine S; Stipanovic, Robert D



Combinatorial screening of heterogeneous catalysis in selective oxidation of naphthalene by laser-induced fluorescence imaging.  


Heterogeneous catalysis is one of the most important processes in the petroleum and the chemical industries. To be able to screen catalysts at high throughput will dramatically improve performance and reduce costs. Here we used laser-induced fluorescence imaging as a high-throughput screening technique in the combinatorial discovery of active catalysts for naphthalene oxidation. Binary catalysts of V-Mo-O, V-Sn-O, V-Ti-O, and V-W-O in various 15-member libraries were screened. Laser ablation ICPMS was employed to confirm the composition of the individual catalysts in the combinatorial library. The addition of MoO3, WO3, SnO2, and TiO2 to V2O5 did not improve the catalytic activity in the conversion of naphthalene to naphthoquinone, but the overall activity was found to increase for certain binary samples. The screening of ternary catalysts of V-Sn-Mo-O revealed that the combination of V (45%)-Sn (45%)-Mo (10%) gave 70% higher catalytic activity than pure V2O5 in converting naphthalene to naphthoquinone. Reaction temperature and sample preparation effects on the activity and selectivity of catalysts are also studied in a combinatorial manner. PMID:11575790

Su, H; Hou, Y; Houk, R S; Schrader, G L; Yeung, E S



Quinone emissions from gasoline and diesel motor vehicles.  


Gas- and particle-phase emissions from gasoline and diesel vehicles operated on chassis dynamometers were collected using annular denuders, quartz filters, and PUF substrates. Quinone species were measured using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine derivatization in conjunction with gas chromatography-mass spectrometry and high-performance liquid chromatography-mass spectrometry. Nine quinones were observed, ranging from C6 to C16. New species identified in motor vehicle exhaust include methyl-1,4-benzoquinone, 2-methyl-1,4-naphthoquinone (MNQN), and aceanthrenequinone. Gas-phase motor vehicle emissions of quinones are also reported for the first time. Six gas-phase quinones were quantified with emission rates of 2-28 000 microg L(-1) fuel consumed. The most abundant gas-phase quinones were 1,4-benzoquinone (BON) and MNQN. The gas-phase fraction was > or = 69% of quinone mass for light-duty gasoline emissions, and > or = 84% for heavy-duty diesel emissions. Eight particle-phase quinones were observed between 2 and 1600 microg L(-1), with BQN the most abundant species followed by 9,10-phenanthrenequinone and 1,2-naphthoquinone. Current particle-phase quinone measurements agree well with the few available previous results. Further research is needed concerning the gas-particle partitioning behavior of quinones in ambient and combustion source conditions. PMID:17695895

Jakober, Chris A; Riddle, Sarah G; Robert, Michael A; Destaillats, Hugo; Charles, M Judith; Green, Peter G; Kleeman, Michael J



Combination of chiroptical, absorption and fluorescence spectroscopic methods reveals multiple, hydrophobicity-driven human serum albumin binding of the antimalarial atovaquone and related hydroxynaphthoquinone compounds.  


High-affinity human serum albumin (HSA) binding of the C3-substituted antimalarial 2-hydroxy-1,4-naphthoquinone derivative atovaquone (ATQ) has been demonstrated and studied by circular dichroism (CD), UV/VIS absorption, fluorescence spectroscopy and affinity chromatography methods. The analysis of induced CD data generated upon HSA binding of ATQ revealed two high-affinity binding sites (K(a) ? 2 × 10(6) M(-1)). CD interaction studies and displacement of specific fluorescent and radioactive marker ligands indicated the contribution of both principal drug binding sites of HSA to complexation of ATQ, and also suggested the possibility of simultaneous binding of ATQ and some other drugs (e.g. warfarin, phenylbutazone, diazepam). Comparison of UV/VIS spectra of ATQ measured in aqueous solutions indicated the prevalence of the anionic species formed by dissociation of the 2-hydroxyl group. HSA binding of related natural hydroxynaphthoquinones, lapachol and lawsone also induces similar CD spectra. The much weaker binding affinity of lawsone (K(a) ? 10(4) M(-1)) bearing no C3 substituent highlights the importance of hydrophobic interactions in the strong HSA binding of ATQ and lapachol. Since neither drug exhibited significant binding to serum ?(1)-acid glycoprotein, HSA must be the principal plasma protein for the binding and transportation of 2-hydroxy-1,4-naphthoquinone-type compounds which are ionized at physiological pH values. PMID:20737064

Zsila, Ferenc; Fitos, Ilona




PubMed Central

MaciasR, Frank M. (Northrop Corporation, Hawthorne, Calif.). Phthiocol and menadione as acetate-replacing factors for Lactobacillus delbrueckii. J. Bacteriol. 82:657–661. 1961.—Lactobacillus delbrueckii (ATCC 9649), when cultured under nitrogen, or in ferrous iron-containing media exposed to air, requires, for the initiation of growth, compounds that are known to behave as electron acceptors. The ferrous iron probably induces what amounts to anaerobic conditions; that is, it blocks access of the organism to oxygen. Several electron carriers, such as methylene blue and naphthoquinones, stimulate growth of the organism in acetate-free media exposed to air. The most active acetate-replacing agent found is phthiocol. Methylene blue does not stimulate growth under nitrogen. It is suggested that the naphthoquinones bring about the initial oxidations required for growth by transferring the electrons to some other constituent of the medium. Growth of the organism in acetate-free media under CO2 indicates that CO2 or its fixation product can behave also as an initial oxidant.

MaciasR, Frank M.



Synergistic TRAIL sensitizers from Barleria alluaudii and Diospyros maritima#  

PubMed Central

Barleria alluaudii and Diospyros maritima were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-?-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (1) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (2), both not previously isolated from natural sources, and the known 2-methyl anthraquinone (3) were identified from B. alluaudii. Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of 1 and 2. Additionally, five known naphthoquinone derivatives, maritinone (4), elliptinone (5), plumbagin (6), (+)-cis-isoshinanolone (7), and ethylidene-6,6?-biplumbagin (8) were isolated from D. maritima. Compounds 1, 2, and 4–6 showed varying levels of synergy with TRAIL. Maritinone (4) and elliptinone (5) showed the highest synergistic effect, with more than a three-fold increase in activity observed with TRAIL than with compound alone.

Whitson, Emily L.; Sun, Han; Thomas, Cheryl L.; Henrich, Curtis J.; Sayers, Thomas J.; McMahon, James B.; Griesinger, Christian; McKee, Tawnya C.



Chemotherapeutic value of parvaquone and buparvaquone against Theileria annulata infection of cattle.  


Parvaquone (BW993C), 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone, and buparvaquone (BW720C) 2-(trans-4-t-butylcyclohexyl-methyl)-3-hydroxy-1,4-naphthoquinone, were evaluated to determine their therapeutic efficacy in the treatment of theileriosis caused by Theileria annulata infection in cattle in Iran. One hundred and fifty-nine pure and crossbred Bos taurus cattle, experimentally or naturally infected with T annulata, were treated. Parvaquone was injected into 86 animals with up to three doses of 20 mg kg-1 or 10 mg kg-1 at intervals of 48 hours between doses. Buparvaquone was injected into 73 animals. Up to three doses of 2.5 mg kg-1 were injected with an interval of 48 hours between doses. The recovery rate of animals treated with parvaquone was 60.7 per cent and with buparvaquone it was 88.7 per cent. No significant side effects of relapse of disease were observed following the use of either compound. It is concluded that buparvaquone at a dose of 2.5 mg kg-1 has a satisfactory therapeutic index and is a more effective treatment of T annulata infection than parvaquone. The prophylactic use of schizont tissue culture vaccine and chemotherapy with buparvaquone could be the most promising means of controlling theileriosis in Iran. PMID:2034901

Hashemi-Fesharki, R



Ubiquinone synthesis and its regulation in Pneumocystis carinii.  


The opportunistic pathogen Pneumocystis causes a type of pneumonia in individuals with defective immune systems such as AIDS patients. Atovaquone, an analog of ubiquinone (coenzyme Q [CoQ]), is effective in clearing mild to moderate cases of the infection. Rat-derived Pneumocystis carinii was the first organism in which CoQ synthesis was clearly demonstrated to occur in both mitochondrial and microsomal subcellular fractions. Atovaquone inhibits microsomal CoQ synthesis with no effect on mitochondrial CoQ synthesis. We here report on additional studies evaluating CoQ synthesis and its regulation in the organism. Buparvaquone also inhibited CoQ synthesis and it reduced the synthesis of all four CoQ homologs in the microsomal but not the mitochondrial fraction. Glyphosate, which inhibits a reaction in the de novo synthesis of the benzoquinone moiety of CoQ reduced cellular ATP levels. Bacterial and plant quinones, and several chemically synthesized phenolics, flavanoids, and naphthoquinones that inhibit electron transport in other organisms were shown to reduce CoQ synthesis in P. carinii. The inhibitory action of naphthoquinone compounds appeared to depend on their molecular size and structural flexibility rather than redox potential. Results of experiments examining the synthesis of the polyprenyl chain of CoQ were consistent with negative feedback control of CoQ synthesis. These studies on P. carinii suggest that cellular sites and the control of CoQ synthesis in different organisms and cell types might be more diverse than previously thought. PMID:17123407

Kaneshiro, Edna S; Basselin, Mireille; Merali, Salim; Kayser, Oliver


Generation and Trapping of 4-Methylene-5-(bromomethylene)-4,5-dihydrothiazole with Dienophiles.  


4-(Bromomethyl)-5-(dibromomethyl)thiazole (1) was prepared in good yields by bromination of 4,5-dimethylthiazole with 3.3 equiv of NBS in the presence of AIBN. Treatment of 1 with sodium iodide led to a thiazole o-quinodimethane 2 which was trapped in situ with dienophiles such as N-phenylmaleimide, DMAD, or acrylate derivatives. From the latter, 6-substituted-4,5-dihydrobenzothiazoles 7 are selectively formed. Anthra[2,3-b]thiazole-4,5-diones 13-15 were obtained from naphthoquinones. With 2- or 3-bromonaphthoquinones (11 or 12), the cycloadditions were found highly regioselective. Structural assignment of the regioisomers was made by a 2D (1)H-(13)C HMBC technique performed on the aromatized cycloadduct 15b. Calculations of HOMO and LUMO frontier orbital coefficients by the semiempirical PM3 method show that the regiochemistry observed in the cycloadditions of 2 toward acrylate dienophiles or naphthoquinones 11 and 12 did not agree with the corresponding values. PMID:11671416

Al Hariri, Mouaffak; Jouve, Karine; Pautet, Félix; Domard, Monique; Fenet, Bernard; Fillion, Houda



Optimization and validation of spectrofluorimetric method for determination of cefadroxile and cefuroxime sodium in pharmaceutical formulations.  


A simple, accurate, precise and validated spectrofluorimetric method is proposed for the determination of two cephalosporins, namely, cefadroxile (cefa) and cefuroxime sodium (cefu) in pharmaceutical formulations. The method is based on a reaction between cephalosporins with 1,2-naphthoquinone-4-sulfonate in alkaline medium, to form fluorescent derivatives that are extracted with chloroform and subsequently measured at 610 and 605 nm after excitation at 470 and 460 nm for cefa and cefu respectively. The optimum experimental conditions have been studied. Beer's law is obeyed over the concentrations of 20-70 ng/mL and 15-40 ng/mL for cefa and cefu, respectively. The detection limits were 4.46 ng/mL and 3.02 ng/mL with a linear regression correlation coefficient of 0.9984 and 0.998, and recoveries ranging 97.50-109.96% and 95.73-98.89% for cefa and cefu, respectively. The effects of pH, temperature, reaction time, 1,2-naphthoquinone-4-sulfonic concentration and extraction solvent on the determination of cefa and cefu, have been examined. The proposed method can be applied for the determination of cefa and cefu in pharmaceutical formulations in quality control laboratories. PMID:23345111

Elbashir, Abdalla A; Ahmed, Shazalia M A; Aboul-Enein, Hassan Y




PubMed Central

It is known that with increasing concentrations of hydroxylamine the rate of photoreduction in the alga Scenedesmus drops to about one-half of the normal rate. From then on photoreduction remains insensitive to hydroxylamine. The present experiments prove that this strange effect is not specific for hydroxylamine. It can be produced with substances having quite different chemical properties, such as o-phenanthroline, 2-methyl-1,4-naphthoquinone (vitamin K), or 2-oxy-3-methyl-naphthoquinone (phthiocol). Once the rate of photoreduction has been brought down to the limit of exactly one-half by a sufficient dose of any one of these substances, the reaction is also stabilized against reversion under the influence of strong light. At saturation intensities the rate of the stabilized photoreduction may be several times that at which the unpoisoned cells revert to photosynthesis. The ratio of one-half between the rates of the stabilized and the normal photoreduction is found at very low light intensities. This indicates a change in the photochemical process. Since the assimilatory quotient remains unaltered, it is the quantum yield which is cut in half under the influence of the poisons. To explain these observations it is assumed that either just one-half of the primary photoproducts are lost, or that they react back entirely while causing a reduction of carbon dioxide in a way similar to that brought about by the oxyhydrogen reaction in the dark.

Gaffron, H.



Single crystal X-ray structure of Lawsone anion: Evidence for coordination of alkali metal ions and formation of naphthosemiquinone radical in basic media  

NASA Astrophysics Data System (ADS)

2-hydroxy-1,4-naphthoquinone; Lawsone (Lw) is a natural compound found in henna leaves. The reaction of lawsone with 'Na' metal (Lw-1), CH3COONa (Lw-2), NaOH (Lw-3), KOH (Lw-4), K2CO3 (Lw-5) and Tris(hydroxymethyl)aminomethane (Lw-6) were studied. Red orange solids obtained for Lw-1 to Lw-6 are characterized by Elemental Analysis, FTIR, 1HNMR and EPR studies. The results reveal the coordination of alkali metals 'Na' and 'K' to lawsone anion. The single crystal X-ray structure of Lw-6 was solved and it crystallizes in triclinic space group P-1 with extensive hydrogen bonding network of CH\\ctdot O, NH\\ctdot O and OH\\ctdot O between cations and anions. Polycrystalline powder X-band EPR spectra of Lw-1 to Lw-5 shows signals ˜2.004 at 133 K, while Lw-6 is EPR silent. The naphthosemiquinone (NSQ-) radical formed in Lw-2 to Lw-5, is due to disproportion reaction of catechol and naphthoquinone.

Salunke-Gawali, Sunita; Kathawate, Laxmi; Shinde, Yogesh; Puranik, Vedavati G.; Weyhermüller, Thomas



Photoinduced reactions of para-quinones with bicyclopropylidene leading to diverse polycyclic compounds with spirocyclopropanes.  


Photoinduced reactions of bicyclopropylidene (BCP) with para-quinones (p-quinones) including benzoquinones, naphthoquinones, and anthraquinones were found to proceed via different cycloaddition pathways and lead to diverse polycyclic products bearing spiropropyl moiety. Photocycloaddition of BCP with benzoquinones gave spirooxetanes as the primary products, which upon irradiation were able to rearrange into the spiro[4.5]deca-6,9-diene-2,8-diones as secondary photoproducts. Chemoselectivity of the photocycloaddition of BCP with naphthoquinones relies largely on the substitution groups linked to the C?C in between the two carbonyl groups to give different types of products. Photoreaction of BCP with 9,10-anthraquinone gave not only the spirooxetane product, but also a novel spiro[indan-1,1'-phthalan]-3'-one product whose formation might be initiated by a transannular attack of the C4 cyclopropyl radical to the para-carbonyl group. Mechanisms involved in the formation of diverse primary or secondary products in the photoreactions of BCP with p-quinones were proposed. Some of the photoreactions also hold potentials as useful synthetic protocols for important spiropolycyclic compounds such as sesquiterpenes. PMID:23692405

Wang, Wei; Zhang, Wen-Jie; Wang, Lei; Quah, Ching Kheng; Fun, Hoong-Kun; Xu, Jian-Hua; Zhang, Yan



The maillard reaction for sunlight protection.  


During seven months of a clinical trial in spring, summer, and fall, 30 UVA/B/Soret band-photosensitive patients used sequential topical applications of dihydroxyacetone (DHA) followed by naphthoquinone only at bedtime and received excellent photoprotection without a single therapeutic failure or loss of any patient to follow-up. Eighteen of the 30 patients extended the limits of their photoprotection repeatedly over a seven-month period to tolerate without sunburns six to eight hours of midday sunlight under all kinds of occupational and recreational environmental conditions. Previously, the use of 3% DHA topically in earlier studies gave only a sun protection factor (SPF) of 3. In this reanalysis of the original notes of a previous clinical study of the melanoidins produced by DHA followed by naphthoquinone in the keratin layers of the epidermis of minimally pigmented Caucasian photosensitive patients, it is determined that these patients received a minimal UVB photoprotection of SPF 18 or more. This represents at least a sixfold amplification of the UVB photoprotective effect over the use of only dihydroxyacetone in the Maillard reaction. PMID:16037237

Fusaro, Ramon M; Rice, Edwin G



Investigating PAH relative reactivity using congener profiles, quinone measurements and back trajectories  

NASA Astrophysics Data System (ADS)

Vapour and particle-associated concentrations of 15 polycyclic aromatic hydrocarbons (PAH) and 11 PAH quinones have been measured in winter and summer campaigns at the rural site, Weybourne in eastern England. Concentrations of individual PAH are 20-140 times smaller than average concentrations at an English urban site. The concentrations of PAH are greatest in air masses originating from southern England relative to those from Scandinavia and the North Atlantic, while quinone to parent PAH ratios show an inverse behaviour, being highest in the more aged North Atlantic polar air masses. While concentration of 1,2-naphthoquinone decline from summer to winter, those of 1,4-naphthoquinone and anthraquinone increase suggesting a photochemical formation pathway. A comparison of congener concentration profiles measured at Weybourne with those from an urban source area (Birmingham) reveals differential losses at the rural site, especially evident in fluoranthene: pyrene ratios and consistent with the known rates of vapour phase reactions of 3 and 4 ring compounds with hydroxyl radical. The ratios of quinones to their parent PAH at Weybourne are greater than those in the urban source area indicating either more rapid loss processes for PAH, or formation of quinones during advection of the air mass, or probably both.

Alam, M. S.; Delgado-Saborit, J. M.; Stark, C.; Harrison, R. M.



QM/MM Modeling Finds Diels-Alder Reactions are Accelerated Less On the Surface of Water than In Water  

PubMed Central

Quantum and molecular mechanics (QM/MM) calculations for the Diels-Alder reactions of cyclopentadiene with 1,4-naphthoquinone, methyl vinyl ketone, and acrylonitrile have been carried out at the vacuum-water interface and in the gas phase. In conjunction with previous studies of these cycloadditions in dilute solution, a more complete picture of aqueous environmental effects emerges with implications for the origin of observed rate accelerations using heterogeneous aqueous suspensions, “on water” conditions. The pure TIP4P water slab maintains bulk density and hydrogen bonding properties in central water layers. The bulk region merges to vacuum over a ca. 5-Å band with progressive diminution of density and hydrogen bonding. The relative free energies of activation and transition structures for the reactions at the interface are found to be intermediate between those calculated in the gas phase and in bulk water, i.e., for the reaction with 1,4-naphthoquinone, the ??G ‡’s relative to the gas phase are ?3.6 and ?7.3 kcal/mol at the interface and in bulk water, respectively. Thus, the results do not support the notion that a water surface is more effective than bulk water for catalysis of such pericyclic reactions. The trend is in qualitative agreement with expectations based on density considerations and estimates of experimental rate constants for the gas phase, a heterogeneous aqueous suspension, and dilute aqueous solution for the reaction of cyclopentadiene with methyl vinyl ketone. Computed energy pair distributions reveal a uniform loss of 0.5 – 1.0 hydrogen bond for the reactants and transition states in progressing from bulk water to the vacuum-water interface. Orientational effects are apparent at the surface, e.g., the carbonyl group in the methyl vinyl ketone transition structure is preferentially oriented into the surface. Also, the transition structure for the 1,4-naphthoquinone case is buried more in the surface, and the free energy of activation for this reaction is most similar to the result in bulk water.

Thomas, Laura L.; Tirado-Rives, Julian; Jorgensen, William L.



Abiotic transformation of catechol and 1-naphthol in aqueous solution-influence of environmental factors.  


The abiotic transformation of catechol and 1-naphthol singly and in mixtures was tested in sterile Tris-HCl buffer with regard to several environmental factors including temperature (7 degrees C, 20 degrees C and 30 degrees C), lighting conditions, pH (between 7.0 and 8.5) and dissolved oxygen (at partial pressures of 0.0, 220, 2200, 11000 and 22000 Pa). Irrespective of lighting conditions. catechol autoxidation was confirmed in aerated medium with a rate independent of the presence of 1-naphthol but proportional to the dissolved oxygen concentration, to the pH (its half-disappearance occurred in 24h at pH 8.5) and, to a lesser extent, to the incubating temperature (at 20 degrees C, 20% disappeared in 10 days at pH 7.0). Under alkaline conditions, the reaction of the anionic form (catecholate) with an equimolar concentration of molecular oxygen (O2) led presumably to hydrogen peroxide anion (HO2-) and coloured polymerization products. When tested alone, 1-naphthol was not significantly influenced either by lighting conditions, incubating temperature or dissolved oxygen concentration. It was also found to be quite stable with respect to pH, with a 15-fold weaker transformation rate than for catechol at the highest pH used. When tested in a mixture with catechol, 1-naphthol was found to be involved in a new chemical oxidation reaction catalyzed by catecholate. The transformation of one mole of 1-naphthol consumes four moles of oxygen. In the presence of catechol, the stoichiometry of the 1-naphthol transformation, under the influence of oxygen, suggests the possible formation of 2,5,6,8-tetrahydroxy 1,4-naphthoquinone via Lawsone (2-hydroxy 1,4-naphthoquinone) and naphthopurpurine (2,5,8-trihydroxy 1,4-naphthoquinone) as hypothetic intermediates. This is the first report of the autoxidation of 1-naphthol, catalyzed by catechol, in aqueous solution, in the absence of UV irradiation. PMID:11561636

Borraccino, R; Kharoune, M; Giot, R; Agathos, S N; Nyns, E J; Naveau, H P; Pauss, A



Photoinduced reduction of divalent mercury by quinones in the presence of formic acid under anaerobic conditions.  


The laser flash photolysis technique (?(exc)=355 nm) was used to investigate the mechanism of the HgCl(2) reduction mediated by CO(2)(-) radicals generated from quenching of the triplet states of 1,4-naphthoquinone (NQ) by formic acid. Kinetic simulations of the experimental signals support the proposed reaction mechanism. This system is of potential interest in the development of UV-A photoinduced photolytic procedures for the treatment of Hg(II) contaminated waters. The successful replacement of NQ with a commercial fulvic acid, as a model compound of dissolved organic matter, showed that the method is applicable to organic matter-containing waters without the addition of quinones. PMID:22884492

Berkovic, Andrea M; Bertolotti, Sonia G; Villata, Laura S; Gonzalez, Mónica C; Pis Diez, Reinaldo; Mártire, Daniel O



Allergic contact dermatitis to pure henna.  


Henna is a naturally occurring brown dye made from the leaves of the tree Lawsonia inermis. The active ingredient of henna is lawsone (2-hydroxy-1, 4-naphthoquinone). It is traditionally used in Islamic and Hindu cultures as a hair coloring and as a dye for decorating the nails or making temporary skin tattoos. Actually, henna has a very low allergic potential. In most cases, allergic reactions not caused by henna, but by the chemical coloring additives that are added to henna mixtures. These additives include agents such as daiminotoluenes and diaminobenzenes. In this article, we report a case of allergic contact dermatitis from pure henna that is also used for the relief of rheumatic pain. PMID:19281720

Polat, Muhterem; Dikilita?, Meltem; Ozta?, Pinar; Alli, Nuran



Antioxidant and immunomodulatory constituents of henna leaves.  


The immunomodulatory bioassay-guided fractionation of the methanolic extract of henna (Lawsonia inermis L.; syn. Lawsonia alba L.) leaves resulted in the isolation of seven compounds; three have been isolated for the first time from the genus, namely p-coumaric acid, 2-methoxy-3-methyl-1,4-naphthoquinone and apiin, along with the previously isolated compounds: lawsone, apigenin, luteolin, and cosmosiin. Structural elucidation of the isolated compounds was based upon their physical, chemical as well as spectroscopic characters. Their immuomodulatory profile was studied using an in vitro immunoassay, the lymphocyte transformation assay. The ABTS [2,2'-azino-bis (3-ethyl benzthiazoline-6-sulfonic acid)], free radical scavenging assay depicted that all isolated compounds exhibited antioxidant activity comparable to that of ascorbic acid. PMID:15813363

Mikhaeil, Botros R; Badria, Farid A; Maatooq, Galal T; Amer, Mohamed M A


Effects of fluorescence on the spatial resolution of photoresist materials  

NASA Astrophysics Data System (ADS)

Five-substituted diazo-naphthoquinones (DNQs) are photolyzed in novolac and in various solvents in the presence of H2O. HPLC analysis reveals that, depending on the matrix or the solvent, a large fraction of the DNQ is converted into products other than indene carboxylic acid (ICA). These include products from fragmentation, dimerization, and azo- coupling as well as products from the reaction of the solvent with intermediates in the main photoreaction. A larger amount of fragmentation products is found by excimer laser exposure at 308 nm or 248 nm. The side products mentioned above are fluorescent and their fluorescence band overlaps with the first UV-absorption band of the DNQ. Photolysis of the photosensitizer by this fluorescence may affect the spatial resolution of a photoresist. Numerical simulation of the magnitude of this effect shows that, in practice, the conversion of photosensitizer due to fluorescence is in the order of a few percent at most.

Vleggaar, J. J.; Huizer, A. H.; Varma, Cyril A.



Bioassay-guided isolation of urease and ?-chymotrypsin inhibitory constituents from the stems of Lawsonia alba Lam. (Henna).  


Seven constituents were isolated from the stems of Lawsonia alba Lam., following an activity-guided isolation, which include two new constituents, namely lawsorosemarinol (1) and lawsofructose (2), one known compound 2-(?-d-glucopyranosyloxy)-1, 4-naphthoquinone (3) and four compounds, 4-hydroxy coumarine (4), 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate (5), 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate (6) and 7-hydroxy-4-methyl coumarin (7) first time isolated from Lawsonia alba. Their structure elucidation was based on spectroscopic data analyses. Compounds 3 and 7 showed a moderate inhibition of urease activity, while rest of them showed less than 50% inhibition. These compounds did not show any significant inhibition against ?-chymotrypsin. PMID:23103954

Uddin, Nizam; Siddiqui, Bina Shaheen; Begum, Sabira; Ali, Muhammad Imran; Marasini, Bishnu P; Khan, Ajmal; Choudhary, M Iqbal



Eco-friendly synthesis and antiproliferative evaluation of some oxygen substituted diaryl ketones.  


A broad variety of oxygen-substituted diaryl ketones has been synthesized by solar energy-induced Friedel Crafts acylations of 1,4-benzo- and 1,4-naphthoquinones with benzaldehydes. The in vitro antiproliferative properties of the photoproducts were assessed on prostate (DU-145), bladder (T24) and breast (MCF7) human-derived tumor cell lines and compared to non-tumor mouse fibroblasts (Balb/3T3). Among the tested compounds, it was found that those containing a 3,4,5-trimethoxyphenyl A-ring, such as 12 and 22 are more active on DU-145, with EC50 values of 1.2 and 5.9 ?M, respectively. By comparing their effects on the three cancer cell lines, the analogue 22 has the best mean selective index (2.4). PMID:23959193

Arenas, Paola; Peña, Andrés; Ríos, David; Benites, Julio; Muccioli, Giulio G; Calderon, Pedro Buc; Valderrama, Jaime A



Interactions between manganese oxides and multiple-ringed aromatic compounds  

SciTech Connect

Objective is to determine whether Mn reductive dissolution can oxidize multiple-ringed aromatics, such as PAHs, in an oxic environment Research indicated that certain PAHs (eg, dihydrodiols and diones that form free-radical intermediates) are susceptible to oxidation and polymerization. Over 14 days, 83, 76, 54, 70, and 20% of the Mn was reduced by 2,3-, 1,3-, and 1,4-naphthalenediol, quinizarin, and 1,4-naphthoquinone, respectively. 100, 100, and 65% of the first three PAHs were oxidized, respectively. Aromatics with diol functional groups were more easily oxidized than those with only dione groups. Relatively insoluble compounds like quinizarin can be oxidized; insoluble ''humic-like'' material precipitated, indicating a polymerization-humification process. Results suggest that electron transfer/organic release from the oxide surface is the rate-limiting step.

Whelan, G. (Pacific Northwest Lab., Richland, WA (United States)); Sims, R.C. (Utah State Univ., Logan, UT (United States). Dept. of Civil and Environmental Engineering)



Interactions between manganese oxides and multiple-ringed aromatic compounds  

SciTech Connect

Objective is to determine whether Mn reductive dissolution can oxidize multiple-ringed aromatics, such as PAHs, in an oxic environment? Research indicated that certain PAHs (eg, dihydrodiols and diones that form free-radical intermediates) are susceptible to oxidation and polymerization. Over 14 days, 83, 76, 54, 70, and 20% of the Mn was reduced by 2,3-, 1,3-, and 1,4-naphthalenediol, quinizarin, and 1,4-naphthoquinone, respectively. 100, 100, and 65% of the first three PAHs were oxidized, respectively. Aromatics with diol functional groups were more easily oxidized than those with only dione groups. Relatively insoluble compounds like quinizarin can be oxidized; insoluble ``humic-like`` material precipitated, indicating a polymerization-humification process. Results suggest that electron transfer/organic release from the oxide surface is the rate-limiting step.

Whelan, G. [Pacific Northwest Lab., Richland, WA (United States); Sims, R.C. [Utah State Univ., Logan, UT (United States). Dept. of Civil and Environmental Engineering



Synthesis of naphthofuranquinones with activity against Trypanosoma cruzi.  


Four new naphthofuranquinones, obtained from 2-hydroxy-3-allyl-naphthoquinone (1) and nor-lapachol (2), have their structures established by physical and X-ray analysis and their activity evaluated against Trypanosoma cruzi. Compounds 3 and 4 were obtained by addition of iodine to 1 followed by cyclization generating a furan ring. Compound 5 was obtained through the acid-catalyzed reaction by dissolution of 1 in sulfuric acid. Compound 6 was synthesized by addition of bromine and aniline to 2. The IC(50)/24 h for 3-6 in assays with T. cruzi trypomastigotes was between 157 and 640 microM, while the value for crystal violet was 536.0 +/- 3.0 microM. Compounds 3-5 also inhibited epimastigote proliferation. The trypanocidal activity of the new naphthofuranquinones endowed with redox properties reinforces a rational approach in the chemotherapy of Chagas' disease. PMID:16500733

Silva, Raphael S F; Costa, Elaine M; Trindade, Ursula L T; Teixeira, Daniel V; Pinto, Maria de Carmo F R; Santos, Gustavo L; Malta, Valeria R S; De Simone, Carlos Alberto; Pinto, Antonio Ventura; de Castro, Solange L



Lapachol induces clastogenic effects in rats.  


Lapachol is a naturally occurring naphthoquinone derivative found in the heartwood of several plants, particularly those of the genus Tabebuia (Bignoneaceae). Despite its use as a therapeutic product with anti-inflammatory, analgesic, antipsoriatic, trypanocidal effects, among others, its in vivo mutagenic potential has still not been investigated. This paper reports the effects after a single oral administration of lapachol in the in vivo micronucleus (MN) and chromosome aberration (CA) assays. Both assays were performed using bone marrow cells from male Wistar rats. The animals were treated by oral gavage with hydroalcoholic solutions of lapachol at the doses of 122, 244 and 365 mg/kg, chosen on the basis of the LD(50) in male rats. The results show that the higher administered lapachol dose induced a significant increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) and CAs in rat bone marrow cells, indicating that lapachol shows clastogenic effects under the experimental conditions used. PMID:20112181

Maistro, Edson Luis; Fernandes, Diego Mota; Pereira, Fernanda Maria; Andrade, Sergio Faloni



Reproductive toxicity of lapachol in adult male Wistar rats submitted to short-term treatment.  


Lapachol is a therapeutic naphthoquinone, but little is known about its general and reproductive toxicity. In female rats, a high incidence of resorptions and fetal mortality has been reported. This work analyses the effect of the short-term administration of lapachol on vital and reproductive organs, and sperm production in Wistar rats. Adult animals were treated with 1 mL of lapachol hydroalcohol solution (100 mg/kg of body weight) for 5 days and killed 3 (T1) and 14 days (T2) after the end of treatment. Body and organ weights and sperm production were evaluated. The administration of lapachol significantly reduced the weight of the seminal vesicle (T1 animals). No significant alteration of gamete production, body weight and the weight of the other organs analysed were detected. The results suggest a reproductive toxicity effect of lapachol, indicating the seminal vesicle as a possible target organ. PMID:17421057

de Cássia da Silveira E Sá, Rita; de Oliveira Guerra, Martha



Azatrioxa[8]circulenes: planar anti-aromatic cyclooctatetraenes.  


We describe herein the first synthesis of a new class of anti-aromatic planar cyclooctatetraenes: the azatrioxa[8]circulenes. This was achieved by treating a suitably functionalised 3,6-dihydroxycarbazole with 1,4-benzoquinones or a 1,4-naphthoquinone. We fully characterised the azatrioxa[8]circulenes by using optical, electrochemical and computational techniques as well as by single-crystal X-ray crystallography. The results of a computational study (NICS) suggest that the central planar cyclooctatetraene is anti-aromatic when the molecules are in neutral or oxidised states (2+), and that the corresponding dianions are aromatic. We discuss the aromatic/anti-aromatic nature of the planar cyclooctatetraenes and compare them with the isoelectronic tetraoxa[8]circulenes. PMID:23400907

Nielsen, Christian B; Brock-Nannestad, Theis; Hammershøj, Peter; Reenberg, Theis K; Schau-Magnussen, Magnus; Trpcevski, Denis; Hensel, Thomas; Salcedo, Roberto; Baryshnikov, Gleb V; Minaev, Boris F; Pittelkow, Michael



Laser flash photolysis and magnetic-field-effect studies on interaction of thymine and thymidine with menadione: role of sugar in controlling reaction pattern  

NASA Astrophysics Data System (ADS)

The magnetic field effect (MFE) in conjunction with laser flash photolysis has been used for the study of the interaction of one of the small drug like quinone molecules, 2-methyl, 1,4-naphthoquinone, commonly known as menadione (MQ), with one of the DNA bases, thymine (THN), and its corresponding nucleoside, thymidine (THDN), in acetonitrile (ACN) and sodium dodecylsulfate (SDS) micelles. It has been observed that THN undergoes electron transfer (ET) and hydrogen (H) abstraction with MQ, while THDN undergoes only H abstraction in both the media. However, our earlier studies showed that a purine base, adenine (ADN), and its nucleoside, 2'-deoxyadenosine (ADS), undergo ET in ACN and H abstraction in SDS. Here we have attempted to explain the differences in the reactions of these DNA bases with MQ. We also reveal the crucial role of a sugar unit in altering the behavior of purine and pyrimidine bases with respect to ET and H abstraction.

Bose, Adity; Dey, Debarati; Basu, Samita



One-pot, sequential four-component synthesis of benzo[c]pyrano[3,2-a]phenazine, bis-benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an efficient and reusable solid base catalyst.  


1,4-Diazabicyclo[2.2.2]octane (DABCO) has been used as an efficient and reusable solid base catalyst for the one-pot, two-step, four-component synthesis of pyrano[3,2-a]phenazine derivatives by the condensation reaction of 2-hydroxy-1,4-naphthoquinone, 1,2-diamines, carbonyl compounds and alkylmalonates under conventional heating as well as microwave irradiation. This procedure has also been applied successfully for the synthesis of novel bis- benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives. Using this procedure, all the products were obtained in good to excellent yields. The catalyst has been recovered and reused several times without any loss of reactivity. PMID:23665995

Hasaninejad, Alireza; Firoozi, Somayeh



Control of tropical theileriosis (Theileria annulata infection) of cattle.  


Tropical bovine theileriosis caused by Theileria annulata and transmitted by ticks of the genus Hyalomma may be controlled by one or more of the following methods: i) management, with particular emphasis on movement control; ii) vector control by application of acaricides, preventing transmission of disease; iii) treatment of clinical disease using specific chemotherapeutics; iv) immunization with live vaccines; and v) the use of cattle resistant to ticks or the disease. Of these the most important and effective control method is the use of a live cell culture vaccine attenuated by prolonged culture in vitro of mononuclear cells persistently infected with macroschizonts of T. annulata. This vaccine, used chiefly in susceptible taurine dairy cattle, can now be complemented by using novel chemotherapeutic naphthoquinones--parvaquone and buparvaquone--which are very effective in treatment of the clinical disease in these valuable cattle. PMID:2126619

Brown, C G



Activity of buparvaquone against Theileria cervi in white-tailed deer.  


Buparvaquone, a naphthoquinone with known efficacy against Theileria parva parva in cattle, was tested for activity against Theileria cervi piroplasms in both an in vitro culture system and in vivo in experimentally infected white-tailed deer. The in vitro data showed a significant decrease in the incorporation of 3H-hypoxanthine by infected red blood cells treated with buparvaquone when compared to that seen with imidocarb and chloroquine treatment. In both intact and splenectomized deer treated with buparvaquone (2.5 mg kg-1) a gradual decrease in piroplasm parasitaemia was observed following treatment. However, in the splenectomized deer, parasitaemia levels returned to near pretreatment values after approximately 2 weeks. PMID:1902608

Mitema, E S; Kocan, A A; Mukolwe, S W; Sangiah, S; Sherban, D



Phytochemical and biological study of radal Lomatia hirsuta (Proteaceae).  


The anti-inflammatory property of Lomatia hirsuta (Lam.) Diels ex Macbr. (Proteaceae), leaves (radal), a plant used in Chilean traditional medicine for bronchial troubles and asthma, was evaluated. The biological assays showed infusion of L. hirsuta leaves inhibits the inflammation induced by lambda-carrageenan corresponding to a 29.2% anti-inflammatory effect, and to 53.5% of the maximum effect observed with sodium naproxen (4 mg/kg) in the same experimental conditions. The coumarins, umbelliferone and scopoletin, were the major compounds isolated, along with quercetine, rhamnetin and iso-rhamnetin, with minor quantities or quercitrine and no presence of toxic naphthoquinone derivates. These results supported the folk use of L. hirsuta. PMID:9254109

Erazo, S; García, R; Backhouse, N; Lemus I 1st; Delporte, C; Andrade, C



Synthesis and cytotoxic activities of some 2-Arylnaphtho [2,3-d]oxazole-4,9-dione derivatives on androgen-dependent (LNCaP) and androgen-independent (PC3) human prostate cancer cell lines  

PubMed Central

Summary The synthesis of five 2-arylnaphtho[2,3-d]oxazole- 4,9-dione derivatives was accomplished by refluxing 2-amino-3-bromo-1,4-naphthoquinone with appropriate benzoyl chloride analogs at elevated temperatures. In vitro anticancer evaluation of these compounds was performed on androgen-dependent, LNCaP, and androgen-independent, PC3, human prostate cancer cell lines. In general, these compounds displayed slightly stronger cytotoxicity on the androgen-dependent LNCaP than on the androgen-independent PC3 prostate cancer cell lines. The meta-substituted 2-(3-Chloro-phenyl)-naphtho[2,3-d]oxazole-4,9- dione (10) appear to display the best cytotoxicity on both cell lines with an IC50 of 0.03 ?M on LNCaP and 0.08 ?M on PC3 after 5 days of exposure.

Brandy, Yakini; Ononiwu, Innocent; Adedeji, Dolapo; Williams, Vonetta; Mouamba, Claudia; Kanaan, Yasmine; Copeland, Robert L.; Wright, Dwayne A.; Butcher, Ray J.; Denmeade, Samuel R.



Anaerobic degradation of monoazo dyes  

SciTech Connect

The anaerobic degradation of two monoazo dyes, acid red 88 (AR88) and acid orange 7, was studied utilizing serum bottle assays. When either dye was present between .05 and 50 mg/L as the sole substrate, inhibition was demonstrated, with no mineralization occurring. However, when a supplemental carbon and energy source was available no inhibition was evidence with mineralization occurring at intermediate concentrations. The degradation of AR88 and metabolite formation was examined utilizing laboratory-scale semi-continuous anaerobic reactors. Addition of 50 mg/L of dye resulted in >98% removal, although mineralization was not achieved. Metabolites identified were naphthionic acid, 2-naphthol, 1,2-naphthoquinone, isoquinoline, and quinacridone. The presence of the metabolites, some of which were products of complexation and polymerization, exerted a slight inhibitory effect on the non-methanogens. The availability of a supplemental carbon source demonstrated an effect on the metabolites that are evolved and the rate at which they are formed.

Kremer, F.V.



[Effect of the interaction of tannins with coexisting substances. VIII. Inhibitory effect of tannins on discoloration of natural pigments].  


The discoloration of shikonin (1) and beta-carotene (2), occurring during storage of their ethanol solutions in the presence of oxygen in an illuminated room, was remarkably suppressed by hydrolyzable tannins, such as geraniin (4) and tannic acid JP (3) in the solution. The inhibitory effect of tannins was enhanced by the coexistence of metallic ion. The irradiation with ultraviolet lamp (254 and 365 nm) gave, at the first stage of the discoloration, two products, one of which was found to be 5,8-dihydroxy-2-(1-hydroxy-3-oxo-4-methyl-4-pentenyl)-1,4-naphthoquinone (7). The presence of hydrolyzable tannins induced higher accumulation of these two products in the solution, showing that the secondary structural transformations of these two products were strongly inhibited by these coexisting tannins. These results suggest that tannins could be efficient inhibitors of discoloration of natural pigments. PMID:7738780

Mori, K; Chou, T; Yoshida, T; Okuda, T



Redox Potentials of Certain Vitamins K: Implications for a Role in Sulfite Reduction by Obligately Anaerobic Bacteria  

PubMed Central

Redox potentials of a menaquinone (MK-6), isolated in earlier researches from two species of the obligately anaerobic genus, Desulfovibrio, as well as two other vitamins K2—menaquinones (MK-5) and (MK-9)— have been determined polarographically. The measurements have been validated by determination of redox potentials of 1,4-naphthoquinone and vitamin K1 which agree with published potentiometric values. Em7 for menaquinone (MK-6) is -0.067 ± 0.010 V. Redox potentials calculated for terminal acceptor couples currently proposed in the mechanisms of sulfate reduction by Desulfovibrio are consistent with the involvement of menaquinone (MK-6) in at least one of the steps postulated during electron transfer with ultimate production of sulfide.

Wagner, G. C.; Kassner, R. J.; Kamen, M. D.



Diels-Alder reactions of 4-alkenylthiazoles: a new approach to thiazole functionalization.  


Somewhat unexpectedly, the computed highest occupied molecular orbital (HOMO) energies of some 4-alkenylthiazoles afforded values close to those calculated for the Danishefsky-Kitahara and Rawal dienes. In fact, 4-alkenylthiazoles behave as all-carbon dienes in Diels-Alder reactions with the participation of the formal C-C double bond of the thiazole ring and the side-chain double bond. The reactions with N-substituted maleimides, maleic anhydride, and naphthoquinone take place with high levels of stereocontrol to give the corresponding endo-cycloadducts in good to excellent yields. Depending on the dienophile, the cycloadduct further transforms under the reaction conditions through either a 1,3-hydrogen shift, dehydrogenation, or an ene reaction or Michael addition with another molecule of dienophile. These unprecedented results open new synthetic perspectives for the functionalization of the thiazole ring. PMID:17316049

Alajarín, Mateo; Cabrera, José; Pastor, Aurelia; Sánchez-Andrada, Pilar; Bautista, Delia



Preliminary oxidation in histochemical staining methods for cholesterol.  


The need for preliminary oxidation with histochemical methods for cholesterol was investigated on silica-coated sheets and in tissue sections. The techniques used were the Schultz reaction, perchloric acid-naphthoquinone (PAN), Lewis & Lobban's ferric alum-sulphuric acid reagent and Okamoto's iodine-sulphuric acid. The oxidants assessed were ferric chloride, ferric alum, potassium permanganate, ammonium sulphamate and ultraviolet light. The best combinations amongst those tested in order of reactivity were FeCl3-PAN, ferric alum-Schultz, Lewis-Lobban (no additional oxidant), iodine-sulphuric acid (no additional oxidant). Authentic preparations of cholesterol oxidation products were stained with these methods, but the nature of the oxidized product in the preliminary stage could not be determined. PMID:6157826

Adams, C W; High, O B



Dimeric Fe (II, III) complex of quinoneoxime as functional model of PAP enzyme: Mössbauer, magneto-structural and DNA cleavage studies  

Microsoft Academic Search

Purple acid phosphatase, (PAP), is known to contain dinuclear Fe2\\u000a ?+?2,?+?3 site with characteristic Fe?+?3 ? Tyr ligand to metal charge transfer in coordination. Phthiocoloxime (3-methyl-2-hydroxy-1,4-naphthoquinone-1-oxime) ligand\\u000a L, mimics (His\\/Tyr) ligation with controlled and unique charge transfers resulting in valence tautomeric coordination with\\u000a mixed valent diiron site in model compound Fe-1: [?-OH-Fe2\\u000a ?+?2,?+?3 (o-NQCH3ox) (o-NSQCH3ox)2 (CAT) H2O]. Fe-2: [Fe?+?3(o-NQCH3ox) (p-NQCH3ox)2]2

Sunita Salunke-Gawali; Khursheed Ahmed; François Varret; Jorge Linares; Santosh Zaware; Sadgopal Date; Sandhya Rane



Dimeric Fe (II, III) complex of quinoneoxime as functional model of PAP enzyme: Mössbauer, magneto-structural and DNA cleavage studies  

Microsoft Academic Search

Purple acid phosphatase, (PAP), is known to contain dinuclear Fe2\\u000a ?+?2,?+?3 site with characteristic Fe?+?3 ? Tyr ligand to metal charge transfer in coordination. Phthiocoloxime (3-methyl-2-hydroxy-1,4-naphthoquinone-1-oxime) ligand\\u000a L, mimics (His\\/Tyr) ligation with controlled and unique charge transfers resulting in valence tautomeric coordination with\\u000a mixed valent diiron site in model compound Fe-1: [?-OH-Fe2\\u000a ?+?2,?+?3 (o-NQCH3ox) (o-NSQCH3ox)2 (CAT) H2O]. Fe-2: [Fe?+?3(o-NQCH3ox) (p-NQCH3ox)2]2

Sunita Salunke-Gawali; Khursheed Ahmed; François Varret; Jorge Linares; Santosh Zaware; Sadgopal Date; Sandhya Rane


Secondary metabolites in in vitro cultured plants of the genus Drosera.  


Extracts from plantlets of different species of the genus Drosera, grown as in vitro cultures, were evaluated for the level of phenolic secondary metabolites from the group of naphthoquinones and flavonols. The profiles of natural products in the extracts obtained from different species were monitored by HPLC with UV detection at 260 and 330 nm. On the basis of the data obtained, Drosera binata, the species with the highest amount of plumbagin, was selected for further studies. The most effective method of extraction of quinones was established and the composition of phenolic secondary metabolites in the tissues was determined. For the identification of phenolic compounds, HPLC-UV and HPLC-ESI/MS were applied. PMID:15997845

Marczak, L; Kawiak, A; Lojkowska, E; Stobiecki, M


Antimicrobial activity and chemical investigation of Brazilian Drosera.  


The antimicrobial activity of three different extracts (hexanic, ethyl acetate, methanol) obtained from Brazilian Drosera species (D. communis, D. montana var. montana, D. brevifolia, D. villosa var. graomogolensis, D. villosa var. villosa, Drosera sp. 1, and Drosera sp. 2 ) were tested against Staphylococcus aureus (ATCC 25923), Enterococcus faecium (ATCC23212), Pseudomonas aeruginosa (ATCC27853), Escherichia coli (ATCC11229), Salmonella choleraesuis (ATCC10708), Klebsiella pneumoniae (ATCC13883), and Candida albicans (a human isolate). Better antimicrobial activity was observed with D. communis and D. montana var. montana ethyl acetate extracts. Phytochemical analyses from D. communis, D. montana var. montana and D. brevifolia yielded 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin); long chain aliphatic hydrocarbons were isolated from D. communis and from D. villosa var. villosa, a mixture of long chain aliphatic alcohols and carboxylic acids, was isolated from D. communis and 3b-O-acetylaleuritolic acid from D. villosa var. villosa. PMID:15654434

Ferreira, Dalva Trevisan; Andrei, César Cornélio; Saridakis, Halha Ostrensky; Faria, Terezinha de Jesus; Vinhato, Elisângela; Carvalho, Kátia Eliane; Daniel, Juliana Feijó Souza; Machado, Sílvio Luiz; Saridakis, Dennis Panayotis; Braz-Filho, Raimundo



Comparison of the antiinflammatory effects of Drosera rotundifolia and Drosera madagascariensis in the HET-CAM assay.  


The antiinflammatory effects of ethanol and aqueous extracts from Drosera rotundifolia and from Drosera madagascariensis were compared in vivo in the HET-CAM assay. Both extracts from D. rotundifolia and the ethanol extract from D. madagascariensis showed remarkable efficacy at doses of 500 microg/pellet. The inhibition of the inflammation by the extracts was stronger than that by 50 microg hydrocortisone/pellet. In contrast, there was only a very weak effect observed at a dose of 500 microg/pellet of the water extract from D. madagascariensis. The chemical analyses of the extracts showed that the effect cannot be attributed to naphthoquinones, but might be due to flavonoids. Ellagic acid obviously plays an important role in the antiangiogenic effect of the Drosera extracts. PMID:16041727

Paper, Dietrich H; Karall, Elisabeth; Kremser, Michaela; Krenn, Liselotte



Anti-inflammatory and spasmolytic activity of extracts from Droserae herba.  


An ethanolic extract of Drosera madagascariensis inhibited human neutrophil elastase with an IC50 of 9.4 microg/ml. The naphthoquinones present in the extract were not responsible for this effect, but flavonoids like quercetin (IC50 0.8 microg/ml), hyperoside (IC50 0.15 microg/ml) and isoquercitrin (IC50 0.7 microg/ml) contributed to inhibition of the enzyme. In guinea-pig ileum the extract (0.5-1 mg/ml) induced a spasmolytic effect via affecting cholinergic M3 receptors and histamine H1 receptors, respectively. At contractile prostanoid receptors of guinea-pig trachea the Drosera extract was not effective. PMID:11417917

Melzig, M F; Pertz, H H; Krenn, L



In vitro antispasmodic and anti-inflammatory effects of Drosera rotundifolia.  


In investigations of the anti-inflammatory and spasmolytic effects of Drosera rotundifolia two extracts were tested in different in vitro assays. An aqueous and an ethanolic extract inhibited human neutrophil elastase, achieving IC50 values of 5 and 1 microg/mL, respectively. The very low naphthoquinone concentrations in the extracts seem not to be responsible for the effect, as the pure compounds were not effective in the test system used. Thus, flavonoids like hyperoside, quercetin and isoquercitrin, which were detected in the extracts in considerable concentrations, may contribute to the activity. These substances showed activity in the assay. Ellagic acid, detected especially in the ethanolic extract in higher amounts, was substantially less active than the flavonoids. In guinea-pig ileum the extracts led to an antispasmodic effect possibly by affecting an allosteric binding site of the muscarinic M3 receptors. PMID:15344845

Krenn, Liselotte; Beyer, Gabriele; Pertz, Heinz H; Karall, Elisabeth; Kremser, Michaela; Galambosi, Bertalan; Melzig, Matthias F



Modulation of intracellular iron levels by oxidative stress implicates a novel role for iron in signal transduction  

PubMed Central

Reactive oxygen species (ROS) display cytotoxicity that can be exacerbated by iron. Paradoxically, HeLa cells treated with the ROS-generators menadione and 2,3-dimethoxy-1,4-naphthoquinone display increased free labile iron. HeLa cells exposed to ROS undergo apoptosis but iron chelation limits the extent of cell death suggesting the rise in intracellular iron plays a signaling role in this pathway. This idea is supported by the fact that iron chelation also alters the pattern of ROS-induced phosphorylation of stress-activated protein kinases SAPK/JNK and p38 MAPK. Thus, ROS-induced increases in cellular free iron contribute to signaling events triggered during oxidative stress response.

Deb, Suman; Johnson, Erin E.; Robalinho-Teixeira, Raquel L.



Screening and determination of potential xanthine oxidase inhibitors from Radix Salviae Miltiorrhizae using ultrafiltration liquid chromatography-mass spectrometry.  


Xanthine oxidase (XOD) inhibitors play an important role in the treatment of gout and many other diseases related to the superoxide anion metabolism. In this study, an ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) method was developed for the screening and identification of potential XOD inhibitors from Radix Salviae Miltiorrhizae extract. Eleven lipophilic diterpenoid quinines were identified as XOD inhibitors from the extract. The relationship between the structure and activity of the detected compounds was estimated on the basis of the UF-LC-MS data. The results demonstrate that the 1,2-naphthoquinone group is necessary for the XOD inhibitory activity of the compounds, and that furan and hydroxyl on the alicyclic ring could enhance the activity of the compounds at different levels. These results may explain and support the medical use of the extract of Radix S. Miltiorrhizae for the prevention and treatment of hyperuricemia and gout. PMID:23466446

Liu, Yang; Liu, Shu; Liu, Zhiqiang



Solubilities of p-quinone and 9,10-anthraquinone in supercritical carbon dioxide  

SciTech Connect

Equilibrium solubilities of p-quinone (1,4-benzoquinone) and 9,10-anthraquinone at 35 C and 45 C in supercritical carbon dioxide over a pressure range of about (85--300) bar have been measured using a supercritical fluid extractor coupled with a high-pressure liquid chromatography apparatus. The solubility results, along with those reported in the literature for 1,4-naphthoquinone, are correlated with a modified Peng-Robinson equation of state. The ability of a supercritical fluid to separate a multicomponent mixture is unique, since it utilizes the salient features of both distillation and liquid extraction. The solubility of a solute in a supercritical fluid is the most important thermophysical property that has to be determined and modeled for an efficient design of any extraction based on supercritical solvents.

Coutsikos, P.; Magoulas, K.; Tassios, D. [National Technical Univ. of Athens (Greece)



Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study.  


Electron microscopy has proven to be a reliable and essential tool to determine morphological alterations and target organelles in the investigation of new drugs for Chagas disease. In this review, we focused on evaluating different agents that induce death of Trypanosoma cruzi, i.e. lysophospholipids analogues, naphthoquinones and derivatives, cytoskeletal inhibitors and natural products. Apoptosis-like presents as morphological characteristics DNA fragmentation, membrane blebbing and apoptotic body formation. Autophagy involves autophagosome formation, with the appearance of membranes surrounding organelles and cytosolic structures. Necrosis causes the loss of osmotic balance, an increase of cytoplasmic vacuolization and plasma membrane disruption. Mitochondrion appears as a central checkpoint in both apoptosis and necrosis. Our evidences of ultrastructural changes to T. cruzi treated with the different classes of compounds point to dramatic mitochondrial alterations and similar autophagic phenotypes. Lysophospholipid analogues interfere in the lipid biosynthesis in epimastigotes, altering the amount of both phospholipids and sterols, and consequently the physical properties of the membrane. Naphthoquinone derivatives led to a strong DNA fragmentation in trypomastigotes and to the release of cysteine proteases from reservosomes to cytosol in epimastigotes, starting a proteolytic process which results in parasite death. The susceptibility of reservosomes was also observed in parasites treated with propolis, suggesting impairment of lipid metabolism, compromising membrane fluidity and leading to lysis. The cytoskeletal agents blocked mitosis of epimastigotes, arresting cell cycle and impairing the parasite proliferation. The variety of drug stimuli converge to the same pathway of death suggests an intense cross-talking between the three types of PCD in the protozoa. PMID:18849169

Menna-Barreto, Rubem F S; Salomão, Kelly; Dantas, Andréia P; Santa-Rita, Ricardo M; Soares, Maurilio J; Barbosa, Helene S; de Castro, Solange L



Profiling the NIH Small Molecule Repository for Compounds That Generate H2O2 by Redox Cycling in Reducing Environments  

PubMed Central

We have screened the Library of Pharmacologically Active Compounds (LOPAC) and the National Institutes of Health (NIH) Small Molecule Repository (SMR) libraries in a horseradish peroxidase–phenol red (HRP-PR) H2O2 detection assay to identify redox cycling compounds (RCCs) capable of generating H2O2 in buffers containing dithiothreitol (DTT). Two RCCs were identified in the LOPAC set, the ortho-naphthoquinone ?-lapachone and the para-naphthoquinone NSC 95397. Thirty-seven (0.02%) concentration-dependent RCCs were identified from 195,826 compounds in the NIH SMR library; 3 singleton structures, 9 ortho-quinones, 2 para-quinones, 4 pyrimidotriazinediones, 15 arylsulfonamides, 2 nitrothiophene-2-carboxylates, and 2 tolyl hydrazides. Sixty percent of the ortho-quinones and 80% of the pyrimidotriazinediones in the library were confirmed as RCCs. In contrast, only 3.9% of the para-quinones were confirmed as RCCs. Fifteen of the 251 arylsulfonamides in the library were confirmed as RCCs, and since we screened 17,868 compounds with a sulfonamide functional group we conclude that the redox cycling activity of the arylsulfonamide RCCs is due to peripheral reactive enone, aromatic, or heterocyclic functions. Cross-target queries of the University of Pittsburgh Drug Discovery Institute (UPDDI) and PubChem databases revealed that the RCCs exhibited promiscuous bioactivity profiles and have populated both screening databases with significantly higher numbers of active flags than non-RCCs. RCCs were promiscuously active against protein targets known to be susceptible to oxidation, but were also active in cell growth inhibition assays, and against other targets thought to be insensitive to oxidation. Profiling compound libraries or the hits from screening campaigns in the HRP-PR H2O2 detection assay significantly reduce the timelines and resources required to identify and eliminate promiscuous nuisance RCCs from the candidates for lead optimization.



Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity (Review).  


Vitamin Ks (VKs) are fat-soluble quinone compounds known to have various bioactivities. This review describes the inflammatory effects of VKs and their related quinone derivatives based on DNA polymerase (pol) inhibition. VK3, but not VK1 or VK2 (=MK-4), inhibited the activity of human pol ?, which is the DNA replicative pol in mitochondria. Of the intermediate compounds between VK2 and VK3 (namely MK-3, MK-2 and MK-1), MK-2 was the strongest inhibitor of mammalian pols ?, ? and ?, which belong to the B-, Y- and X-families of pols, respectively. Among the VK3 based quinone derivatives, such as 1,4-naphthoquinone (NQ), 2-dimethyl-1,4-naphthoquinone (1,2-dimethyl-NQ), 1,4-benzoquinone (BQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ), NQ was the strongest inhibitor of mammalian pols ? and ?, in particular, DNA repair-related pol ?. Among the all compounds tested, NQ displayed the strongest suppression of tumor necrosis factor (TNF)-? production induced by lipopolysaccharide (LPS) in a cell culture system using RAW264.7 mouse macrophages. NQ also suppressed the expression of pol ? protein in these cells, after LPS-treated RAW264.7 cells were stimulated to induce pol ? expression. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of NQ into mice suppressed TNF-? production in peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), NQ markedly suppressed DSS-evoked colitis. The promising anti-inflammatory candidates based on the inhibition of DNA repair-related pols, such as pol ?, by VKs quinone derivatives, such as NQ, are discussed. PMID:23338798

Mizushina, Yoshiyuki; Nishiumi, Shin; Nishida, Masayuki; Yoshida, Hiromi; Azuma, Takeshi; Yoshida, Masaru



Environmental fate and toxicology of carbaryl.  


Carbaryl is an agricultural and garden insecticide that controls a broad spectrum of insects. Although moderately water soluble, it neither vaporizes nor volatilizes readily. However, upon spray application the insecticide is susceptible to drift. It is unstable under alkaline conditions, thus easily hydrolyzed. Carbaryl has been detected in water at ppb concentrations but degradation is relatively rapid, with 1-naphthol identified as the major degradation product. Indirect and direct photolysis of carbaryl produces different naphthoquinones as well as some hydroxyl substituted naphthoquinones. Sorption of the insecticide to soil is kinetically rapid. However, although both the mineral and organic fractions contribute, because of its moderate water solubility it is only minimally sorbed. Also, sorption to soil minerals strongly depends on the presence of specific exchangeable cations and increases with organic matter aromaticity and age. Soil microbes (bacteria and fungi) are capable of degrading carbaryl; the process is more rapid in anoxic than aerobic systems and with increased temperature and moisture. Carbaryl presents a significant problem to pregnant dogs and their offspring, but some have questioned the applicability of these data to humans. In addition, for toxicokinetic and/or physiological reasons, it has been argued that dogs are more sensitive than humans to carbaryl-induced reproductive or developmental toxicity. However, these arguments are based on either older pharmacokinetic studies or on speculation about possible reproductive differences between dogs on the one hand and rats and humans on the other. In view of the wider evidence from both human epidemiological and laboratory animal studies, the question of the possible developmental and reproductive toxicity of carbaryl should be considered open and requiring further study. PMID:19025094

Gunasekara, Amrith S; Rubin, Andrew L; Goh, Kean S; Spurlock, Frank C; Tjeerdema, Ronald S



Peroxidase-catalyzed oxidation of azo dyes: mechanism of disperse Yellow 3 degradation.  


Disperse Yellow 3 [2-(4'-acetamidophenylazo)-4-methylphenol] (DY3) (I) is an important yellow dye used in industry and is also a carcinogen. Earlier we demonstrated that lignin-degrading cultures of white-rot basidiomycete Phanerochaete chrysosporium degrade DY3 to CO2. In this report, we have examined the degradation of DY3 and its naphthol analog, 1-(4'-acetamidophenylazo)-2-naphthol (NDY3) (II) by lignin peroxidase, horseradish peroxidase, and Mn(III)-malonate complex (a manganese peroxidase mimic). Lignin and manganese peroxidases are two extracellular peroxidase produced by ligninolytic cultures of P. chrysosporium and are involved in the degradation of lignin and various other environmental pollutants by this fungus. DY3 oxidation by peroxidases yields 4-methyl-1,2-benzoquinone (III), acetanilide (IV), and a dimer of DY3 (V) as products. NDY3 oxidation yields acetanilide (IV) and 1,2-naphthoquinone (VI). In deuterium incorporation experiments with DY3, 55-67% incorporation of deuterium from dioxane-d8 into acetanilide (IV) is observed. However, when D2O is the donor, deuterium is not incorporated into acetanilide (IV). Based on these results, a mechanism for azo dye degradation is proposed. The H2O2-oxidized forms of a peroxidase oxidize the phenolic ring of DY3, or its analogs, by two electrons to produce a carbonium ion, which is located on the carbon bearing the azo linkage. Water attacks the carbonium ion, producing an unstable intermediate which breaks down to generate 1,2-naphthoquinone (VI) or 4-methyl-1,2-benzoquinone (III) and 4-acetamido-phenyldiazene. O2, H2O2-oxidized peroxidase, or a metal ion, oxidize the phenyldiazene by one electron to produce a phenyldiazene radical, which cleaves homolytically to generate 4-acetamidophenyl radical and molecular nitrogen. The 4-acetamidophenyl radical then abstracts a hydrogen radical from the surroundings to produce acetanilide (IV). DY3 degradation by whole cultures of P. chrysosporium yields acetanilide as the major product. This suggests that lignin peroxidase and manganese peroxidase are involved in the in vivo metabolism of DY3 by P. chrysosporium. PMID:8031141

Spadaro, J T; Renganathan, V



In vivo exposure of Dreissena polymorpha mussels to the quinones menadione and lawsone: menadione is more toxic to mussels than lawsone.  


The principal aim of this study was to assess whether the two quinones, menadione (2-methyl-1,4-naphthoquinone) and lawsone (2-hydroxy-1,4-naphthoquinone), elicit differential toxicity in mussels as has been reported for higher organisms. Therefore, the effects of short-term (48 h) and long-term (20 days) exposure of the two quinones at concentrations of 0.56 and 1 mg l(-1) to zebra mussels, Dreissena polymorpha, under laboratory conditions were studied. After the short-term exposure, the specific activities of the two-electron quinone oxidoreductase (DT-diaphorase) and the one-electron catalysing quinone reductases NADPH-cytochrome c reductase and NADH-cytochrome c reductase were determined in the gills and the rest of the soft tissues (soft mussel tissues minus the gills) of both treated and control mussels. At the higher concentrations of menadione and lawsone used, a significant reduction of the activity of NADPH-cytochrome c reductase in the gills and in the rest of the soft mussel tissues (by 33-34% and 31-43%, respectively) was observed. The activities of DT-diaphorase and NADH-cytochrome c reductase were not significantly affected. Interestingly, DT-diaphorase was observed in the gills, an organ requiring protection against antioxidants. Furthermore, a single-cell electrophoretic assay (comet assay) performed with gill cells to assess DNA damage by the quinones did not show any significant difference between the treated and the control organisms. This indicates that the formation of reactive species by the quinone metabolism in vivo in the mussels was possibly suppressed through the concerted action of DT-diaphorase and antioxidant enzymes. The results of in vitro experiments with gill extracts confirmed the protective role of DT-diaphorase. The rate of the two-electron quinone reduction was found to be five times that of the one-electron quinone reduction. The results of the long-term exposure unambiguously demonstrated that in mussels menadione, unlike in higher organisms, is more toxic than lawsone. The lack of detectability of xanthine oxidase in the mussel tissues could explain the comparatively lower toxicity of lawsone in the invertebtrate, lending support to a previous suggestion that xanthine oxidase might be responsible for the mechanism of toxicity of lawsone in higher organisms in vivo. PMID:15052609

Osman, A M; Rotteveel, S; den Besten, P J; van Noort, P C M


Vitamin K3 analogs induce selective tumor cytotoxicity in neuroblastoma.  


We investigated the cytotoxicity of eight vitamin K3 (VK3) analogs against neuroblastoma cell lines (IMR-32, LA-N-1, NB-39, and SK-N-SH) and normal cell lines (human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF)) using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. 2-[(2-Methoxy)ethylthio]-3-methyl-1,4-naphthoquinone (VK3-OCH(3)) showed especially potent cytotoxic activities against neuroblastoma cells compared with normal cells. In a Hoechst 33342 staining experiment, apoptotic morphologies characterized by cell shrinkage, nuclear condensation, and nuclear fragmentation were observed in IMR-32 and LA-N-1 cells after 48 h of treatment with 10(-5) M of VK3-OCH(3). To clarify the molecular mechanisms of apoptosis induced by VK3-OCH(3), we examined the expression of apoptosis related proteins using a Proteome Profiler Array and western blotting. Heme oxygenase (HO)-1 was remarkably increased by VK3-OCH(3) compared with the control (173% in IMR-32 and 170% in LA-N-1 at 24 h). Moreover, caveolin-1 was induced by VK3-OCH(3) at 48 h. In addition, VK3-OCH(3) arrested the cell cycle at the G2/M phase in IMR-32 cells. These results suggest that VK3-OCH(3) exhibited a selective antitumor activity via HO-1-related mechanisms. PMID:22466570

Kitano, Toru; Yoda, Hiroyuki; Tabata, Keiichi; Miura, Motofumi; Toriyama, Masaharu; Motohashi, Shigeyasu; Suzuki, Takashi




PubMed Central

The title mol­ecule, C13H4O2S5, is folded by 47.83?(6)° along the S?S vector of the [1,4]dithiine six-membered ring, with the naphtho­quinone and [1,3]dithiole-2-thione moieties being nearly planar [largest deviations from least-squares planes = 0.028?(2) and 0.016?(1)?Å, respectively]. This boat conformation is close to that observed in the analogous compound [Mendez-Rojas et al. (2001). J. Chem. Crystallogr. 31, 17–28] including a 2-oxo group [folding angle: 42.3?(1)° at 213?(2)?K]. Both compounds are indeed isomorphous, and the small difference in the folding angle probably results from the involvement of the thioxo group of the title compound in inter­molecular S?S contacts [3.5761?(13)?Å]. In the crystal structure, mol­ecules are stacked in the [100] direction, with dithiole rings making ?–? inter­actions. In a stack, alternating short and long separations are observed between the centroids of dithiole rings, 3.5254?(17) and 4.7010?(18)?Å.

Mendez-Rojas, Miguel Angel; Bernes, Sylvain; Perez-Benitez, Aaron; Romero Zarazua, Maria Fernanda; Castellanos-Uribe, Adrian





The title mol-ecule, C(13)H(4)O(2)S(5), is folded by 47.83?(6)° along the S?S vector of the [1,4]dithiine six-membered ring, with the naphtho-quinone and [1,3]dithiole-2-thione moieties being nearly planar [largest deviations from least-squares planes = 0.028?(2) and 0.016?(1)?Å, respectively]. This boat conformation is close to that observed in the analogous compound [Mendez-Rojas et al. (2001). J. Chem. Crystallogr.31, 17-28] including a 2-oxo group [folding angle: 42.3?(1)° at 213?(2)?K]. Both compounds are indeed isomorphous, and the small difference in the folding angle probably results from the involvement of the thioxo group of the title compound in inter-molecular S?S contacts [3.5761?(13)?Å]. In the crystal structure, mol-ecules are stacked in the [100] direction, with dithiole rings making ?-? inter-actions. In a stack, alternating short and long separations are observed between the centroids of dithiole rings, 3.5254?(17) and 4.7010?(18)?Å. PMID:22219881

Méndez-Rojas, Miguel Angel; Bernès, Sylvain; Pérez-Benítez, Aarón; Romero Zarazúa, María Fernanda; Castellanos-Uribe, Adrián



Quantification of para-phenylenediamine and heavy metals in henna dye.  


Henna (Lawsonia inermis, family Lythraceae) is a shrub cultivated in India, Sri Lanka and North Africa and contains the active dye lawsone (2-hydroxy-1,4-naphthoquinone). Henna dye is obtained from the dried leaves, which are powdered and mixed with oil or water and are used to prepare hair and body dyes. Temporary henna tattoos are readily available worldwide, last on the skin for several weeks and offer a self-limited, convenient alternative to a permanent tattoo. The addition of para-phenylenediamine (PPD), which is widely recognised as a sensitizer, increases the risk of allergic contact dermatitis from henna tattoo mixtures, and a number of cases have been reported. We examined 15 henna samples available in Korea for the presence of PPD and heavy metals such as nickel, cobalt, chromium, lead and mercury using high-performance liquid chromatography (HPLC), atomic absorption spectroscopy (AAS), mercury analyser and inductively coupled plasma emission spectroscopy. PPD, nickel and cobalt were detected in 3, 11 and 4 samples, respectively. PMID:16842550

Kang, Ik-Joon; Lee, Mu-Hyoung



Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor-2  

PubMed Central

BACKGROUND AND PURPOSE Angiogenesis-based therapy is an effective anti-tumour strategy and previous reports have shown some beneficial effects of a naturally occurring bioactive compound plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). Here, we sought to determine the biological effects of plumbagin on signalling mechanisms during tumour angiogenesis. EXPERIMENTAL APPROACH The effects of plumbagin were evaluated in various in vitro assays which utilised human umbilical vein endothelial cells (HUVEC) proliferation, migration and tube formation. Plumbagin was also evaluated in vivo using chicken embryo chorioallantoic membrane (CAM) and mouse corneal micropocket models., Human colon carcinoma and prostate cancer xenograft mouse models were used to evaluate the effects of plumbagin on angiogenesis. Immunofluorescence, GST pull-down and Western blotting were employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated Ras signalling pathways. KEY RESULTS Plumbagin not only inhibited endothelial cell proliferation, migration and tube formation but also suppressed chicken chorioallantoic membrane neovascularzation and VEGF-induced mouse corneal angiogenesis. Moreover, plumbagin suppressed tumour angiogenesis and tumour growth in human colon carcinoma and prostate cancer xenograft mouse models. At a molecular level, plumbagin blocked the Ras/Rac/cofilin and Ras/MEK signalling pathways mediated by VEGFR2 in HUVECs. CONCLUSIONS AND IMPLICATIONS Plumbagin inhibited tumour angiogenesis and tumour growth by interference with the VEGFR2-mediated Ras signalling pathway in endothelial cells. Our findings demonstrate a molecular basis for the effects of plumbagin and suggest that this compound might have therapeutic ant-tumour effects.

Lai, Li; Liu, Junchen; Zhai, Dong; Lin, Qingxiang; He, Lijun; Dong, Yanmin; Zhang, Jing; Lu, Binbin; Chen, Yihua; Yi, Zhengfang; Liu, Mingyao



Synthesis, photochemical and photoinduced antibacterial activity studies of meso-Tetra(pyren-1-yl)porphyrin and its Ni, Cu and Zn complexes.  


The synthesis of the meso-tetra(pyren-1-yl)porphyrin (1) was successfully accomplished by means of the pyrrole condensation with pyrene-1-carb-aldehyde in acidic media. Its metallization was carried out in an almost quantitative yield to obtain the corresponding complexes of Ni(II) (2), Cu(II) (3) and Zn (4). Their photophysical properties such as fluorescence quantum yield and energy transfer to oxygen for an efficient generation of singlet oxygen were determined. Their photophysical and photochemical properties were compared with those of other similar porphyrin derivatives such as tetraphenylporphyrin and tetranaphthylporphyrin. Photochemical studies on their effectiveness as photosensitizer were carried out by means of the photoinduced oxidation of aromatic alcohols like Î-naphthol to naphthoquinone. The antibacterial photoactivity assay for compounds 1â4 was testeted against Escherichia coli (ATCC 8739) and its proliferation and viability were measured by chemiluminescence. An efficient inactivation of E. coli was observed. This was more efficient for compounds 2 and 3, following the direct relationship to high generation of singlet oxygen by these compounds. PMID:21179316

Zoltan, Tamara; Vargas, Franklin; Rivas, Carlos; Lãpez, Verãnica; Perez, Jhackelym; Biasutto, Antonio



Cytotoxicity and In Vitro Antileishmanial Activity of Antimony (V), Bismuth (V), and Tin (IV) Complexes of Lapachol  

PubMed Central

Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis often associated with drug resistance. Lapachol [2-hydroxy-3-(3?-methyl-2-butenyl)-1,4-naphthoquinone] displays a wide range of antimicrobial properties against many pathogens. In this study, using the classic microscopic in vitro model, we have analyzed the effects of a series of lapachol and chlorides complexes with antimony (V), bismuth (V), and tin (IV) against L. amazonensis. All seven compounds exhibited antileishmanial activity, but most of the antimony (V) and bismuth (V) complexes were toxic against human HepG2 cells and murine macrophages. The best IC50 values (0.17 ± 0.03 and 0.10 ± 0.11??g/mL) were observed for Tin (IV) complexes (3) [(Lp)(Ph3Sn)] and (6) (Ph3SnCl2), respectively. Their selective indexes (SIs) were 70.65 and 120.35 for HepG2 cells, respectively. However, while analyzing murine macrophages, the SI decreased. Those compounds were moderately toxic for HepG2 cells and toxic for murine macrophages, still underlying the need of chemical modification in this class of compounds.

Rocha, Marcele Neves; Nogueira, Paula Monalisa; Demicheli, Cynthia; de Oliveira, Ludmila Goncalvez; da Silva, Meiriane Mariano; Frezard, Frederic; Melo, Maria Norma; Soares, Rodrigo Pedro



Lateral extension of ? conjugation along the bay regions of bisanthene through a Diels-Alder cycloaddition reaction.  


Diels-Alder cycloaddition reactions at the bay regions of bisanthene (1) with dienophiles such as 1,4-naphthoquinone have been investigated. The products were submitted to nucleophilic addition followed by reductive aromatization reactions to afford the laterally extended bisanthene derivatives 2 and 3. Attempted synthesis of a larger expanded bisanthene 4 revealed an unexpected hydrogenation reaction at the last reductive aromatization step. Unusual Michael addition was observed on quinone 14, which was obtained by Diels-Alder reaction between 1 and 1,4-anthraquinone. Compounds 1-3 exhibited near-infrared (NIR) absorption and emission with high-to-moderate fluorescent quantum yields. Their structures and absorption spectra were studied by density function theory and non-planar twisted structures were calculated for 2 and 3. All compounds showed amphoteric redox behavior with multiple oxidation/reduction waves. Oxidative titration with SbCl(5) gave stable radical cations, and the process was followed by UV/Vis/NIR spectroscopic measurements. Their photostability was measured and correlated to their different geometries and electronic structures. PMID:22083876

Li, Jinling; Jiao, Chongjun; Huang, Kuo-Wei; Wu, Jishan



Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells  

PubMed Central

Chemotherapy is a mainstay of cancer treatment. Due to increased drug resistance and the severe side effects of currently used therapeutics, new candidate compounds are required for improvement of therapy success. Shikonin, a natural naphthoquinone, was used in traditional Chinese medicine for the treatment of different inflammatory diseases and recent studies revealed the anticancer activities of shikonin. We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines. Transcriptome-wide mRNA expression studies showed that shikonin induced genetic pathways regulating cell cycle, mitochondrial function, levels of reactive oxygen species, and cytoskeletal formation. Taking advantage of the inherent fluorescence of shikonin, we analyzed its uptake and distribution in live cells with high spatial and temporal resolution using flow cytometry and confocal microscopy. Shikonin was specifically accumulated in the mitochondria, and this accumulation was associated with a shikonin-dependent deregulation of cellular Ca2+ and ROS levels. This deregulation led to a breakdown of the mitochondrial membrane potential, dysfunction of microtubules, cell-cycle arrest, and ultimately induction of apoptosis. Seeing as both the metabolism and the structure of mitochondria show marked differences between cancer cells and normal cells, shikonin is a promising candidate for the next generation of chemotherapy.

Wiench, Benjamin; Eichhorn, Tolga; Paulsen, Malte; Efferth, Thomas



Discovery and Development of Natural Product-derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach?†  

PubMed Central

Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogs, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analog synthesis, as well as structure-activity relationship and mechanism of action studies. Current clinical trials agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in Phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called “maturation inhibitors”. In addition, an etoposide analog, GL-331, progressed to anticancer Phase II clinical trials, and the curcumin analog JC-9 is in Phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trials candidates will also be discussed.

Lee, Kuo-Hsiung



Mechanistic and structural basis for inhibition of thymidylate synthase ThyX  

PubMed Central

Nature has established two mechanistically and structurally unrelated families of thymidylate synthases that produce de novo thymidylate or dTMP, an essential DNA precursor. Representatives of the alternative flavin-dependent thymidylate synthase family, ThyX, are found in a large number of microbial genomes, but are absent in humans. We have exploited the nucleotide binding pocket of ThyX proteins to identify non-substrate-based tight-binding ThyX inhibitors that inhibited growth of genetically modified Escherichia coli cells dependent on thyX in a manner mimicking a genetic knockout of thymidylate synthase. We also solved the crystal structure of a viral ThyX bound to 2-hydroxy-3-(4-methoxybenzyl)-1,4-naphthoquinone at a resolution of 2.6 Å. This inhibitor was found to bind within the conserved active site of the tetrameric ThyX enzyme, at the interface of two monomers, partially overlapping with the dUMP binding pocket. Our studies provide new chemical tools for investigating the ThyX reaction mechanism and establish a novel mechanistic and structural basis for inhibition of thymidylate synthesis. As essential ThyX proteins are found e.g. in Mycobacterium tuberculosis and Helicobacter pylori, our studies have also potential to pave the way towards the development of new anti-microbial compounds.

Basta, Tamara; Boum, Yap; Briffotaux, Julien; Becker, Hubert F.; Lamarre-Jouenne, Isabelle; Lambry, Jean-Christophe; Skouloubris, Stephane; Liebl, Ursula; Graille, Marc; van Tilbeurgh, Herman; Myllykallio, Hannu



Studies on hydrogenase activity and chlorobenzene respiration in Dehalococcoides sp. strain CBDB1.  


Hydrogen oxidation and electron transport were studied in the chlorobenzene-utilizing anaerobe Dehalococcoides sp. strain CBDB1. While Cu(2+) and Hg(2+) ions irreversibly inhibited hydrogenase activity in intact cells, Ni(2+) ions inhibited reversibly. About 80% of the initial hydrogenase activity was inactivated within 30 s when the cells were exposed to air. In contrast, hydrogenase was active at a redox potential of +10 mV when this redox potential was established anoxically with a redox indicator. Viologen dyes served both as electron acceptor for hydrogenase and electron donor for the dehalogenase. A menaquinone analogue, 2,3-dimethyl 1,4-naphthoquinone, served neither as electron acceptor for the hydrogenase nor as electron donor for the dehalogenase. In addition, the menaquinone antagonist 2-n-heptyl-4-hydroxyquinoline-N-oxide had no effect on dechlorination catalyzed by cell suspensions or isolated membranes with hydrogen as electron donor, lending further support to the notion that menaquinone is not involved in electron transport. The ionophores tetrachlorosalicylanilide and carbonylcyanide m-chlorophenylhydrazone did not inhibit dechlorination by cell suspensions, indicating that strain CBDB1 does not require reverse electron transport. The ATP-synthase inhibitor N,N'-dicyclohexylcarbodiimide inhibited the dechlorination reaction with cell suspensions; however, the latter effect was partially relieved by the addition of tetrachlorosalicylanilide. 1,2,3,4-tetrachlorobenzene strongly inhibited dechlorination of other chlorobenzenes by cell suspensions with hydrogen as electron donor, but it did not interfere with either hydrogenase or dehalogenase activity. PMID:15490122

Jayachandran, Gopalakrishnan; Görisch, Helmut; Adrian, Lorenz



Beneficial Effect of Shikonin on Experimental Colitis Induced by Dextran Sulfate Sodium in Balb/C Mice  

PubMed Central

The naphthoquinone shikonin, a major component of the root of Lithospermum erythrorhizon, now is studied as an anti-inflammatory agent in the treatment of ulcerative colitis (UC). Acute UC was induced in Balb/C mice by oral administration of 5% dextran sodium sulfate (DSS). The disease activity index was evaluated, and a histologic study was carried out. Orally administered shikonin reduces induced UC in a dose-dependent manner, preventing the shortening of the colorectum and decreasing weight loss by 5% while improving the appearance of feces and preventing bloody stools. The disease activity index score was much lower in shikonin-treated mice than in the colitic group, as well as the myeloperoxidase activity. The expression of cyclooxygenase-2 was reduced by 75%, activation of NF-?B was reduced by 44%, and that of pSTAT-3 by 47%, as well as TNF-?, IL-1?, and IL-6 production. Similar results were obtained in primary macrophages culture. This is the first report of shikonin's ability to attenuate acute UC induced by DSS. Shikonin acts by blocking the activation of two major targets: NF-?B and STAT-3, and thus constitutes a promising potential therapeutic agent for the management of the inflammatory bowel disease.

Andujar, Isabel; Rios, Jose Luis; Giner, Rosa Maria; Miguel Cerda, Jose; Recio, Maria del Carmen



Electron shuttling across the interface of CdSe nanoparticles monitored by femtosecond laser spectroscopy  

SciTech Connect

The formation and decay of the optical hole (bleach) for 4 nm CdSe nanoparticles (NPs) with adsorbed electron acceptors (1,4-benzoquinone and 1,2-naphthoquinone) and the rise and decay of the reduced electron acceptors formed after interfacial electron transfer from the CdSe NPs were investigated by femtosecond laser spectroscopy. The ultrashort (200--400 fs) rise times of the bleach at the band-gap energy of the CdSe NP as well as of the acceptor radical anion are found to increase with increasing the excitation energy. This suggests that the electron transfer from the CdSe NP to the quinone electron acceptor occurs after thermalization of the excited hot electrons. The decay times of the transient absorption for the electron acceptor radical anions are found to be comparable to that of the CdSe NP bleach recovery time (3 ps). This suggests that the surface quinones shuttle the electron from the conduction band to the valence band of the excited NP. The authors contrast this behavior with the excited-state dynamics of the recently investigated CdS-MV{sup 2+} system in which the electron acceptor does not shuttle the accepted electron back to the hole in CdS.

Burda, C.; Green, T.C.; Link, S.; El-Sayed, M.A. [Georgia Inst. of Tech., Atlanta, GA (United States). Laser Dynamics Lab.



Identification of novel inhibitors of DNA methylation by screening of a chemical library.  


In order to discover new inhibitors of the DNA methyltransferase 3A/3L complex, we used a medium-throughput nonradioactive screen on a random collection of 1120 small organic compounds. After a primary hit detection against DNA methylation activity of the murine Dnmt3A/3L catalytic complex, we further evaluated the EC50 of the 12 most potent hits as well as their cytotoxicity on DU145 prostate cancer cultured cells. Interestingly, most of the inhibitors showed low micromolar activities and little cytotoxicity. Dichlone, a small halogenated naphthoquinone, classically used as pesticide and fungicide, showed the lowest EC50 at 460 nM. We briefly assessed the selectivity of a subset of our new inhibitors against hDNMT1 and bacterial Dnmts, including M. SssI and EcoDam, and the protein lysine methyltransferase PKMT G9a and the mode of inhibition. Globally, the tested molecules showed a clear preference for the DNA methyltransferases, but poor selectivity among them. Two molecules including Dichlone efficiently reactivated YFP gene expression in a stable HEK293 cell line by promoter demethylation. Their efficacy was comparable to the DNMT inhibitor of reference 5-azacytidine. PMID:23294304

Ceccaldi, Alexandre; Rajavelu, Arumugam; Ragozin, Sergey; Sénamaud-Beaufort, Catherine; Bashtrykov, Pavel; Testa, Noé; Dali-Ali, Hana; Maulay-Bailly, Christine; Amand, Séverine; Guianvarc'h, Dominique; Jeltsch, Albert; Arimondo, Paola B



Effect of nitrogen source on end products of naphthalene degradation  

SciTech Connect

Soil cultures, enrichment cultures, and pure culture isolates produced substantial quantities of salicylic acid from naphthalene in a mineral salts medium containing NH/sub 4/Cl as the nitrogen source. However, when KNO/sub 3/ was substituted for NH/sub 4/Cl, these same cultures failed to accumulate detectable quantities of salicylic acid but did not turn the medium yellow. When an isolate identified as a Pseudomonas species was used, viable cell numbers were much greater in the medium containing KNO/sub 3/ but up to 94% of the naphthalene was utilized in both media. The differences between nitrogen sources could not be accounted for by pH alone since results obtained using buffered media were similar. Growth with NH/sub 4/NO/sub 3/ displayed a pattern similar to that obtained when NH/sub 4/Cl was used. The yellow coloration in the medium containing KNO/sub 3/ was apparently due to more than one compound, none of which were 1,2-naphthoquinone or acidic in nature, as suggested by other investigators. Further attempts to identify the yellow compounds by high-pressure liquid chromatography, infrared analysis, and gas chromatography-mass spectrometry have been unsuccessful thus far.

Aranha, H.G.; Brown, L.R.



Scanning electrochemical microscopy of menadione-glutathione conjugate export from yeast cells  

PubMed Central

The uptake of menadione (2-methyl-1,4-naphthoquinone), which is toxic to yeast cells, and its expulsion as a glutathione complex were studied by scanning electrochemical microscopy. The progression of the in vitro reaction between menadione and glutathione was monitored electrochemically by cyclic voltammetry and correlated with the spectroscopic (UV–visible) behavior. By observing the scanning electrochemical microscope tip current of yeast cells suspended in a menadione-containing solution, the export of the conjugate from the cells with time could be measured. Similar experiments were performed on immobilized yeast cell aggregates stressed by a menadione solution. From the export of the menadione-glutathione conjugate detected at a 1-?m-diameter electrode situated 10 ?m from the cells, a flux of about 30,000 thiodione molecules per second per cell was extracted. Numerical simulations based on an explicit finite difference method further revealed that the observation of a constant efflux of thiodione from the cells suggested the rate was limited by the uptake of menadione and that the efflux through the glutathione-conjugate pump was at least an order of magnitude faster.

Mauzeroll, Janine; Bard, Allen J.



Antifungal and antioxidant activities of the phytomedicine pipsissewa, Chimaphila umbellata.  


Bioassay-guided fractionation of Chimaphila umbellata (L.) W. Bart (Pyrolaceae) ethanol extracts led to the identification of 2,7-dimethyl-1,4-naphthoquinone (chimaphilin) as the principal antifungal component. The structure of chimaphilin was confirmed by 1H and 13C NMR spectroscopy. The antifungal activity of chimaphilin was evaluated using the microdilution method with Saccharomyces cerevisiae (0.05mg/mL) and the dandruff-associated fungi Malassezia globosa (0.39mg/mL) and Malassezia restricta (0.55mg/mL). Pronounced antioxidant activity of C. umbellata crude extract was also identified using the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, suggesting this phytomedicine has an antioxidant function in wound healing. A chemical-genetic profile was completed with chimaphilin using approximately 4700 S. cerevisiae gene deletion mutants. Cellular roles of deleted genes in the most susceptible mutants and secondary assays indicate that the targets for chimaphilin include pathways involved in cell wall biogenesis and transcription. PMID:17950387

Galván, Imelda J; Mir-Rashed, Nadereh; Jessulat, Matthew; Atanya, Monica; Golshani, Ashkan; Durst, Tony; Petit, Philippe; Amiguet, Virginie Treyvaud; Boekhout, Teun; Summerbell, Richard; Cruz, Isabel; Arnason, John T; Smith, Myron L



Cytotoxicity and In Vitro Antileishmanial Activity of Antimony (V), Bismuth (V), and Tin (IV) Complexes of Lapachol.  


Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis often associated with drug resistance. Lapachol [2-hydroxy-3-(3'-methyl-2-butenyl)-1,4-naphthoquinone] displays a wide range of antimicrobial properties against many pathogens. In this study, using the classic microscopic in vitro model, we have analyzed the effects of a series of lapachol and chlorides complexes with antimony (V), bismuth (V), and tin (IV) against L. amazonensis. All seven compounds exhibited antileishmanial activity, but most of the antimony (V) and bismuth (V) complexes were toxic against human HepG2 cells and murine macrophages. The best IC50 values (0.17 ± 0.03 and 0.10 ± 0.11??g/mL) were observed for Tin (IV) complexes (3) [(Lp)(Ph3Sn)] and (6) (Ph3SnCl2), respectively. Their selective indexes (SIs) were 70.65 and 120.35 for HepG2 cells, respectively. However, while analyzing murine macrophages, the SI decreased. Those compounds were moderately toxic for HepG2 cells and toxic for murine macrophages, still underlying the need of chemical modification in this class of compounds. PMID:23781165

Rocha, Marcele Neves; Nogueira, Paula Monalisa; Demicheli, Cynthia; de Oliveira, Ludmila Gonçalvez; da Silva, Meiriane Mariano; Frézard, Frédéric; Melo, Maria Norma; Soares, Rodrigo Pedro



Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1.  


Plasmodium falciparum heat shock protein 70 (PfHsp70-1) is thought to play an essential role in parasite survival and virulence in the human host, making it a potential antimalarial drug target. A malate dehydrogenase based aggregation suppression assay was adapted for the screening of small molecule modulators of Hsp70. A number of small molecules of natural (marine prenylated alkaloids and terrestrial plant naphthoquinones) and related synthetic origin were screened for their effects on the protein aggregation suppression activity of purified recombinant PfHsp70-1. Five compounds (malonganenone A-C, lapachol and bromo-?-lapachona) were found to inhibit the chaperone activity of PfHsp70-1 in a concentration dependent manner, with lapachol preferentially inhibiting PfHsp70-1 compared to another control Hsp70. Using growth inhibition assays on P. falciparum infected erythrocytes, all of the compounds, except for malonganenone B, were found to inhibit parasite growth with IC(50) values in the low micromolar range. Overall, this study has identified two novel classes of small molecule inhibitors of PfHsp70-1, one representing a new class of antiplasmodial compounds (malonganenones). In addition to demonstrating the validity of PfHsp70-1 as a possible drug target, the compounds reported in this study will be potentially useful as molecular probes for fundamental studies on Hsp70 chaperone function. PMID:21426241

Cockburn, Ingrid L; Pesce, Eva-Rachele; Pryzborski, Jude M; Davies-Coleman, Michael T; Clark, Peter G K; Keyzers, Robert A; Stephens, Linda L; Blatch, Gregory L



The anatomy and chemistry of the colour bands of grasstree stems (Xanthorrhoea preissii) used for plant age and fire history determination.  


A new method of ageing and determining the fire history of grasstrees, based on colour bands running along the stem, has been developed. As part of our evaluation of the technique, we examined the structural and chemical basis of the colour differences. Exposed ends of the leaf bases are cream, brown and black, with the inner cortex, especially in the black leaf bases, being darker than the outer cortex. There was no structural difference between the three leaf base types. Tannin concentration increased from cream to brown to black leaf bases, and from the inner to outer cortex, and remained quite stable over many years. Both water-soluble and insoluble pigments contribute to the darkness of the black leaf bases. A hydrophobic naphthoquinone was present in the conducting tissues of the vascular bundles, and related naphthalene-derivatives were present in the surrounding tissues. We conclude that the colour differences between the leaf bases have a chemical basis that can be linked to environmental changes: tannin cells to phenological effects, and naphthalene-derivatives in the vascular core to the passage of fire. PMID:12099535

Colangelo, Wendy I; Lamont, Byron B; Jones, Anthea S; Ward, David J; Bombardieri, Sandro



Synthesis and anti-Trypanosoma cruzi activity of derivatives from nor-lapachones and lapachones.  


New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease. PMID:18378461

da Silva Júnior, Eufrânio N; de Souza, Maria Cecília B V; Fernandes, Michelle C; Menna-Barreto, Rubem F S; Pinto, Maria do Carmo F R; de Assis Lopes, Francisco; de Simone, Carlos Alberto; Andrade, Carlos Kleber Z; Pinto, Antônio V; Ferreira, Vitor F; de Castro, Solange L



Fragmentation studies and electrospray ionization mass spectrometry of lapachol: protonated, deprotonated and cationized species.  


Electrospray ionization mass spectrometric analysis of lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) was accomplished in order to elucidate the gas-phase dissociation reactions of this important biologically active natural product. The occurrence of protonated and cationized species in the positive mode and of deprotonated species in the negative mode was explored by means of collision-induced dissociation (CID) experiments. For the protonated molecule, the H(2)O and C(4)H(8) losses occur by two competitive channels. For the deprotonated molecule, the even-electron rule is not conserved, and the radicalar species are eliminated by formation of distonic anions. The fragmentation mechanism for each ion was suggested on the basis of computational thermochemistry. Atomic charges, relative energies, and frontier orbitals were employed aiming at a better understanding of the gas-phase reactivity of lapachol. Potential energy surfaces for fragmentation reactions were obtained by the B3LYP/6-31+G(d,p) model. PMID:20552691

Vessecchi, Ricardo; Emery, Flavio S; Galembeck, Sérgio E; Lopes, Norberto P



A new type of pterocarpanquinone that affects Toxoplasma gondii tachyzoites in vitro.  


Toxoplasma gondii, the agent of Toxoplasmosis, is an obligate intracellular protozoan able to infect a wide range of vertebrate cells, including nonprofessional and professional phagocytes. Therefore, drugs must have intracellular activities in order to control this parasite. The most common therapy for Toxoplasmosis is the combination of sulfadiazine and pyrimethamine. This treatment is associated with adverse reactions, thus, the development of new drugs is necessary. In previous studies, naphthoquinone derivatives showed anti-cancer activity functioning as agents capable of acting on groups of DNA, preventing cancer cells duplication. These derivatives also display anti-parasitic activity against Plasmodium falciparum and Leishmania amazonensis. The derivative pterocarpanquinone tested in this work resulted from the molecular hybridization between pterocarpans and naphtoquinone that presents anti-tumoral and anti-parasitic activities of lapachol. The aim of this work was to determine if this derivative is able to change T. gondii growth within LLC-MK2 cells. The drug did not arrest host cell growth, but was able to decrease the infection index of T. gondii with an IC(50) of 2.5 ?M. Scanning and transmission electron microscopy analysis showed morphological changes of parasites including membrane damage. The parasite that survived tended to encyst as seen by Dolichos biflorus lectin staining and Bag-1 expression. These results suggest that pterocarpanquinones are drugs potentially important for the killing and encystment of T. gondii. PMID:22177332

Portes, Juliana de Araujo; Netto, Chaquip Daher; da Silva, Alcides José Monteiro; Costa, Paulo Roberto Ribeiro; DaMatta, Renato Augusto; dos Santos, Thiago Alves Teixeira; De Souza, Wanderley; Seabra, Sergio Henrique



Antimalarial activity of phenazines from lapachol, beta-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.  


The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites. PMID:14980653

de Andrade-Neto, Valter F; Goulart, Marília O F; da Silva Filho, Jorge F; da Silva, Matuzalém J; Pinto, Maria do Carmo F R; Pinto, Antônio V; Zalis, Mariano G; Carvalho, Luzia H; Krettli, Antoniana U



Fetal growth in rats treated with lapachol.  


Lapachol is a naphthoquinone well known for its therapeutic potential. Previous studies have shown that lapachol does not interfere with embryonic development during the pre-implantation period. However, when administered during the organogenic period at the same dose level, it induces a high fetal death incidence. To evaluate the effect of lapachol during fetogenesis, 20 pregnant Wistar rats were randomly divided into two groups: vehicle (10 mL of a 50% aqueous ethanol solution/kg body weight) and treated (100 mg of lapachol/kg body weight). Lapachol was administered from the 17th to 20th day of pregnancy. The following variables were analyzed: maternal body weight from 16th to 21st day of pregnancy, food intake from 17th to 21st day of pregnancy, clinical signs of physical discomfort, ovarian weights, implantations, resorptions and mortality indices, fetal and placenta weights, external malformations, and fetal organ weights. Results indicated that lapachol was not toxic to mothers, although it was fetotoxic leading to fetal growth retardation. PMID:12413627

Felício, André Carvalho; Chang, Cláudia Veiga; Brandão, Marcos Antônio; Peters, Vera Maria; Guerra, Martha de Oliveira



Dihydrodiol dehydrogenase and polycyclic aromatic hydrocarbon metabolism  

SciTech Connect

Carcinogenic activation of polycyclic aromatic hydrocarbons by microsomal monoxygenases proceeds through trans-dihydrodiol metabolites to diol-epoxide ultimate carcinogens. This thesis directly investigated the role of dihydrodiol dehydrogenase, a cytosolic NAD(P)-linked oxidoreductase, in the detoxification of polycyclic aromatic trans-dihydrodiols. A wide variety of non-K-region trans-dihydrodiols were synthesized and shown to be substrates for the homogeneous rat liver dehydrogenase, including several potent proximate carcinogens derived from 7,12-dimethylbenz(a)anthracene, 5-methylchrysene, and benzo(a)pyrene. Since microsomal activation of polycyclic aromatic hydrocarbons is highly stereospecific, the stereochemical course of enzymatic trans-dihydrodiol oxidation was monitored using circular dichroism spectropolarimetry. The major product formed from the dehydrogenase-catalyzed oxidation of the trans-1,2-dihydrodiol of naphthalene was characterized using UV, IR, NMR, and mass spectroscopy, and appears to be 4-hydroxy-1,2-naphthoquinone. Mass spectral analysis suggests that an analogous hydroxylated o-quinone is formed as the major product of benzo(a)pyrene-7,8-dihydrodiol oxidation. Enzymatic oxidation of trans-dihydrodiols was shown to be potently inhibited by all of the major classes of the nonsteroidal antiinflammatory drugs. Enhancement of trans-dihydrodiol proximate carcinogen oxidation may protect against possible adverse effects of the aspirin-like drugs, and help maintain the balance between activation and detoxification of polycyclic aromatic hydrocarbons.

Smithgall, T.E.



Colorimetric cell proliferation assay for microorganisms in microtiter plate using water-soluble tetrazolium salts.  


A colorimetric method to assay cell proliferation of microorganisms in 96-well microtiter plates using water-soluble tetrazolium salts and electron mediators was developed. Combinations of 6 kinds of water-soluble tetrazolium salts and 27 kinds of electron mediators that considered the metabolic efficiency of microorganisms and the influence with medium components were investigated. 2-Methyl-1,4-naphthoquinone (NQ) was reduced most effectively by various species of microorganisms, and a combination of WST-8 as a water-soluble tetrazolium salt with 2-methyl-1,4-NQ repressed the increase in background due to medium components. In the presence of 2-methyl-1,4-NQ, WST-8 was reduced by microbial cells to formazan, which exhibited maximum absorbance at 460 nm. The proposed tetrazolium method could be applied to measure proliferations of various microbial cells including 3 kinds of yeast, 9 kinds of Gram-positive bacteria, and 10 kinds of Gram-negative bacteria. Linear relationships between the absorbance and viable microbial cell density were obtained in all microorganisms, suggesting that the absorbance change reflected the microbial cell proliferation. PMID:18586343

Tsukatani, Tadayuki; Suenaga, Hikaru; Higuchi, Tomoko; Akao, Tetsuyuki; Ishiyama, Munetaka; Ezoe, Kimitoshi; Matsumoto, Kiyoshi



Oxygen-Insensitive Nitroreductases NfsA and NfsB of Escherichia coli Function under Anaerobic Conditions as Lawsone-Dependent Azo Reductases  

PubMed Central

Quinones can function as redox mediators in the unspecific anaerobic reduction of azo compounds by various bacterial species. These quinones are enzymatically reduced by the bacteria and the resulting hydroquinones then reduce in a purely chemical redox reaction the azo compounds outside of the cells. Recently, it has been demonstrated that the addition of lawsone (2-hydroxy-1,4-naphthoquinone) to anaerobically incubated cells of Escherichia coli resulted in a pronounced increase in the reduction rates of different sulfonated and polymeric azo compounds. In the present study it was attempted to identify the enzyme system(s) responsible for the reduction of lawsone by E. coli and thus for the lawsone-dependent anaerobic azo reductase activity. An NADH-dependent lawsone reductase activity was found in the cytosolic fraction of the cells. The enzyme was purified by column chromatography and the amino-terminal amino acid sequence of the protein was determined. The sequence obtained was identical to the sequence of an oxygen-insensitive nitroreductase (NfsB) described earlier from this organism. Subsequent biochemical tests with the purified lawsone reductase activity confirmed that the lawsone reductase activity detected was identical with NfsB. In addition it was proven that also a second oxygen-insensitive nitroreductase of E. coli (NfsA) is able to reduce lawsone and thus to function under adequate conditions as quinone-dependent azo reductase.

Rau, Jorg; Stolz, Andreas



Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone.  


Bupravaquone is a new naphthoquinone antibiotic against Cryptosporidium parvum and other parasites. It has attracted interest for the treatment of C. parvum infections, because of the lack of a drug in the treatment of mostly AIDS patients. The bioavailability of bupravaquone is limited when given orally. To overcome the problem of the high elimination rate caused by diarrhoea, typical for C. parvum infections, bupravaquone was formulated as a mucoadhesive nanosuspension, i.e. combining the properties of mucoadhesive drug delivery systems, in this case hydro gels, with nanosuspensions. In this study different polymers/hydro gels were employed to create a prolonged retention time for the drug in the infected gastrointestinal tract (GIT). The second step to improve the bioavailability of bupravaquone was the formulation as nanosuspension. Therefore various concentrations of bupravaquone with different surfactants were tested. The production of these nanosuspensions was carried out by high pressure homogenisation. In addition to the classical stepwise production, about a new one step production method is described. PMID:11282227

Jacobs, C; Kayser, O; Müller, R H



Labeling quinone-binding sites in photosynthetic reaction centers: a 38-kilodalton protein associated with the acceptor side of photosystem II  

SciTech Connect

2-Acetoxymethyl-1,4-naphthoquinone (2-AcOMeNQ) binds with rapid kinetics and high affinity to the primary quinone Q/sub A/ site of reaction centers from Rhodopseudomonas capsulata. Binding of 2-AcOMeNQ fully restores electron-transfer activity with kinetics that is similar, but not identical, to that seen with ubiquinone-50. When bound at the Q/sub A/ site, 2-AcOMeNQ preferentially labels the L subunit. This preference suggests that 2-AcOMeNQ labels primarily the region of a quinone-binding site that is close to the first isoprenoid unit of the side chain, which is expected from the location and structure of the reaction region of the molecule. In photosystem II particles from Synechococcus sp., 2-AcOMeNQ primarily labels two polypeptides with apparent molecular masses of 38 and 19 kDa. Labeling of only the 38-kDa polypeptide is sufficiently sensitive to 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) to conclude that it is involved in binding quinones on the acceptor side of photosystem II. Although the authors have not yet identified the 38-kDa protein, its properties suggest that it is the D2 protein. From the DCMU-sensitive labeling and from homologies to functionally important regions of the bacterial reaction-center subunits, they propose that the 38-kDa protein is intimately involved in binding the cofactors that mediate primary photochemistry.

Worland, S.T.; Yamagishi, A.; Isaacs, S.; Sauer, K.; Hearst, J.E.



A mutant of Escherichia coli fumarate reductase decoupled from electron transport.  

PubMed Central

The terminal electron-transfer enzyme fumarate reductase of Escherichia coli is a complex iron-sulfur flavoenzyme composed of four nonidentical subunits organized into two domains: FrdA and -B (a membrane-extrinsic catalytic domain) and FrdC and -D (a transmembrane anchor domain). We have identified a mutation within the membrane-intrinsic domain that alters the electron transfer properties of the iron-sulfur and flavin redox centers of the catalytic domain. Functional electron flow from the quinone analog 2,3-dimethyl-1,4-naphthoquinone or from the electron transport chain is impaired. However, the mutant enzyme can be reduced normally by single-electron donors such as the dye benzyl viologen. The mutant phenotype results from a single A----G transition changing His-82, within the second transmembrane alpha-helix of the FrdC anchor sequence, to an arginine. The mutation, physically located within the anchor domain, is manifested by altered catalytic properties, indicating that the intrinsic and extrinsic domains are conformationally connected. These results confirm the important role of the anchor subunits in functional electron transport and have implications for communication between intrinsic and extrinsic domains of membrane proteins. Images

Weiner, J H; Cammack, R; Cole, S T; Condon, C; Honore, N; Lemire, B D; Shaw, G



[Paramagnetic calcium melanins].  


Treatment of catechol, pyrogallol, DOPA, dopamine, norepinephrine, and natural polyhydroxy-1,4-naphthoquinone echinochrome by aqueous solution of potassium superoxide (KO2) in the presence of CaCl2 leads to the formation of water-insoluble dark pigments with stable paramagnetic properties ("calcium melanins"). In control experiments in the same procedure without Ca2+, the pigments were not formed. EPR spectra of the calcium melanins had little difference from each other and from known melanins in shape, line width, and the g factor about 2,004. Addition of EDTA water solution to dried paramagnetic pigments leads to their fast dissolving and disappearing of EPR signal. Formation of similar polymers is also observed during autoxidation of o-diphenols in Ca(2+)-containing alkaline buffer solution, however, this process takes a few days instead of few seconds in the presence of KO2. Thus, calcium (and other divalent cation M2+) can consider as a key structural element in formation of M(2+)-catecholate paramagnetic Polymer. We assume the existence of two types of paramagnetic centers in melanin-like polymer: M(2+)-stabilized o-semiquinone radical or bi-radical complex containing o-semiquinone and superoxide anion radicals, stabilized by M2+. PMID:23650854

Lebedev, A V; Ivanova, M V; Timoshin, A A; Ruuge, E K


NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury.  


The gap junction protein connexin43 (Cx43) was markedly increased in podocytes in a rat model of nephrosis induced by puromycin. However, the mechanisms and roles of the altered Cx43 in podocytes are still unclear. Given that oxidative stress mediates podocyte injury under a variety of pathological situations, we examined the possible involvement of an oxidative stress-related mechanism in the regulation of Cx43. Incubation of podocytes with puromycin led to a time- and concentration-dependent loss of cell viability, which was preceded by an elevation in Cx43 levels. Concomitantly, puromycin also induced NOX4 expression and promoted superoxide (O(2)(·-)) generation. Inhibition of NADPH oxidase with apocynin and diphenyleneiodonium chloride or addition of the superoxide dismutase mimetic tempol completely abrogated, whereas the O(2)(·-) donors menadione and 2,3-dimethoxy-1,4-naphthoquinone reproduced, the effects of puromycin on Cx43 expression and cell injury. Further analysis demonstrated that treatment of podocytes with several structurally different gap-junction inhibitors significantly attenuated the cytotoxicity of puromycin. Our results thus indicate that NADPH oxidase-mediated upregulation of Cx43 contributes to podocyte injury. PMID:22824863

Yan, Qiaojing; Gao, Kun; Chi, Yuan; Li, Kai; Zhu, Ying; Wan, Yigang; Sun, Wei; Matsue, Hiroyuki; Kitamura, Masanori; Yao, Jian



Nepenthes insignis uses a C2-portion of the carbon skeleton of L-alanine acquired via its carnivorous organs, to build up the allelochemical plumbagin.  


Tropical pitcher plants (Nepenthes) catch animals in their specialized cup-shaped leaves, digest the prey by secreting enzymes, and actively take up the resulting compounds. The benefit of this behaviour is the ability to grow and compete in nutrient-poor habitats. Our present in vitro study shows that not only the nitrogen of alanine fed to the carnivorous organs is used by the plant but that in addition intact C2-units derived from C-2 and C-3 of stable isotope labelled L-alanine serve as building blocks, here exemplarily for the synthesis of the secondary metabolite plumbagin, a potent allelochemical. This result adds a new facet to the benefit of carnivory for plants. The availability of plumbagin by a de novo synthesis probably enhances the plants' fitness in their defence against phytophagous and pathogenic organisms. A missing specific uptake or CoA activation mechanism might be the reason that acetate fed to the pitchers was not incorporated into the naphthoquinone plumbagin. The dihydronaphthoquinone glucosides rossoliside and plumbaside A, here isolated for the first time from Nepenthes, by contrast, showed no incorporation after feeding of any of the two precursors, suggesting these compounds to be storage forms with probably very low turnover rates. PMID:11867092

Rischer, Heiko; Hamm, Andreas; Bringmann, Gerhard



An overview on chlorophylls and quinones in the photosystem I-type reaction centers.  


Minor but key chlorophylls (Chls) and quinones in photosystem (PS) I-type reaction centers (RCs) are overviewed in regard to their molecular structures. In the PS I-type RCs, the prime-type chlorophylls, namely, bacteriochlorophyll (BChl) a' in green sulfur bacteria, BChl g' in heliobacteria, Chl a' in Chl a-type PS I, and Chl d' in Chl d-type PS I, function as the special pairs, either as homodimers, (BChl a')(2) and (BChl g')(2) in anoxygenic organisms, or heterodimers, Chl a/a' and Chl d/d' in oxygenic photosynthesis. Conversions of BChl g to Chl a and Chl a to Chl d take place spontaneously under mild condition in vitro. The primary electron acceptors, A (0), are Chl a-derivatives even in anoxygenic PS I-type RCs. The secondary electron acceptors are naphthoquinones, whereas the side chains may have been modified after the birth of cyanobacteria, leading to succession from menaquinone to phylloquinone in oxygenic PS I. PMID:20165917

Ohashi, Shunsuke; Iemura, Tatsuya; Okada, Naoki; Itoh, Shingo; Furukawa, Hayato; Okuda, Masaaki; Ohnishi-Kameyama, Mayumi; Ogawa, Takuro; Miyashita, Hideaki; Watanabe, Tadashi; Itoh, Shigeru; Oh-oka, Hirozo; Inoue, Kazuhito; Kobayashi, Masami



Concise synthesis and two-photon-excited deep-blue emission of 1,8-diazapyrenes.  


Efficient violet-blue-emitting molecules are especially useful for applications in full-color displays, solid-state lighting, as well as in two-photon absorption (TPA) excited frequency-upconverted violet-blue lasing. However, the reported violet-blue-emitting molecules generally possess small TPA cross sections. In this work, new 1,8-diazapyrenes derivatives 3 with blue two-photon-excited fluorescence emission were concisely synthesized by the coupling reaction of readily available 1,4-naphthoquinone O,O-diacetyl dioxime (1) with internal alkynes 2 under the [{RhCl(2)Cp*}(2)]-Cu(OAc)(2) (Cp*=pentamethylcyclopentadienyl ligand) bimetallic catalytic system. Elongation of the ?-conjugated length of 1,8-diazapyrenes 3 led to the increase of TPA cross sections without the expense of a redshift of the emission wavelength, probably due to the rigid planar structure of chromophores. It is especially noteworthy that 2,3,6,7-tetra(4-bromophenyl)-1,8-diazapyrene (3c) has a larger TPA cross section than those of other molecules reported so far. These experimental results are explained in terms of the effects of extension of the ?-conjugated system, intramolecular charge transfer, and reduced detuning energy. PMID:22700525

He, Tingchao; Too, Pei Chui; Chen, Rui; Chiba, Shunsuke; Sun, Handong



Studies on Aristolochia III. Isolation and biological evaluation of constituents of Aristolochia indica roots for fertility-regulating activity.  


An ethanol extract of Aristolochia indica roots decreased fertility in both rats and hamsters when administered postcoitally (days 1-10 and 1-6, respectively). Petroleum ether (A), CHCl3 (B), and aqueous (C) fractions, tested similarly in rats, were inactive and/or toxic. Partition of fraction B afforded non-acidic (D) and acidic (E) fractions. Savinin (1), isolated from fraction D and not previously reported from the Aristolochiaceae , was inactive when administered postcoitally to rats. Aristolochic acid-I (2), reported previously from A. indica and isolated from fraction E, was inactive when administered postcoitally to rats and toxic when administered postcoitally to hamsters. (12S)-7,12- Secoishwaran -12-ol (3), previously reported from A. indica and isolated from fraction A, did not interrupt pregnancy when administered to mice on day 6 of pregnancy. Four additional compounds, aristolic acid (4) [prepared from aristolochic acid-I (2)], methyl aristolate (5) [prepared by methylating aristolic acid (4)], and cis- and trans-p-coumaric acid (both oblate commercially), were similarly tested in mice and found to be inactive. Aristolic acid (4), and the cis- and trans-p-coumaric acids also were inactive when administered postcoitally (days 1-10) to rats. Seven compounds reported previously from A. indica were also isolated, as were a new naphthoquinone, aristolindiquinone (6) (fraction E), and magnoflorine (fraction C). PMID:6539809

Che, C T; Ahmed, M S; Kang, S S; Waller, D P; Bingel, A S; Martin, A; Rajamahendran, P; Bunyapraphatsara, N; Lankin, D C; Cordell, G A


A Novel Dark-Inducible Protein, LeDI-2, and Its Involvement in Root-Specific Secondary Metabolism in Lithospermum erythrorhizon1  

PubMed Central

Lithospermum erythrorhizon produces red naphthoquinone pigments that are shikonin derivatives. They are accumulated exclusively in the roots of this plant. The biosynthesis of shikonin is strongly inhibited by light, even though other environmental conditions are optimized. Thus, L. erythrorhizon dark-inducible genes (LeDIs) were isolated to investigate the regulatory mechanism of shikonin biosynthesis. LeDI-2, showing the strict dark-specific expression, was further characterized by use of cell suspension cultures and hairy root cultures as model systems. Its mRNA accumulation showed a similar pattern with that of shikonin. In the intact plants LeDI-2 expression was observed solely in the root, and the longitudinal distribution of its mRNA was also in accordance to that of shikonin. LeDI-2 encoded a very hydrophobic polypeptide of 114 amino acids that shared significant similarities with some root-specific polypeptides such as ZRP3 (maize) and RcC3 (rice). Reduction of LeDI-2 expression by its antisense DNA in hairy roots of L. erythrorhizon decreased the shikonin accumulation, whereas other biosynthetic enzymes, e.g. p-hydroxybenzoic acid:geranyltransferase, which catalyzed a critical biosynthetic step, showed similar activity as the wild-type clone. This is the first report of the gene that is involved in production of secondary metabolites without affecting biosynthetic enzyme activities.

Yazaki, Kazufumi; Matsuoka, Hideaki; Shimomura, Koichiro; Bechthold, Andreas; Sato, Fumihiko



Spectrophotometric and spectrofluorimetric determination of atomoxetine in pharmaceutical preparations.  


Visible spectrophotometric and spectrofluorimetric methods were developed for the determination of atomoxetine in pharmaceutical preparations. The spectrophotometric method was based on a nucleophilic substitution reaction of atomoxetine with 1,2-naphthoquinone-4-sulphonate (NQS) in an alkaline medium to form an orange-colored product. The absorbance-concentration plot is rectilinear over the range 5-40 microg mL(-1). The limits of detection and quantification were calculated to be 0.02 microg mL(-1) and 0.06 microg mL(-1), respectively. The spectrofluorimetric method was based on the derivatization reaction of 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) with atomoxetine to produce a fluorescent derivative. The formed highly fluorescent derivative that was measured at 462 nm after excitation at 533 nm. The fluorescence-concentration plot is rectilinear over the range 10-500 ng mL(-1). The limits of detection and quantification were calculated to be 0.19 ng mL(-1) and 0.57 ng mL(-1). The analytical performance of both methods was fully validated, and the results were satisfactory. The methods have been successfully applied for the determination of the studied drug in capsules and the results obtained ware in good agreement with those obtained by the reference method. PMID:22204127

Ulu, S T



Determination of streptomycin residue in cucumber and Chinese cabbage by high-performance liquid chromatography with postcolumn derivatization and fluorometric detection.  


A sensitive and accurate method was developed for the determination of streptomycin using HPLC followed by postcolumn derivatization and fluorometric detection. The analyte was extracted, using aqueous solution from cucumber and Chinese cabbage, by a two-step SPE procedure. The extraction, cleanup, and chromatography conditions were optimized, and the performance of the analysis method was evaluated. The conditions of chromatography were as follows: the separation was performed on a C18 column; the isocratic mobile phase consisted of acetonitrile and a mixed solution containing 10 mM sodium 1,2-naphthoquinone-4-sulfonate and 0.4 mM sodium 1-heptanesulfonate (25+75, v/v); and the flow rate was 1 mL/min. The fluorescence detector was set at an excitation wavelength of 263 nm and an emission wavelength of 435 nm. The calibration curve was linear over the range of 50-2000 ng/mL, with a correlation coefficient of 0.9995. The LOD and LOQ were 10 and 30 ng/g, respectively, in both cucumber and Chinese cabbage. The method was validated for selectivity, linearity, precision, and accuracy. The intraday and interday precision and accuracy were within 10%. The mean recoveries from spiked samples were more than 75%, with RSD lower than 10%. PMID:22649941

Chen, Benjing; Zhang, Hongyan; Lin, Baoxiang; Ge, Jing; Qiu, Lihong


Decontamination of chemical-warfare agent simulants by polymer surfaces doped with the singlet oxygen generator zinc octaphenoxyphthalocyanine.  


Using reactive singlet oxygen ((1)O2), the oxidation of chemical-warfare agent (CWA) simulants has been demonstrated. The zinc octaphenoxyphthalocyanine (ZnOPPc) complex was demonstrated to be an efficient photosensitizer for converting molecular oxygen (O2) to (1)O2 using broad-spectrum light (450-800 nm) from a 250 W halogen lamp. This photosensitization produces (1)O2 in solution as well as within polymer matrices. The oxidation of 1-naphthol to naphthoquinone was used to monitor the rate of (1)O2 generation in the commercially available polymer film Hydrothane that incorporates ZnOPPc. Using electrospinning, nanofibers of ZnOPPc in Hydrothane and polycarbonate were formed and analyzed for their ability to oxidize demeton-S, a CWA simulant, on the surface of the polymers and were found to have similar reactivity as their corresponding films. The Hydrothane films were then used to oxidize CWA simulants malathion, 2-chloroethyl phenyl sulfide (CEPS), and 2-chloroethyl ethyl sulfide (CEES). Through this oxidation process, the CWA simulants are converted into less toxic compounds, thus decontaminating the surface using only O2 from the air and light. PMID:24060426

Gephart, Raymond T; Coneski, Peter N; Wynne, James H



Phytochemistry of the carnivorous sundew genus drosera (droseraceae) - future perspectives and ethnopharmacological relevance.  


Species of the carnivorous genus Drosera L. have long been a source of valuable natural products. The various phytochemicals characteristic of these species, particularly 1,4-naphthoquinones and flavonoids, have contributed to the diverse utilization of sundews in traditional medicine systems worldwide. A growing number of studies have sought to investigate the comparative phytochemistry of Drosera species for improved sources of pharmaceutically important compounds. The outcomes of these studies are here collated, with emergent trends discussed in detail. Important factors which affect production of secondary metabolites in plants are critically examined, such as environmental influences and in vitro culture, and recommendations subsequently presented based on this. Explicitly, the current review aims to i) present an updated, comprehensive listing of the phytochemical constituents of the genus (including quantitative data where available), ii) summarize important factors which may influence the production of phytopharmaceuticals in plants, and iii) recommend guidelines for future research based on the above, including improved standardization and quality control. We have also included a section discussing future perspectives of research on Drosera spp. based on three different research lines i) the potential to produce much needed lead compounds for treatment of tuberculosis, ii) the potential role of anthocyanins in nitrogen transport, and iii) research into 'Natural Deep Eutectic' solvents produced by Drosera spp. in the droplets or 'dew' employed to capture insect prey. PMID:24130022

Egan, Paul A; van der Kooy, Frank



Main constituents of a commercial Drosera fluid extract and their antagonist activity at muscarinic M3 receptors in guinea-pig ileum.  


The range of known constituents of Drosera species is extended by identification of myricetin 3-O-galactoside, from D. madagascariensis, and (+)-cis-isoshinanolone, obtained from a commercial fluid extract. They are accompanied by the naphthoquinones droserone and plumbagin, typical of this taxon, and a series of ubiquitous flavonols, including the rarely found gossypitrin present in the latter source. Conspicuously, the commercial form of D. peltata, non-accepted by the commission E, was found to be devoid of flavonoids. In addition, the fortuitous availability of the authentic enigmatic sample 'CON', previously isolated from D. rotundifolia, led to its characterization as common quercetin. Experiments performed on isolated guinea-pig ileum demonstrated that quercetin respectively 'CON' moderately inhibited carbachol-induced contractions at 10 microM (pD'2 5.09 +/- 0.02), while (+)-cis-isoshinanolone (100 microM) was inactive. This result indicates that quercetin derivatives may well contribute to the therapeutic use of Drosera preparations. PMID:11933852

Kolodziej, H; Pertz, H H; Humke, A



Induction of apoptosis in HL-60 cells through the ROS-mediated mitochondrial pathway by ramentaceone from Drosera aliciae.  


Ramentaceone (1) is a naphthoquinone constituent of Drosera aliciae that exhibits potent cytotoxic activity against various tumor cell lines. However, its molecular mechanism of cell death induction has still not been determined. The present study demonstrates that 1 induces apoptosis in human leukemia HL-60 cells. Typical morphological and biochemical features of apoptosis were observed in 1-treated cells. Compound 1 induced a concentration-dependent increase in the sub-G1 fraction of the cell cycle. A decrease in the mitochondrial transmembrane potential (??m) was also observed. Furthermore, 1 reduced the ratio of anti-apoptotic Bcl-2 to pro-apoptotic Bax and Bak, induced cytochrome c release, and increased the activity of caspase 3. The generation of reactive oxygen species (ROS) was detected in 1-treated HL-60 cells, which was attenuated by the pretreatment of cells with a free radical scavenger, N-acetylcysteine (NAC). NAC also prevented the increase of the sub-G1 fraction induced by 1. These results indicate that ramentaceone induces cell death through the ROS-mediated mitochondrial pathway. PMID:22250825

Kawiak, Anna; Zawacka-Pankau, Joanna; Wasilewska, Aleksandra; Stasilojc, Grzegorz; Bigda, Jacek; Lojkowska, Ewa



Interaction of Keap1 Modified by 2-tert-Butyl-1,4-benzoquinone with GSH: Evidence for S-Transarylation.  


2-tert-Butyl-1,4-benzoquinone (TBQ), an electrophilic metabolite of butylated hydroxyanisole (BHA), causes activation of Nrf2 together with S-arylation of its negative regulator Keap1 in RAW264.7 cells. In a previous study, we found that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) covalently modified with 1,2-naphthoquinone (1,2-NQ) undergoes S-transarylation by GSH, resulting in a decline of the GAPDH-1,2-NQ adduct and formation of a 1,2-NQ-SG adduct ( Miura , T. et al. ( 2011 ) Chem. Res. Toxicol. 24 , 1836 -1844 ). In the present study, we explored the possibility of GSH-dependent S-transarylation of the Keap1-TBQ adduct. Pretreatment with l-buthionine-(S,R)-sulfoximine and N-acetylcysteine prior to TBQ exposure of HepG2 cells suggested that the Keap1-TBQ adduct appears to undergo GSH-mediated S-transarylation because the resulting alterations in the intracellular GSH concentration affected Nrf2 activation caused by TBQ. In support of this hypothesis, a cell-free study demonstrated that incubation of the Keap1-TBQ adduct with GSH results in the removal of TBQ from Keap1 with the production of mono- and di-GSH adducts of TB(H)Q. These results suggest that GSH plays a role in reversible covalent modification of TBQ derived from BHA to Keap1 through the formation of a C-S bond. PMID:23718696

Abiko, Yumi; Kumagai, Yoshito



Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC-UV and HPTLC.  


This paper presents a comparative study of anatomy of leaves, stems and roots of three species of Plumbago, namely P. auriculata Lam., P. indica L. and P. zeylanica L. by light microscopy. The paper also provides qualitative and quantitative analysis of the naphthoquinone, plumbagin-a major constituent present in these species-using UPLC-UV. Microscopic examinations revealed the presence of distinctive differences in the anatomical features of the leaf, stem and root of the three species, and these can thus be used for identification and authentication of these species. UPLC-UV analysis showed the highest concentration of plumbagin in the roots of P. zeylanica (1.62% w/w) followed by the roots of P. indica (0.97% w/w) and then P. auriculata (0.33-0.53% w/w). In contrast, plumbagin was not detected in the stems and leaves of P. indica and in the leaves of P. auriculata, whereas very low concentrations (<0.02% w/w) of plumbagin were detected in the stems and leaves of P. zeylanica and in the stems of P. auriculata. HPTLC fingerprints of the leaf and root of the three species exhibited distinguishable profiles, while those of the stems were undifferentiated. PMID:23151906

Galal, Ahmed M; Raman, Vijayasankar; Avula, Bharathi; Wang, Yan-Hong; Rumalla, Chidananda Swamy; Weerasooriya, Aruna Dharmapriya; Khan, Ikhlas A



In photosynthetic reaction centers, the free energy difference for electron transfer between quinones bound at the primary and secondary quinone-binding sites governs the observed secondary site specificity.  

PubMed Central

The secondary quinone-binding site (QB site) of bacterial reaction centers from Rhodobacter sphaeroides is generally regarded to be highly specific for its native ubiquinone-10 molecule. We demonstrate here that this is a misconception rooted in the kinetic methods used to assay for occupancy of a quinone in the QB site. We show that observance of occupancy of the QB site, revealed by kinetic assay, is sensitive to the free-energy difference for electron transfer between the quinone at the primary quinone-binding site (QA site) and the QB site (-delta G0e-). For many of the compounds previously tested for binding at the QB site, the -delta G0e- between QA and QB is too small to permit detection of the functional quinone in the QB site. With an increased -delta G0e- achieved by replacing the native ubiquinone-10 at the QA site with lower-potential quinones or by testing higher-potential QB candidates, it is shown that the QB site binds and functions with the unsubstituted 1,4-benzoquinone, 1,4-naphthoquinone, and 9,10-phenanthraquinone, as well as with their various substituted forms. Moreover, quinones with the ortho-carbonyl configuration appear to function in a similar manner to quinones with the para-carbonyl configuration.

Giangiacomo, K M; Dutton, P L



A Quantitative High-Throughput In Vitro Splicing Assay Identifies Inhibitors of Spliceosome Catalysis  

PubMed Central

Despite intensive research, there are very few reagents with which to modulate and dissect the mRNA splicing pathway. Here, we describe a novel approach to identify such tools, based on detection of the exon junction complex (EJC), a unique molecular signature that splicing leaves on mRNAs. We developed a high-throughput, splicing-dependent EJC immunoprecipitation (EJIPT) assay to quantitate mRNAs spliced from biotin-tagged pre-mRNAs in cell extracts, using antibodies to EJC components Y14 and eukaryotic translation initiation factor 4aIII (eIF4AIII). Deploying EJIPT we performed high-throughput screening (HTS) in conjunction with secondary assays to identify splicing inhibitors. We describe the identification of 1,4-naphthoquinones and 1,4-heterocyclic quinones with known anticancer activity as potent and selective splicing inhibitors. Interestingly, and unlike previously described small molecules, most of which target early steps, our inhibitors represented by the benzothiazole-4,7-dione, BN82685, block the second of two trans-esterification reactions in splicing, preventing the release of intron lariat and ligation of exons. We show that BN82685 inhibits activated spliceosomes' elaborate structural rearrangements that are required for second-step catalysis, allowing definition of spliceosomes stalled in midcatalysis. EJIPT provides a platform for characterization and discovery of splicing and EJC modulators.

Berg, Michael G.; Wan, Lili; Younis, Ihab; Diem, Michael D.; Soo, Michael; Wang, Congli



Screening of Potential anti-Trypanosoma cruzi Candidates: In Vitro and In Vivo Studies  

PubMed Central

Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major “neglected” diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives.

Soeiro, Maria de Nazare C; de Castro, Solange Lisboa



Screening of Potential anti-Trypanosoma cruzi Candidates: In Vitro and In Vivo Studies.  


Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major "neglected" diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives. PMID:21629508

Soeiro, Maria de Nazaré C; de Castro, Solange Lisboa



Vitamin K3 (menadione) and related quinones, like tumor-promoting phorbol esters, alter the affinity of epidermal growth factor for its membrane receptors.  


The effects of vitamin K3, quinones, fat-soluble vitamins, and various naturally occurring and synthetic compounds on the binding of 125I-epidermal growth factor (EGF) to mink lung cells or murine 3T3 cells in culture were studied. Vitamin K3, but not other fat-soluble vitamins, markeldy inhibits the binding of 125I-labeled EGF to treated cells, but does not affect the binding of insulin, concanavalin A, alpha-2-macroglobulin, and murine leukemia virus glycoprotein, gp70, to their membrane receptors. The binding of multiplication stimulating activity to treated cells is also reduced to some extent. Vitamin K3 alters the affinity of the receptors for EGF without changing the total number of available receptors per cell. Vitamin K3 modulation of EGF-receptor interaction is a temperature- and time-dependent phenomenon. EGF-receptor interaction is also significantly modulated by 1,4-naphthoquinone, 1,4-benzoquinone, and phenanthrenequinone but not by other quinones of anthracyclic antibiotics. PMID:6251065

Shoyab, M; Todaro, G J



Application of cyclic biamperometry to viability and cytotoxicity assessment in human corneal epithelial cells.  


The application of cyclic biamperometry to viability and cytotoxicity assessments of human corneal epithelial cells has been investigated. Electrochemical measurements have been compared in PBS containing 5.0 mM glucose and minimal essential growth medium. Three different lipophilic mediators including dichlorophenol indophenol, 2-methyl-1,4-naphthoquinone (also called menadione or vitamin K3) and N,N,N',N'-tetramethyl-p-phenylenediamine have been evaluated for shuttling electrons across the cell membrane to the external medium. Transfer of these electrons to ferricyanide in the extra cellular medium results in the accumulation of ferrocyanide. The amount of ferrocyanide is then determined using cyclic biamperometry and is related to the extent of cell metabolic activity and therefore cell viability. To illustrate cytotoxicity assessment of chemicals, hydrogen peroxide, benzalkonium chloride and sodium dodecyl sulfate have been chosen as sample toxins, the cytotoxicities of which have been evaluated and compared to values reported in the literature. Similar values have been reported using colorimetric assays; however, the simplicity of this electrochemical assay can, in principle, open the way to miniaturization onto lab-on-chip devices and its incorporation into tiered-testing approaches for cytotoxicity assessment. PMID:23443523

Rahimi, Mehdi; Youn, Hyun-Yi; McCanna, David J; Sivak, Jacob G; Mikkelsen, Susan R



Harvesting energy from the marine sediment-water interface II. Kinetic activity of anode materials.  


Here, we report a comparative study on the kinetic activity of various anodes of a recently described microbial fuel cell consisting of an anode imbedded in marine sediment and a cathode in overlying seawater. Using plain graphite anodes, it was demonstrated that a significant portion of the anodic current results from oxidation of sediment organic matter catalyzed by microorganisms colonizing the anode and capable of directly reducing the anode without added exogenous electron-transfer mediators. Here, graphite anodes incorporating microbial oxidants are evaluated in the laboratory relative to plain graphite with the goal of increasing power density by increasing current density. Anodes evaluated include graphite modified by adsorption of anthraquinone-1,6-disulfonic acid (AQDS) or 1,4-naphthoquinone (NQ), a graphite-ceramic composite containing Mn2+ and Ni2+, and graphite modified with a graphite paste containing Fe3O4 or Fe3O4 and Ni2+. It was found that these anodes possess between 1.5- and 2.2-fold greater kinetic activity than plain graphite. Fuel cells were deployed in a coastal site near Tuckerton, NJ (USA) that utilized two of these anodes. These fuel cells generated ca. 5-fold greater current density than a previously characterized fuel cell equipped with a plain graphite anode, and operated at the same site. PMID:16574400

Lowy, Daniel A; Tender, Leonard M; Zeikus, J Gregory; Park, Doo Hyun; Lovley, Derek R



Quinone-mediated microbial synthesis of reduced graphene oxide with peroxidase-like activity.  


The effects of different quinones on graphene oxide (GO) reduction by Shewanella oneidensis MR-1 and the peroxidase activity of the resultant reduced graphene oxide (QRGO) were studied. The presence of 100?M anthraquinone-2-sulfonate (AQS), anthraquinone-2,6-disulfonate and 5-hydroxy-1,4-naphthoquinone could lead to 1.6-2.8-fold increase in GO reduction rate, whereas anthraquinone-2-carboxylate slowed down the reduction. The stimulating effects of AQS increased with the increase of its concentration (10-100?M). The mediated effects were proved by direct GO reduction by microbially reduced AQS. The mediated reduction of GO to QRGO was characterized by UV-vis, XRD, FTIR, Raman spectra, XPS, TEM and AFM, respectively. The as-prepared QRGO possessed peroxidase-like activity, which could catalyze the oxidation of 3,3'5,5'-tetramethylbenzidine by H2O2, and followed Michealis-Menten kinetics. A colorimetric sensor for quantitative determination of glucose based on the peroxidase activity of QRGO was developed over a range of 1-120?M with a detection limit of 1?M. PMID:24140856

Liu, Guangfei; Zhang, Xin; Zhou, Jiti; Wang, Aijie; Wang, Jing; Jin, Ruofei; Lv, Hong



A novel o-naphtoquinone inhibits N-cadherin expression and blocks melanoma cell invasion via AKT signaling.  


The down-regulation or loss of epithelial markers is often accompanied by the up-regulation of mesenchymal markers. E-cadherin generally suppresses invasiveness, whereas N-cadherin promotes invasion and metastasis in vitro. The aim of this work is to investigate the role of biflorin, a naphthoquinone with proven anticancer properties, on the expression of N-cadherin and AKT proteins in MDA-MB-435 invasive melanoma cancer cells after 12h of exposure to 1, 2.5 and 5?M biflorin. Biflorin inhibited MDA-MB-435 invasion in a dose-dependent manner (p<0.01). Likewise, biflorin down-regulated N-cadherin and AKT-1 expression in a dose-dependent manner. Biflorin did not inhibit the adhesion of MDA-MB-435 cells to any tested substrates. Additionally, biflorin blocked the invasiveness of cells by down-regulating N-cadherin, most likely via AKT-1 signaling. As such, biflorin may be a novel anticancer agent and a new prototype for drug design. PMID:23912027

Montenegro, Raquel Carvalho; de Vasconcellos, Marne Carvalho; Barbosa, Gleyce Dos Santos; Burbano, Rommel M R; Souza, Luciana G S; Lemos, Telma L G; Costa-Lotufo, Letícia V; de Moraes, Manoel Odorico



Homogeneous purification and characterization of LePGT1--a membrane-bound aromatic substrate prenyltransferase involved in secondary metabolism of Lithospermum erythrorhizon.  


Membrane-bound type prenyltransferases for aromatic substrates play crucial roles in the biosynthesis of various natural compounds. Lithospermum erythrorhizon p-hydroxybenzoate: geranyltransferase (LePGT1), which contains multiple transmembrane ?-helices, is involved in the biosynthesis of a red naphthoquinone pigment, shikonin. Taking LePGT1 as a model membrane-bound aromatic substrate prenyltransferase, we utilized a baculovirus-Sf9 expression system to generate a high yield LePGT1 polypeptide, reaching ~ 1000-fold higher expression level compared with a yeast expression system. Efficient solubilization procedures and biochemical purification methods were developed to extract LePGT1 from the membrane fraction of Sf9 cells. As a result, 80 ?g of LePGT1 was purified from 150 mL culture to almost homogeneity as judged by SDS/PAGE. Using purified LePGT1, enzymatic characterization, e.g. substrate specificity, divalent cation requirement and kinetic analysis, was done. In addition, inhibition experiments revealed that aromatic compounds having two phenolic hydroxyl groups effectively inhibited LePGT1 enzyme activity, suggesting a novel recognition mechanism for aromatic substrates. As the first example of solubilization and purification of this membrane-bound protein family, the methods established in this study will provide valuable information for the precise biochemical characterization of aromatic prenyltransferases as well as for crystallographic analysis of this novel enzyme family. PMID:23490165

Ohara, Kazuaki; Mito, Koji; Yazaki, Kazufumi



Tyrosinase inhibitors from Calceolaria integrifolia s.l.: Calceolaria talcana aerial parts.  


As a defense mechanism of the aerial parts of Calceolaria talcana (Calceolariaceae; formerly Scrophulariaceae) against herbivore offenses and insect pest attack, diterpenoids, triterpenoids, phenylethanoids, flavonoids, and iridoids are rapidly accumulated along the aerial parts, resulting in a unique natural biopesticide complex from this plant. In addition to verbascoside a series of known compounds were screened for their inhibitory activity against mushroom tyrosinase and protease enzymes. Ethyl acetate and n-hexane extracts, together with cyclopropyl-7,15-ent-pimaradiene (1), abietatriene (2), ursolic acid (3), ?-lupeol (4), ?-sitosterol (5), 2-hydroxy-3-(1,1-dimethylallyl)-1,4-naphthoquinone (6), ?-dunnione (7), verbascoside (8), martynoside (9), and some known model compounds proved to be inhibitors of oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) catalyzed by tyrosinase (EC with an IC50 between 10.0 and 200 ppm or ?M, respectively, suggesting that phenolic moieties in the molecules assayed are important for the activity. PMID:23607420

Muñoz, Evelyn; Avila, Jose G; Alarcón, Julio; Kubo, Isao; Werner, Enrique; Céspedes, Carlos L



Mechanisms for naphthalene removal during electrolytic aeration.  


Batch tests were performed to investigate chemical and physical processes that may result during electrolytic aeration of a contaminated aquifer using naphthalene as a model contaminant. Naphthalene degradation of 58-66% took place electrolytically and occurred at the same rates at a pH of 4 and 7. 1,4-naphthoquinone was identified as a product of the electrolysis. Stripping due to gases produced at the electrodes did not result in any naphthalene loss. Hydrogen peroxide (which may be produced at the cathode) did not have any effect on naphthalene, but the addition of ferrous iron (which may be present in aquifers) resulted in 67-99% disappearance of naphthalene. Chlorine (which may be produced from the anodic oxidation of chloride) can effectively degrade naphthalene at pH of 4, but not at a pH of 7. Mono-, di- and poly chloronaphthalenes were identified as oxidation products. Ferric iron coagulation (due to the oxidation of ferrous iron) did not significantly contribute to naphthalene loss. Overall, electrolytic oxidation and chemical oxidation due to the electrolytic by-products formed are significant abiotic processes that could occur and should be accounted for if bioremediation of PAH-contaminated sites via electrolytic aeration is considered. Possible undesirable products such as chlorinated compounds may be formed when significant amounts of chlorides are present. PMID:12531271

Goel, Ramesh K; Flora, Joseph R V; Ferry, John



New spectrofluorimetric method for determination of cephalosporins in pharmaceutical formulations.  


Simple, accurate and sensitive spectrofluorimetric method has been proposed for the determination of three cephalosporins, namely; cefixime (cefi), cephalexine (ceph), cefotaxime sodium (cefo) in pharmaceutical formulations. The method is based on a reaction between cephalosporins with 1, 2-naphthoquinone-4-sulfonic (NQS) in alkaline medium, at pH values of 12.0 for cefi and 13.0 for ceph and cefo to give highly fluorescent derivatives extracted with chloroform and subsequently measured at 600,580 and 580 nm after excitation at 520,455 and 490 nm for cefi, ceph and cefo respectively. The optimum experimental conditions have been studied. Beer's law is obeyed over the concentrations of 10-35 ng/mL, 10-60 ng/mL and 20-45 ng/mL for cefi,ceph and cefo, respectively. The detection limits were 2.02 ng/mL, 2.09 ng/mL and 2.30 ng/mL for cefi, ceph and cefo, respectively, with a linear regression correlation coefficient of 0.9987, 0.9995 and 0.9991 and recoveries in range from 98.5-107.04, 95.17-101.00 and 95.00-109.55% for cefi, ceph and cefo, respectively. This method is simple and can be applied for the determination of cefi, ceph and cefo in pharmaceutical formulations in quality control laboratories. PMID:22160361

Elbashir, Abdalla A; Ahmed, Shazalia M Ali; Aboul-Enein, Hassan Y



New spectrophotometric methods for the determination of moxifloxacin in pharmaceutical formulations.  


Two rapid, simple and sensitive spectrophotometric methods for the quantitative analysis of moxifloxacin (MOX) in pharmaceutical formulations have been described. The first method (A) involves reaction of MOX with 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline medium (pH 11.0) which results in an orange-coloured product exhibiting maximum absorption (lambda(max)) at 411 nm. The second method (B) is based on the oxidation of the MOX with a known excess of cerium (IV) sulfate and the residual oxidant is determined by treating with a fixed amount of methyl orange, and measuring the absorbance at 507 nm. The molar absorptivities for methods A and B were 4.9 x 10(3) and 6.5 x 10(4) L mol(-1) cm(-1), respectively. Under the optimized reaction conditions, Beer's law correlation of the absorbance with MOX concentration was obtained in the range of 2.5-20 and 0.5-30 microgmL(-1) for method A and B respectively. The intra-day precision expressed as relative standard deviation (RSD) was < 1.6% for both methods. The methods were validated in terms of accuracy and precision and were successfully applied to the determination of MOX in its pharmaceutical dosage form. The proposed methods are useful for routine analysis of MOX in quality control laboratories. PMID:23841346

Elbashir, Abdalla A; Ebraheem, Sara A M; Elwagee, Alawia H E; Aboul-Enein, Hassan Y



Spectrophotometric determination of boron based on charge transfer reaction.  


Boron determination by a charge transfer spectrophotometric method is described. Accompanied the reaction, a charge transfer complex can be formed by lysine with sodium 1, 2-naphthoquinone-4-sulfonate and boron in alkaline solution (pH 12.00). Subsequently, a new reaction mechanism has been proposed and discussed. The absorbance at the maximal absorption wavelength is 574 nm and boron concentration agrees well with Beer's law in a range of 2.16-43.24 ?g mL(-1). The linear regression equation is A=-0.01867+0.01326C (?g mL(-1)), with a linearly correlation coefficient of 0.9935. The relative standard deviation (R.S.D.) of eleven parallel determinations is 2.1% with a detection limit (3?/k) of 2.00 ?g mL(-1). The recovery ranges from 96.4% to 104.5% with the satisfactory results. This method has been successfully applied to determine boron in pharmaceutical samples directly. PMID:21530377

Ma, Linjin; Zhang, Zhenxuan; Li, Quanmin



Menaquinone analogs inhibit growth of bacterial pathogens.  


Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 ?g/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents. PMID:23959313

Schlievert, Patrick M; Merriman, Joseph A; Salgado-Pabón, Wilmara; Mueller, Elizabeth A; Spaulding, Adam R; Vu, Bao G; Chuang-Smith, Olivia N; Kohler, Petra L; Kirby, John R



The metabolism of 9-chloro-?-lapachone and its effects in isolated hepatocytes. The involvement of NAD(P)H:quinone oxidoreductase 1 (NQO1).  


A ?-lapachone analogue (3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione) (9-chloro ?-lapachone), named CGQ, with antitumoral, antiviral and antitrypanocidal activities was assayed for cytotoxic effects on isolated rat hepatocytes. The incubation of hepatocytes with this o-naphthoquinone showed (a) decreased adenylate energy charge, as a result of a decrease in ATP, and an increase in AMP levels; (b) increased NADP(+) content, with a concomitant decrease of NADPH, NADH and NAD(+) content; (c) decreased GSH content, accompanied by an increase in GSSG formation; (d) stimulated oxygen uptake as well as increased superoxide anion production and hydrogen peroxide formation; (e) inhibited lipid peroxidation; (f) hepatocyte viability was not reduced unless the NQO1 inhibitor dicoumarol was present. We hypothesize that the cytotoxicity of CGQ in dicoumarol-treated hepatocytes was the result of inhibition of the NQO1 detoxification pathway, thus allowing more quinone to be metabolized towards the one-electron pathway to form reactive semiquinones and/or reactive oxygen species. The results obtained indicate a protective role of NQO1 in preventing CGQ cytotoxicity in isolated rat hepatocytes. PMID:23047025

Fernandez Villamil, Silvia H; Carrizo, Patricia H; Di Rosso, Maria E; Molina Portela, Maria P; Dubin, Marta



Evidence for NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated quinone-dependent redox cycling via plasma membrane electron transport: A sensitive cellular assay for NQO1.  


2,3-Dimethoxy 1,4-naphthoquinone (DMNQ), which redox cycles via two-electron reduction, mediates reduction of the cell-impermeative tetrazolium dye WST-1 in kidney epithelial cells (MDCK), which express high levels of NQO1, but not in HL60 or CHO cells, which are NQO1 deficient. DMNQ-dependent WST-1 reduction by MDCK cells was strongly inhibited by low concentrations of the NQO1 inhibitor dicoumarol and was also inhibited by diphenyleneiodonium, capsaicin, and superoxide dismutase (SOD), but not by the uncoupler FCCP or the complex IV inhibitor cyanide. This suggests that DMNQ-dependent WST-1 reduction by MDCK cells is catalyzed by NQO1 via redox cycling and plasma membrane electron transport (PMET). Interestingly, we observed an association between DMNQ/WST-1 reduction and extracellular H(2)O(2) production as determined by Amplex red. Exposure of MDCK cells to DMNQ for 48 h caused cellular toxicity that was extensively reversed by co-incubation with dicoumarol or exogenous SOD, catalase, or N-acetylcysteine. No effects were observed in NQO1-deficient CHO and HL60 cells. In conclusion, we have developed a simple real-time cellular assay for NQO1 and show that PMET plays a significant role in DMNQ redox cycling via NQO1, leading to cellular toxicity in cells with high NQO1 levels. PMID:19932748

Tan, An S; Berridge, Michael V



Effect of Plumbagin on some glucose metabolising enzymes studied in rats in experimental hepatoma.  


Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) isolated from Plumbago zeylanica Linn, when administered orally, at a dosage of 4 mg/kg body weight induces tumour regression in 3-methyl-4-dimethyl aminoazobenzene (3MeDAB) induced hepatoma in Wistar male rats. The purpose of this investigation was to identify the changes in the rate of glycolysis and gluconeogenesis in tumour-bearing rats and the effects of treatment with Plumbagin. The levels of certain glycolytic enzymes, namely, hexokinase; phosphoglucoisomerase; and aldolase levels increased (p < 0.001) in hepatoma bearing rats, whereas they decreased in Plumbagin administered rats to near normal levels. Certain gluconeogenic enzymes, namely, glucose-6-phosphatase and fructose-1,6-diphosphatase decreased (p < 0.001) in tumour hosts, whereas Plumbagin administration increased the gluconeogenic enzyme levels in the treated animals. These investigations indicate the molecular basis of the different biological behaviour of 3MeDAB induced hepatoma and the anticarcinogenic property of Plumbagin against hepatoma studied in rats. PMID:8264573

Parimala, R; Sachdanandam, P



Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani.  


World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC50?20.7?M), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC50?7.2?M) as compared to diospyrin (IC50?12.6?M) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC50?0.18?M). Also, treatment of infected BALB/c mice with D17 at 2mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR. PMID:23973194

Hazra, Sudipta; Ghosh, Subhalakshmi; Sarma, Madhushree Das; Sharma, Smriti; Das, Mousumi; Saudagar, Prakash; Prajapati, Vijay Kumar; Dubey, Vikash Kumar; Sundar, Shyam; Hazra, Banasri



Photochemistry of a photosynthetic reaction center immobilized in lipidic cubic phases  

SciTech Connect

Photosynthetic reaction centers, isolated and purified from the facultative phototrophic bacterium Chloroflexus aurantiacus, were immobilized in optically transparent lipidic cubic phases composed of 42% (w/w) 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine and 58% (w/w) water. The immobilized photosynthetic protein retains its native properties, as indicated by visible and circular dichroic spectra. The ground state visible spectrum of the immobilized reaction centers is very similar to the corresponding spectrum in aqueous solution, indicating that the protein pigments are not extracted into the lipidic regions of the cubic phase. The secondary structure of the protein is maintained in the immobilized state, as determined by far-UV circular dichroism spectroscopy in the 200- to 250-nm range. Moreover, immobilized reaction centers retain their photochemical activity: a reversible photo-oxidation of the primary electron donor (P) is seen upon continuous illumination. Furthermore, the entrapment of reaction centers does not affect the kinetics of charge recombination between the photo-oxidized primary donor (P{sup +}) and the photoreduced primary quinone acceptor, generated by a short flash of light. Reaction centers devoided of the secondary quinone acceptor can be easily reconstituted in cubic phases by means of their coimmobilization with 1,4-naphthoquinone.

Hochkoeppler, A.; Venturoli, G.; Zannoni, D. [Univ. of Bologna (Italy). Dept. of Biology; Landau, E.M.; Luisi, P.L. [ETH Zentrum, Zuerich (Switzerland). Inst. fuer Polymere; Feick, R. [Max-Planck Inst. fuer Biochemie, Martinsried (Germany)



Analysis of atmospheric concentrations of quinones and polycyclic aromatic hydrocarbons in vapour and particulate phases  

NASA Astrophysics Data System (ADS)

Polycyclic aromatic hydrocarbons (PAH) are often measured in studies of atmospheric chemistry or health effects of air pollution, due to their known human carcinogenicity. In recent years, PAH quinone derivatives have also become a focus of interest, primarily because they can contribute to oxidative stress. This work reports concentrations of 17 PAH and 15 quinones measured in air samples collected at a trafficked roadside. Data are presented for four compounds not previously reported in ambient air: 2-methyl-1,4-naphthoquinone, 2,6-di-tert-butyl-1,4-benzoquinone, methyl-1,4-benzoquinone and 2,3-dimethylanthraquinone, and a large vapour phase component is measured, not analysed in most earlier studies. Analyses are reported also for SRM 1649a and 1649b, including many compounds (8 for SRM 1649a and 12 for SRM 1649b) for which concentrations have not previously been reported. This work assesses the vapour/particle phase distribution of PAHs and quinones in relation to their molecular weight, vapour pressure, polarity and Henry's Law constant, finding that both molecular weight and vapour pressure (which are correlated) are good predictors of the partitioning.

Delgado-Saborit, Juana Maria; Alam, Mohammed S.; Godri Pollitt, Krystal J.; Stark, Christopher; Harrison, Roy M.



Library synthesis and antibacterial investigation of cationic anthraquinone analogs.  


We report the parallel synthesis of a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium chloride salts, which are analogs to cationic anthraquinones. Three synthetic protocols were examined leading to a convenient and facile library synthesis of the cationic anthraquinone analogs that contain double alkyl chains of various lengths (C(2)-C(12)) at N-1 and N-3 positions. The antibacterial activities of these compounds were evaluated against Gram-positive bacterium Staphylococcus aureus and Gram-negative bacterium Escherichia coli. The antibacterial activities of these compounds were expected to be associated with the structural features of naphthoquinone, cation and lypophilic alkyl chain and, interestingly, they showed much higher levels of antibacterial activities against G+ than G- bacteria. In addition, when the total number of carbon atoms of the alkyl groups at both N-1 and N-3 positions lies between 9 and 18, the bactericidal activity against S. aureus increased with increasing alkyl chain length at both N-atoms with MIC ? 1 ?g/mL. PMID:22324350

Fosso, Marina Y; Chan, Ka Yee; Gregory, Rylee; Chang, Cheng-Wei Tom



Potential of herbs in skin protection from ultraviolet radiation  

PubMed Central

Herbs have been used in medicines and cosmetics from centuries. Their potential to treat different skin diseases, to adorn and improve the skin appearance is well-known. As ultraviolet (UV) radiation can cause sunburns, wrinkles, lower immunity against infections, premature aging, and cancer, there is permanent need for protection from UV radiation and prevention from their side effects. Herbs and herbal preparations have a high potential due to their antioxidant activity, primarily. Antioxidants such as vitamins (vitamin C, vitamin E), flavonoids, and phenolic acids play the main role in fighting against free radical species that are the main cause of numerous negative skin changes. Although isolated plant compounds have a high potential in protection of the skin, whole herbs extracts showed better potential due to their complex composition. Many studies showed that green and black tea (polyphenols) ameliorate adverse skin reactions following UV exposure. The gel from aloe is believed to stimulate skin and assist in new cell growth. Spectrophotometer testing indicates that as a concentrated extract of Krameria triandra it absorbs 25 to 30% of the amount of UV radiation typically absorbed by octyl methoxycinnamate. Sesame oil resists 30% of UV rays, while coconut, peanut, olive, and cottonseed oils block out about 20%. A “sclerojuglonic” compound which is forming from naphthoquinone and keratin is the reaction product that provides UV protection. Traditional use of plant in medication or beautification is the basis for researches and making new trends in cosmetics. This review covers all essential aspects of potential of herbs as radioprotective agents and its future prospects.

Korac, Radava R.; Khambholja, Kapil M.



Cytotoxicity of lawsone and cytoprotective activity of antioxidants in catalase mutant Escherichia coli.  


Lawsone is an active naphthoquinone derivative isolated from henna (Lawsonia inermis L.), a widely used hair dye. Previous study on the toxicity of lawsone remains unclear since the involvement of oxidative stress and the kind of ROS (reactive oxygen species) involved have not been fully resolved yet. This present study reports the cytotoxic effects of lawsone and henna. We carried out CAT assay (a zone of inhibition test of bacterial growth and colony-forming efficiency test of transformant Escherichia coli strains that express mammalian catalase gene derived from normal catalase mice (Cs(a)) and catalase-deficient mutant mice (Cs(b))), Ames mutagenicity assay and H(2)O(2) generation assay. Lawsone generated H(2)O(2) slightly in phosphate buffer system and was not mutagenic in Ames assay using TA 98, TA 100 and TA 102, both in the absence and presence of metabolic activation. Lawsone exposure inhibited the growth of both Cs(a) and Cs(b) strains in a dose-dependent manner. Mean zone diameter for Cs(a) was 9.75+/-0.96 mm and 12.75+/-1.5 mm for Cs(b). Natural henna leaves did not show toxic effects, whereas two out of four samples of marketed henna products were shown toxicity effects. Catalase abolished zone of inhibition (ZOI) of marketed henna products, eliminated ZOI of lawsone in a dose-dependent manner and low concentration of exogenous MnSOD and Cu/ZnSOD eliminated the toxicity. Histidine and DTPA, the metal chelator; BHA and low concentration of capsaicin, the inducer of NADH-quinone reductase, effectively protected Cs(a) and Cs(b) against lawsone in this study. We suggest that lawsone cytotoxicity is probably mediated, at least in part, by the release of O(2)(-), H(2)O(2) and OH(-). PMID:17442476

Sauriasari, Rani; Wang, Da-Hong; Takemura, Yoko; Tsutsui, Ken; Masuoka, Noriyoshi; Sano, Kuniaki; Horita, Masako; Wang, Bing-Ling; Ogino, Keiki



From body art to anticancer activities: perspectives on medicinal properties of henna.  


Nature has been a rich source of therapeutic agents for thousands of years and an impressive number of modern drugs have been isolated from natural sources based on the uses of these plants in traditional medicine. Henna is one such plant commonly known as Persian Henna or Lawsonia inermis, a bushy, flowering tree, commonly found in Australia, Asia and along the Mediterranean coasts of Africa. Paste made from the leaves of Henna plant has been used since the Bronze Age to dye skin, hairs and fingernails especially at the times of festivals. In recent times henna paste has been used for body art paintings and designs in western countries. Despite such widespread use in dyeing and body art painting, Henna extracts and constituents possess numerous biological activities including antioxidant, anti-inflammatory, antibacterial and anticancer activities. The active coloring and biologically active principle of Henna is found to be Lawsone (2- hydroxy-1, 4-naphthoquinone) which can serve as a starting building block for synthesizing large number of therapeutically useful compounds including Atovaquone, Lapachol and Dichloroallyl lawsone which have been shown to possess potent anticancer activities. Some other analogs of Lawsone have been found to exhibit other beneficial biological properties such as antioxidant, anti-inflammatory, antitubercular and antimalarial. The ability of Lawsone to undergo the redox cycling and chelation of trace metal ions has been thought to be partially responsible for some of its biological activities. Despite such diverse biological properties and potent anticancer activities the compound has remained largely unexplored and hence in the present review we have summarized the chemistry and biological activities of Lawsone along with its analogs and metal complexes. PMID:23140289

Pradhan, Rohan; Dandawate, Prasad; Vyas, Alok; Padhye, Subhash; Biersack, Bernhard; Schobert, Rainer; Ahmad, Aamir; Sarkar, Fazlul H



Perturbation of the quinone-binding site of complex II alters the electronic properties of the proximal [3Fe-4S] iron-sulfur cluster.  


Succinate-ubiquinone oxidoreductase (SQR) and menaquinol-fumarate oxidoreductase (QFR) from Escherichia coli are members of the complex II family of enzymes. SQR and QFR catalyze similar reactions with quinones; however, SQR preferentially reacts with higher potential ubiquinones, and QFR preferentially reacts with lower potential naphthoquinones. Both enzymes have a single functional quinone-binding site proximal to a [3Fe-4S] iron-sulfur cluster. A difference between SQR and QFR is that the redox potential of the [3Fe-4S] cluster in SQR is 140 mV higher than that found in QFR. This may reflect the character of the different quinones with which the two enzymes preferentially react. To investigate how the environment around the [3Fe-4S] cluster affects its redox properties and catalysis with quinones, a conserved amino acid proximal to the cluster was mutated in both enzymes. It was found that substitution of SdhB His-207 by threonine (as found in QFR) resulted in a 70-mV lowering of the redox potential of the cluster as measured by EPR. The converse substitution in QFR raised the redox potential of the cluster. X-ray structural analysis suggests that placing a charged residue near the [3Fe-4S] cluster is a primary reason for the alteration in redox potential with the hydrogen bonding environment having a lesser effect. Steady state enzyme kinetic characterization of the mutant enzymes shows that the redox properties of the [3Fe-4S] cluster have only a minor effect on catalysis. PMID:21310949

Ruprecht, Jonathan; Iwata, So; Rothery, Richard A; Weiner, Joel H; Maklashina, Elena; Cecchini, Gary



The anthelmintic effect of plumbagin on Schistosoma mansoni.  


The anthelmintic effects of plumbagin (PB, 5-hydroxy-2-methyl-1,4-naphthoquinone) and praziquantel (PZQ) against adult Schistosoma mansoni in vitro were compared by estimating the relative motility (RM) values, survival indices (SI) and alterations of the tegument of flukes incubated in M-199 medium containing 1, 10 and 100 ?g/ml of the drugs, at 1, 3, 6, 12 and 24 h. For the parasites incubated in 10 ?g/ml, the RM values of the PB-treated group decreased at a more rapid rate than the PZQ-treated group. When incubated in 100 ?g/ml all PB-treated flukes appeared immobile from 1 to 24 h when 91-100% died, while in the PZQ-treated group RM values were higher than that of PB and most flukes were still alive at 1-12 h, and at 24 h only 21% of flukes were killed. Furthermore, male parasites were more affected by PZQ than females as their RM values were significantly less than that of females at all doses. While in PB treatment, males and females showed less difference in response to the drug as their RM values were closer than those treated with PZQ. When observed by SEM, the tegument of untreated S. mansoni displayed no alteration, while in PB treated parasites it exhibited swelling, blebbing, loss of spines, disruption of tubercles and ridges, leading to erosion and lesion, exposure of the basal lamina, and sloughing of the tegument. PZQ induced similar tegumental changes as those observed in PB treatment but at longer incubation time and higher doses. These data indicated that PB had more anthelmintic effect on both sexes of adult S. mansoni than PZQ. PMID:23085370

Lorsuwannarat, Natcha; Saowakon, Naruwan; Ramasoota, Pongrama; Wanichanon, Chaitip; Sobhon, Prasert



Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants.  


Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different solvents (hexane, chloroform, and 70% ethanol-water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional (1)H and (13)C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1-2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S,S')-12-O-methyl(+)-curine (5); and cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity. PMID:21922239

González-Coloma, Azucena; Reina, Matías; Sáenz, Claudia; Lacret, Rodney; Ruiz-Mesia, Lastenia; Arán, Vicente J; Sanz, Jesús; Martínez-Díaz, Rafael A



Cytotoxic Effects of N-(3-Chloro-1,4-dioxo 1,4-dihydronaphthalen-2-yl)-benzamide on Androgen-dependent and -independent Prostate Cancer Cell Lines  

PubMed Central

Background Worldwide among men, prostate cancer ranks third in cancer occurrence and sixth in cancer mortality. A number of 1, 4-naphthoquinone derivatives have been identified that possess significant pharmacological effects associated with antitumor activities. In this study, the in vitro effects of N-(3-chloro-1,4-dioxo 1,4-dihydronaphthalen-2-yl)-benzamide (NCDDNB) were evaluated on androgen-dependent (CWR-22) and androgen-independent (PC-3, DU-145) human prostate cancer cell lines, and on a normal bone marrow cell line (HS-5). Specifically, the in vitro activity of this compound on cell cycle regulation and apoptosis was evaluated. Materials and Methods Established methods of cell viability, cell cycle, Western blot and apoptosis were used. Results The effect of NCDDNB on CWR-22, PC-3, DU-145 and HS-5 cells revealed significant anti-tumor activities with IC50s, of 2.5, 2.5, 6.5, and 25 ?M respectively. The results of cell cycle analysis showed that NCDDNB arrested PC-3, DU-145, and CWR-22 cells in the G1-phase of the cell cycle. The compound showed no effect on the cell cycle progression in the HS-5 bone marrow cell line. These findings were further validated using Western blot analysis. NCDDNB showed the greatest amount of apoptosis in the androgen-independent PC-3 cells in a time-dependent manner with the apoptotic apex at day 5 of treatment. Furthermore, NCDDNB induced-apoptosis in DU-145 and CWR-22 cells peaked at day 3 of treatment. Conclusion Although the mechanism of action of this compound has not been completely elucidated, the effect on the cell cycle and the induction of apoptosis in different prostate cancer cell lines prompted us to carry out a more in-depth preclinical evaluation. This study suggests that NCDDNB may have an impact on treatment of prostate cancer while protecting the bone marrow.




Preliminary evidence on existence of transplasma membrane electron transport in Entamoeba histolytica trophozoites: a key mechanism for maintaining optimal redox balance.  


Entamoeba histolytica, an amitochondriate parasitic protist, was demonstrated to be capable of reducing the oxidized form of alpha-lipoic acid, a non permeable electron acceptor outside the plasma membrane. This transmembrane reduction of non permeable electron acceptors with redox potentials ranging from -290 mV to +360 mV takes place at neutral pH. The transmembrane reduction of non permeable electron acceptors was not inhibited by mitochondrial electron transport inhibitors such as antimycin A, rotenone, cyanide and azide. However, a clear inhibition with complex III inhibitor, 2-(n-heptyl)-4-hydroxyquinoline-N-oxide; modifiers of sulphydryl groups and inhibitors of glycolysis was revealed. The iron-sulphur centre inhibitor thenoyltrifluoroacetone failed to inhibit the reduction of non permeable electron acceptors whereas capsaicin, an inhibitor of energy coupling NADH oxidase, showed substantial inhibition. p-trifluromethoxychlorophenylhydrazone, a protonophore uncoupler, resulted in the stimulation of alpha-lipoic acid reduction but inhibition in oxygen uptake. Mitochondrial electron transport inhibitors substantially inhibited the oxygen uptake in E. histolytica. Transmembrane reduction of alpha-lipoic acid was strongly stimulated by anaerobiosis and anaerobic stimulation was inhibited by 2-(n-heptyl)-4-hydroxyquinoline-N-oxide. Transmembrane redox system of E. histolytica was also found to be sensitive to UV irradiation. All these findings clearly demonstrate the existence of transplasma membrane electron transport system in E. histolytica and possible involvment of a naphthoquinone coenzyme in transmembrane redox of E. histolytica which is different from that of mammalian host and therefore can provide a novel target for future rational chemotherapeutic drug designing. PMID:17039394

Bera, Tanmoy; Nandi, Nilay; Sudhahar, D; Akbar, Md Ali; Sen, Abhik; Das, Pradeep



Alternative quinone substrates and inhibitors of human electron-transfer flavoprotein-ubiquinone oxidoreductase.  


Electron-transfer flavoprotein (ETF)-ubiquinone (2,3-dimethoxy-5-methyl-1,4-benzoquinone) oxidoreductase (ETF-QO) is a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool. ETF is the intermediate electron carrier between the dehydrogenases and ETF-QO. The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues and analogues that contained saturated n-alkyl substituents at the 6 position. These experiments show that optimal substrates contain a ten-carbon-atom side chain, consistent with a preliminary crystal structure that shows that only the first two of ten isoprene units of co-enzyme Q10 (CoQ10) interact with the protein. Derivatives with saturated alkyl side chains are very good substrates, indicating that, unlike other ubiquinone oxidoreductases, there is little preference for the methyl branches or rigidity of the CoQ side chain. Few of the compounds that inhibit ubiquinone oxidoreductases inhibit ETF-QO. Compounds found to act as inhibitors of ETF-QO include 2-n-heptyl-4-hydroxyquinoline N-oxide, a naphthoquinone analogue, 2-(3-methylpentyl)-4,6-dinitrophenol and pentachlorophenol. 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB), which inhibits the mitochondrial bc1 complex and the chloroplast b6 f complex in redox-dependent fashion, can serve as an electron acceptor for human ETF-QO. The observation of simple Michaelis-Menten kinetic patterns and a single type of quinone-binding site, determined by fluorescence titrations of the protein with DBMIB and 6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO monomer. PMID:14640977

Simkovic, Martin; Frerman, Frank E



Lysine-91 of the tetraheme c-type cytochrome CymA is essential for quinone interaction and arsenate respiration in Shewanella sp. strain ANA-3.  


The tetraheme c-type cytochrome, CymA, is essential for arsenate respiratory reduction in Shewanella sp. ANA-3, a model arsenate reducer. CymA is predicted to mediate electron transfer from quinols to the arsenate respiratory reductase (ArrAB). Here, we present biochemical and physiological evidence that CymA interacts with menaquinol (MQH(2)) substrates. Fluorescence quench titration with the MQH(2) analog, 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO), was used to demonstrate quinol binding of E. coli cytoplasmic membranes enriched with various forms of CymA. Wild-type CymA bound HOQNO with a K (d) of 0.1-1 microM. It was also shown that the redox active MQH(2) analog, 2,3-dimethoxy-1,4-naphthoquinone (DMNH(2)), could reduce CymA in cytoplasmic membrane preparations. Based on a CymA homology model made from the NrfH tetraheme cytochrome structure, it was predicted that Lys91 would be involved in CymA-quinol interactions. CymA with a K91Q substitution showed little interaction with HOQNO. In addition, DMNH(2)-dependent reduction of CymA-K91Q was diminished by 45% compared to wild-type CymA. A DeltacymA ANA-3 strain containing a plasmid copy of cymA-K91Q failed to grow with arsenate as an electron acceptor. These results suggest that Lys91 is physiologically important for arsenate respiration and support the hypothesis that CymA interacts with menaquinol resulting in the reduction of the cytochrome. PMID:19760266

Zargar, Kamrun; Saltikov, Chad W



A functional description of CymA, an electron-transfer hub supporting anaerobic respiratory flexibility in Shewanella.  


CymA (tetrahaem cytochrome c) is a member of the NapC/NirT family of quinol dehydrogenases. Essential for the anaerobic respiratory flexibility of shewanellae, CymA transfers electrons from menaquinol to various dedicated systems for the reduction of terminal electron acceptors including fumarate and insoluble minerals of Fe(III). Spectroscopic characterization of CymA from Shewanella oneidensis strain MR-1 identifies three low-spin His/His co-ordinated c-haems and a single high-spin c-haem with His/H(2)O co-ordination lying adjacent to the quinol-binding site. At pH 7, binding of the menaquinol analogue, 2-heptyl-4-hydroxyquinoline-N-oxide, does not alter the mid-point potentials of the high-spin (approximately -240 mV) and low-spin (approximately -110, -190 and -265 mV) haems that appear biased to transfer electrons from the high- to low-spin centres following quinol oxidation. CymA is reduced with menadiol (E(m) = -80 mV) in the presence of NADH (E(m) = -320 mV) and an NADH-menadione (2-methyl-1,4-naphthoquinone) oxidoreductase, but not by menadiol alone. In cytoplasmic membranes reduction of CymA may then require the thermodynamic driving force from NADH, formate or H2 oxidation as the redox poise of the menaquinol pool in isolation is insufficient. Spectroscopic studies suggest that CymA requires a non-haem co-factor for quinol oxidation and that the reduced enzyme forms a 1:1 complex with its redox partner Fcc3 (flavocytochrome c3 fumarate reductase). The implications for CymA supporting the respiratory flexibility of shewanellae are discussed. PMID:22458729

Marritt, Sophie J; Lowe, Thomas G; Bye, Jordan; McMillan, Duncan G G; Shi, Liang; Fredrickson, Jim; Zachara, John; Richardson, David J; Cheesman, Myles R; Jeuken, Lars J C; Butt, Julea N



Improved resolution of thick film resist: effect of development technique  

NASA Astrophysics Data System (ADS)

In view of the fact that little analysis of the mechanism for the achievement of high resolution or a high aspect ratio in the thick-film resist process has been performed, we study development properties with respect to differences between the development methods employed for pattern formation using thick-film resist. This study identifies the most effective development method for thick-film resist and reports the mechanism of development. For this investigation, we use a development rate measurement system, a mask aligner, and lithography simulator to examine the dipping development method, the step puddle development method, the vibration development method, and the reverse development method. We employ a thick-film positive resist composed of diazo-naphthoquinone (DNQ) and Novolak resin, which is coated on a silicon substrate to a thickness of 24 micrometers . After pre-baking, the coated substrate is placed in a vacuum dessicator to remove water, followed by immersion in deionized water for a fixed period. A mask pattern is transferred to the resist coated substrate with a Mask Aligner Q4000 made by Quintel Corporation, and then the rate of development is measured. A laser microscope analysis of the result indicates that the step puddle development method gives the highest pattern resolution and sharpness, followed by the vibration development method, the dipping development method, and lastly the reverse development method. The mechanisms of the development are studied by comparing the development contrast and the energy of activation involved in each development method, and by conducting resist pattern simulations. The results indicate that the factors responsible for retarding the progression of the development process and causing a degradation of pattern profile and resolution are development inhibition due to N2 released from inside the resist during the development process, and due to products that are dissolved in the development solution.

Sensu, Yoshihisa; Sekiguchi, Atsushi; Miyake, Yasuhiro



Phospholipid Furan Fatty Acids and Ubiquinone-8: Lipid Biomarkers That May Protect Dehalococcoides Strains from Free Radicals  

PubMed Central

Dehalococcoides species have a highly restricted lifestyle and are only known to derive energy from reductive dehalogenation reactions. The lipid fraction of two Dehalococcoides isolates, strains BAV1 and FL2, and a tetrachloroethene-to-ethene-dechlorinating Dehalococcoides-containing consortium were analyzed for neutral lipids and phospholipid fatty acids. Unusual phospholipid modifications, including the replacement of unsaturated fatty acids with furan fatty acids, were detected in both Dehalococcoides isolates and the mixed culture. The following three furan fatty acids are reported as present in bacterial phospholipids for the first time: 9-(5-pentyl-2-furyl)-nonanoate (Fu18:2?6), 9-(5-butyl-2-furyl)-nonanoate (Fu17:2?5), and 8-(5-pentyl-2-furyl)-octanoate (Fu17:2?6). The neutral lipids of the Dehalococcoides cultures contained unusually large amounts of benzoquinones (i.e., ubiquinones [UQ]), which is unusual for anaerobes. In particular, the UQ-8 content of Dehalococcoides was 5- to 20-fold greater than that generated in aerobically grown Escherichia coli cultures relative to the phospholipid fatty acid content. Naphthoquinone isoprenologues (MK), which are often found in anaerobically grown bacteria and archaea, were also detected. Dehalococcoides shows a difference in isoprenologue pattern between UQ-8 and MK-5 that is atypical of other bacteria capable of producing both quinone types. The difference in UQ-8 and MK-5 isoprenologue patterns strongly suggests a special function for UQ in Dehalococcoides, and Dehalococcoides may utilize structural modifications in its lipid armamentarium to protect against free radicals that are generated in the process of reductive dechlorination.

White, David C.; Geyer, Roland; Peacock, Aaron D.; Hedrick, David B.; Koenigsberg, Stephen S.; Sung, Youlboong; He, Jianzhong; Loffler, Frank E.



Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation  

PubMed Central

Background Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity. Methodology/Principal Findings Mice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted. Conclusions/Significance These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage.

Pointon, Amy V.; Walker, Tracy M.; Phillips, Kate M.; Luo, Jinli; Riley, Joan; Zhang, Shu-Dong; Parry, Joel D.; Lyon, Jonathan J.; Marczylo, Emma L.; Gant, Timothy W.



Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II  

SciTech Connect

Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin.

Kawiak, Anna [Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk (Poland); Piosik, Jacek [Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk (Poland); Stasilojc, Grzegorz [Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk (Poland); Gwizdek-Wisniewska, Anna [Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk (Poland); Marczak, Lukasz; Stobiecki, Maciej [Institute of Bioorganic Chemistry PAS, Noskowskiego 12/14, 61-704 Poznan (Poland); Bigda, Jacek [Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk (Poland); Lojkowska, Ewa [Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk (Poland)], E-mail:



A proteomic insight into the effects of the immunomodulatory hydroxynaphthoquinone lapachol on activated macrophages.  


We report the effect of an immunomodulatory and anti-mycobacterial naphthoquinone, lapachol, on the bi-dimensional patterns of protein expression of toll-like receptor 2 (TLR2)-agonised and IFN-?-treated THP-1 macrophages. This non-hypothesis driven proteomic analysis intends to shed light on the cellular functions lapachol may be affecting. Proteins of both cytosol and membrane fractions were analysed. After quantification of the protein spots, the protein levels corresponding to macrophages activated in the absence or presence of lapachol were compared. A number of proteins were identified, the levels of which were appreciably and significantly increased or decreased as a result of the action of lapachol on the activated macrophages: cofilin-1, fascin, plastin-2, glucose-6-P-dehydrogenase, adenylyl cyclase-associated protein 1, pyruvate kinase, sentrin-specific protease 6, cathepsin B, cathepsin D, cytosolic aminopeptidase, proteasome ? type-4 protease, tryptophan-tRNA ligase, DnaJ homolog and protein disulphide isomerase. Altogether, the comparative analysis performed indicates that lapachol could be hypothetically causing an impairment of cell migration and/or phagocytic capacity, an increase in NADPH availability, a decrease in pyruvate concentration, protection from proteosomal protein degradation, a decrease in lysosomal protein degradation, an impairment of cytosolic peptide generation, and an interference with NOS2 activation and grp78 function. The present proteomic results suggest issues that should be experimentally addressed ex- and in-vivo, to establish more accurately the potential of lapachol as an anti-infective drug. This study also constitutes a model for the pre-in-vivo evaluation of drug actions. PMID:22705049

Oliveira, Renato A S; Correia-Oliveira, Janaina; Tang, Li-Jun; Garcia, Rodolfo C



Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol.  


Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent. PMID:18294668

Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide



Antimicrobial activity of the methanolic extract and of the chemical constituents isolated from Newbouldia laevis.  


The methanolic extract (NLB) and ten compounds isolated from the root bark of Newbouldia laevis Seem, namely chrysoeriol (1), newbouldiaquinone (2), 2-acetylfuro-1,4-naphthoquinone (3), 2-hydroxy-3-methoxy-9,10-dioxo-9,10-dihydroanthracene-1-carbaldehyde (4), lapachol (5), beta-sitosterol-3-O-beta-D-glucopyranoside (6), oleanolic acid (7), canthic acid (8) newbouldiamide (9) and 2-(4-hydroxyphenyl)-ethyltrioctanoate (10), were tested for in vitro antimicrobial activity. Twenty one microorganisms belonging to six Gram-positive and twelve Gram-negative bacterial species as well as three yeasts from Candida species were tested for their susceptibility to NLB and the pure isolated compounds based on the Agar Hole Diffusion test and the Liquid Dilution method. The Hole Diffusion assay indicated that NLB and compound 7 were active against all tested pathogens while other compounds showed selective activity with the antimicrobial spectra varying from 76% (compound 10) to 95 % (compound 6). Minimal inhibitory concentrations (MIC) also illustrated the important antimicrobial activity of NLB and of the isolated compounds. MIC values obtained varied from 9.76 to 312.50 microg/ml for NLB, and 0.038 to 9.76 microg/ml for pure compounds against most of the tested microorganisms. The antimicrobial activities of compounds 2, 4 and 9 are described here extensively for the first time. The results indicate a promising basis for the use of Newbouldia laevis and some of its active principles in the treatment of infectious diseases. PMID:17718200

Kuete, V; Eyong, K O; Folefoc, G N; Beng, V P; Hussain, H; Krohn, K; Nkengfack, A E



Epidemiological observations on theileriosis following field immunisation using infection and treatment.  


Thirty-seven high grade cattle were immunised against Corridor disease (Theileria parva lawrencei infection) on a farm with a history of heavy and often lethal theilerial challenge. Nineteen cattle were immunised by treating with two doses of long-acting oxytetracyclines given at 20 mg/kg on days 0 and 4 after sporozoite stabilate inoculation, while the other 18 were treated with naphthoquinone buparvaquone, given as a single dose of 2.5 mg/kg simultaneously with stabilate inoculation. All the cattle underwent subclinical theilerial reactions with all but two developing high antibody titres on the IFAT test against T. parva schizont antigen by day 35 after the immunisation. Both buparvaquone and long-acting oxytetracycline appeared equally effective in the immunisation. To date, 26 months later, only two cases of theileriosis parasitologically characteristic of T. p. parva have been reported in the immunised cattle. Following the two cases, investigations showed that when uninfected Rhipicephalus appendiculatus nymphal ticks were deliberately fed on healthy resident cattle on the farm, the resultant adult ticks transmitted acute and lethal theilerial infections to five out of five susceptible cattle. The resultant infections were parasitologically characteristic of T. p. parva infections. Furthermore, the monoclonal antibody profiles of schizont infected cell lines from these infections appeared to be characteristic of T. p. parva. It was thus concluded that resident cattle on the farm could be a potential source of T.p. parva infection which had broken through the immunity of T.p. lawrencei immunised cattle and could constitute a reservoir of theilerial infection for ticks and hence to susceptible stock on the farm. PMID:1907045

Mutugi, J J; Young, A S; Kariuki, D P; Tameno, J M; Morzaria, S P



Plasticity of the Quinone-binding Site of the Complex II Homolog Quinol:Fumarate Reductase.  


Respiratory processes often use quinone oxidoreduction to generate a transmembrane proton gradient, making the 2H(+)/2e(-) quinone chemistry important for ATP synthesis. There are a variety of quinones used as electron carriers between bioenergetic proteins, and some respiratory proteins can functionally interact with more than one quinone type. In the case of complex II homologs, which couple quinone chemistry to the interconversion of succinate and fumarate, the redox potentials of the biologically available ubiquinone and menaquinone aid in driving the chemical reaction in one direction. In the complex II homolog quinol:fumarate reductase, it has been demonstrated that menaquinol oxidation requires at least one proton shuttle, but many of the remaining mechanistic details of menaquinol oxidation are not fully understood, and little is known about ubiquinone reduction. In the current study, structural and computational studies suggest that the sequential removal of the two menaquinol protons may be accompanied by a rotation of the naphthoquinone ring to optimize the interaction with a second proton shuttling pathway. However, kinetic measurements of site-specific mutations of quinol:fumarate reductase variants show that ubiquinone reduction does not use the same pathway. Computational docking of ubiquinone followed by mutagenesis instead suggested redundant proton shuttles lining the ubiquinone-binding site or from direct transfer from solvent. These data show that the quinone-binding site provides an environment that allows multiple amino acid residues to participate in quinone oxidoreduction. This suggests that the quinone-binding site in complex II is inherently plastic and can robustly interact with different types of quinones. PMID:23836905

Singh, Prashant K; Sarwar, Maruf; Maklashina, Elena; Kotlyar, Violetta; Rajagukguk, Sany; Tomasiak, Thomas M; Cecchini, Gary; Iverson, Tina M



High-throughput screening with the Eimeria tenella CDC2-related kinase2/cyclin complex EtCRK2/EtCYC3a  

PubMed Central

The poultry disease coccidiosis, caused by infection with Eimeria spp. apicomplexan parasites, is responsible for enormous economic losses to the global poultry industry. The rapid increase of resistance to therapeutic agents, as well as the expense of vaccination with live attenuated vaccines, requires the development of new effective treatments for coccidiosis. Because of their key regulatory function in the eukaryotic cell cycle, cyclin-dependent kinases (CDKs) are prominent drug targets. The Eimeria tenella CDC2-related kinase 2 (EtCRK2) is a validated drug target that can be activated in vitro by the CDK activator XlRINGO (Xenopus laevis rapid inducer of G2/M progression in oocytes). Bioinformatics analyses revealed four putative E. tenella cyclins (EtCYCs) that are closely related to cyclins found in the human apicomplexan parasite Plasmodium falciparum. EtCYC3a was cloned, expressed in Escherichia coli and purified in a complex with EtCRK2. Using the non-radioactive time-resolved fluorescence energy transfer (TR-FRET) assay, we demonstrated the ability of EtCYC3a to activate EtCRK2 as shown previously for XlRINGO. The EtCRK2/EtCYC3a complex was used for a combined in vitro and in silico high-throughput screening approach, which resulted in three lead structures, a naphthoquinone, an 8-hydroxyquinoline and a 2-pyrimidinyl-aminopiperidine-propane-2-ol. This constitutes a promising starting point for the subsequent lead optimization phase and the development of novel anticoccidial drugs.

Fernandez, Maria L. Suarez; Engels, Kristin K.; Bender, Frank; Gassel, Michael; Marhofer, Richard J.; Mottram, Jeremy C.



Molecular structures and antiproliferative activity of side-chain saturated and homologated analogs of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone  

NASA Astrophysics Data System (ADS)

Side chain homologated derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: pentyl; L-5, hexyl; L-6, heptyl; L-7 and octyl; L-8} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV–visible spectroscopy and LC–MS. Compounds, L-4, {n-alkyl: butyl; L-4}, L-6 and L-8 have been characterized by single crystal X-ray diffraction studies. The single crystal X-ray structures reveal that L-4 and L-8 crystallizes in P21 space group, while L-6 in P21/c space group. Molecules of L-4 and L-8 from polymeric chains through CH⋯O and NH⋯O close contacts. L-6 is a dimer formed by NH⋯O interaction. Slipped ?–? stacking interactions are observed between quinonoid and benzenoid rings of L-4 and L-8. Orientations of alkyl group in L-4 and L-8 is on same side of the chain and polymeric chains run opposite to one another to form zip like structure to the alkyl groups. Antiproliferative activities of L-1 to L-8{n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} were studied in cancer cells of colon (COLO205), brain (U87MG) and pancreas (MIAPaCa2) where L-1, L-2 and L-3 were active in MIAPaCa2 (L-1 = L-2 > L-3) and COLO205 (L-2 = L-3 > L-1) and inactive in U87MG. From antiproliferative studies with compounds L-1 to L-8 it can be concluded that homologation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone with saturated methyl groups yielded tissue specific compounds such as L-2 (for MIAPaCa2) and L-3 (for COLO205) with optimal activity.

Pal, Sanjima; Jadhav, Mahesh; Weyhermüller, Thomas; Patil, Yogesh; Nethaji, M.; Kasabe, Umesh; Kathawate, Laxmi; Konkimalla, V. Badireenath; Salunke-Gawali, Sunita



Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor alpha promoter in vivo.  


Tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of both acute and chronic inflammatory diseases and has been a target for the development of new anti-inflammatory drugs. Shikonins, the naphthoquinone pigments present in the root tissues of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), have been reported to exert anti-inflammatory effects both in vitro and in vivo. In this study, we evaluated the effects of shikonin and its derivatives on the transcriptional activation of human TNF-alpha promoter in a gene gun-transfected mouse skin system by using a luciferase reporter gene assay. The crude plant extract of L. erythrorhizon as well as derived individual compounds shikonin, isobutyryl shikonin, acetyl shikonin, dimethylacryl shikonin and isovaleryl shikonin showed significant dose-dependent inhibition of TNF-alpha promoter activation. Among the tested compounds, shikonin and isobutyryl shikonin exhibited the highest inhibition of TNF-alpha promoter activation and also showed significant suppression of transgenic human TNF-alpha mRNA expression and protein production. We demonstrated that shikonin-inhibitory response was retained in the core TNF-alpha promoter region containing the TATA box and a 48-bp downstream sequence relative to the transcription start site. Further our results indicated that shikonin suppressed the basal transcription and activator-regulated transcription of TNF-alpha by inhibiting the binding of transcription factor IID protein complex (TATA box-binding protein) to TATA box. These in vivo results suggest that shikonins inhibit the transcriptional activation of the human TNF-alpha promoter through interference with the basal transcription machinery. Thus, shikonins may have clinical potential as anti-inflammatory therapeutics. PMID:14645256

Staniforth, Vanisree; Wang, Sheng-Yang; Shyur, Lie-Fen; Yang, Ning-Sun



Deuterium-Labeled Phylloquinone Has Tissue-Specific Conversion to Menaquinone-4 among Fischer 344 Male Rats12  

PubMed Central

Phylloquinone (PK) is converted into menaquinone-4 (MK-4) via side chain removal-addition. Stable isotope use is an effective approach to identify the tissue location of this conversion, which is currently unknown. Following a 14-d PK-deficient diet, male Fischer 344 rats (8 mo; n = 15) were fed 1.6 mg deuterium-labeled PK (L-PK) per kg diet for 0 (control), 1 d (PK-1d), and 7 d (PK-7d). Both L-PK and deuterium-labeled MK-4 (L-MK-4) were detected in tissues in PK-1d and PK-7d, although the results varied. Whereas some tissues had an overall increase in MK-4 in response to L-PK, total brain, testes, and fat MK-4 concentrations did not. In contrast, L-MK-4 concentrations increased in all 3 tissues. The deuterium label was found only on the L-MK-4 naphthoquinone ring, confirming the need for side chain removal for the formation of MK-4. Labeled menadione (MD) was detected in urine and serum in PK-1d and PK-7d, confirming its role as an intermediate. A Caco-2 cell monolayer model was used to study the role of the enterocytes in the conversion process. Neither MK-4 nor MD was detected in Caco-2 cells treated with PK. However, when Caco-2 cells were treated with MD, MK-4 was formed. Similarly, MK-4 was formed in response to MD-treated 293T kidney cells, but not HuH7 liver cells. These data demonstrate that MK-4 is the predominant form of vitamin K in multiple tissues, but there appears to be a tissue-specific regulation for the conversion of PK to MK-4.

Al Rajabi, Ala; Booth, Sarah L.; Peterson, James W.; Choi, Sang Woon; Suttie, John W.; Shea, M. Kyla; Miao, Benchun; Grusak, Michael A.; Fu, Xueyan



Effect of medium composition and light on root and rhinacanthin formation in Rhinacanthus nasutus cultures.  


Rhinacanthus nasutus (L.) Kurz (Acanthaceae) has long been used in Thai traditional medicine for treatment of tinea versicolor, ringworm, pruritic rash, and abscess. The active constituents are known as a group of naphthoquinone esters, rhinacanthins. This work focused on establishment of R. nasutus root cultures and determination of rhinacanthin production. Induction of R. nasutus root formation was accomplished on solid Gamborg's B5 (B5) medium, supplied with 0.1?mg/L indole-3-butyric acid (IBA) and 20?g/L sucrose. The effects of explants (whole leaf explants and four-side excised leaf explants), light and medium composition on root and rhinacanthin formation were investigated. The root formation from the whole leaf explants was 10 times higher than that from the four-side excised leaf explants. In addition, light possessed an inhibitory effect on the root and rhinacanthin formation of R. nasutus. Medium manipulation found that Murashige and Skoog (MS) medium supplied with 3?mg/L IBA and 30?g/L sucrose was the most suitable for induction of the root formation. Unfortunately, the obtained root cultures produced only rhinacanthin-C in very low amount, 0.026?mg/g dry weight (DW), when they were transferred into the same MS liquid medium. With semisolid medium (4?g/L agar) of the same MS composition, however, the root cultures appeared to produce higher content of rhinacanthin-C, -D and -N (3.45, 0.07 and 0.07?mg/g DW, respectively). Our finding suggests that culturing in semisolid medium is capable of improving of rhinacanthin production in R. nasutus root cultures. PMID:20843160

Panichayupakaranant, P; Meerungrueang, W



Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress  

PubMed Central

Cell differentiation is associated with changes in metabolism and function. Understanding these changes during differentiation is important in the context of stem cell research, cancer, and neurodegenerative diseases. An early event in neurodegenerative diseases is the alteration of mitochondrial function and increased oxidative stress. Studies using both undifferentiated and differentiated SH-SY5Y neuroblastoma cells have shown distinct responses to cellular stressors, however the mechanisms remain unclear. We hypothesized that since the regulation of glycolysis and oxidative phosphorylation are modulated during cellular differentiation, this would change bioenergetic function and the response to oxidative stress. To test this, we used retinoic acid (RA) to induce differentiation of SH-SY5Y cells and assessed changes in cellular bioenergetics using extracellular flux analysis. After exposure to RA, the SH-SY5Y cells had an increased mitochondrial membrane potential, without changing mitochondrial number. Differentiated cells exhibited greater stimulation of mitochondrial respiration with uncoupling and an increased bioenergetic reserve capacity. The increased reserve capacity in the differentiated cells was suppressed by the inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG). Furthermore, we found that differentiated cells were substantially more resistant to cytotoxicity and mitochondrial dysfunction induced by reactive lipid species 4-hydroxynonenal (HNE) or the reactive oxygen species generator 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). We then analyzed the levels of selected mitochondrial proteins and found an increase in complex IV subunits which we propose contributes to the increase in reserve capacity in the differentiated cells. Furthermore, we found an increase in MnSOD that could, at least in part, account for the increased resistance to oxidative stress. Our findings suggest that profound changes in mitochondrial metabolism and antioxidant defenses occur upon differentiation of neuroblastoma cells to a neuron-like phenotype.

Schneider, Lonnie; Giordano, Samantha; Zelickson, Blake R.; Johnson, Michelle; Benavides, Gloria; Ouyang, Xiaosen; Fineberg, Naomi; Darley-Usmar, Victor M.; Zhang, Jianhua



Remarkable in vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against tachyzoites and tissue cysts of Toxoplasma gondii.  

PubMed Central

Compound 566C80, 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, was studied for its in vitro and in vivo activities against Toxoplasma gondii. Replication within human foreskin fibroblasts of tachyzoites of seven different strains, five of them isolated from AIDS patients, was inhibited by concentrations as low as 4.8 x 10(-9) M. In vivo, a dose of 100 mg/kg of body weight per day, administered by gavage for 10 days, protected 100% of mice against death due to infection with five different strains of T. gondii, including the highly virulent RH strain. A dose of 50 mg/kg/day protected at least 80% of mice infected with the same inoculum, and a dose as low as 9.3 mg/kg/day protected 40 to 60% of mice. Treatment with 50 mg/kg/day for 30 days completely eradicated parasites from mice infected with four of five strains of T. gondii. 566C80 was active in vitro against the cyst stage of T. gondii at concentrations of 50 to 100 micrograms/ml. In vivo activity against this form of T. gondii was examined in mice infected for 6 weeks with strain ME49 and then treated orally with 100 mg of 566C80 per kg per day for 8 weeks. Treated mice sacrificed at 2-week intervals revealed a steady decline in the numbers of cysts in their brains compared with untreated controls. In addition, mortality as well as clinical signs of brain infection was absent from treated mice, whereas control mice had a high mortality rate and showed clinical signs of central nervous system infection. These results reveal remarkable in vitro and in vivo activities of 566C80 against T. gondii.

Araujo, F G; Huskinson, J; Remington, J S



Alternative quinone substrates and inhibitors of human electron-transfer flavoprotein-ubiquinone oxidoreductase.  

PubMed Central

Electron-transfer flavoprotein (ETF)-ubiquinone (2,3-dimethoxy-5-methyl-1,4-benzoquinone) oxidoreductase (ETF-QO) is a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool. ETF is the intermediate electron carrier between the dehydrogenases and ETF-QO. The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues and analogues that contained saturated n-alkyl substituents at the 6 position. These experiments show that optimal substrates contain a ten-carbon-atom side chain, consistent with a preliminary crystal structure that shows that only the first two of ten isoprene units of co-enzyme Q10 (CoQ10) interact with the protein. Derivatives with saturated alkyl side chains are very good substrates, indicating that, unlike other ubiquinone oxidoreductases, there is little preference for the methyl branches or rigidity of the CoQ side chain. Few of the compounds that inhibit ubiquinone oxidoreductases inhibit ETF-QO. Compounds found to act as inhibitors of ETF-QO include 2-n-heptyl-4-hydroxyquinoline N-oxide, a naphthoquinone analogue, 2-(3-methylpentyl)-4,6-dinitrophenol and pentachlorophenol. 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB), which inhibits the mitochondrial bc1 complex and the chloroplast b6 f complex in redox-dependent fashion, can serve as an electron acceptor for human ETF-QO. The observation of simple Michaelis-Menten kinetic patterns and a single type of quinone-binding site, determined by fluorescence titrations of the protein with DBMIB and 6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO monomer.

Simkovic, Martin; Frerman, Frank E



Effect of nonionic surfactants on the oxidation of carbaryl by anodic Fenton treatment.  


As a potentially promising technology, anodic Fenton treatment (AFT) has been shown to be very successful in pesticide removal. However, the influence of other constituents in the pesticide formulation, such as nonionic surfactants, has not been addressed. In this study, the effect of Triton X (TX) on the degradation kinetics and pathways of carbaryl undergoing AFT was investigated in an effort to facilitate its practical application. The presence of Triton X-100 was found to slow down the carbaryl degradation rate. This result can be attributed to the consumption of hydroxyl radicals ((*)OH) by surfactants and the formation of a carbaryl...TX...Fe(3+) complex, resulting in the unavailability of carbaryl to (*)OH attack. The modified AFT kinetic model previously developed in this laboratory shows an excellent fit to the carbaryl degradation profile (R(2)>0.998), supporting the formation of a carbaryl...TX...Fe(3+) complex. The carbaryl degradation rate decreased as Triton X-100 concentration increased from 20 to 1000 mg L(-1). Both (*)OH consumption by surfactants and complex formation are responsible for the degradation rate reduction below the critical micelle concentration (CMC), whereas the complex and micelle formation becomes a more dominant factor above the CMC. The effect of ethylene oxide (EO) numbers of a given nonionic surfactant mainly lies in the consumption of hydroxyl radicals, which increases with the length of the EO chain, but does not significantly affect the formation of the carbaryl...TX...Fe(3+) complex. Based on the GC-MS and LC-ESI-MS results, no evidence was found that the carbaryl degradation pathway was affected. Carbaryl was typically oxidized to 1-naphthol and 1,4-naphthoquinone similar to what is observed in the absence of surfactants. Triton X-100 was degraded via the breakdown of EO chains and omega-oxidation of the terminal methyl group, which resulted in the production of a series of ethoxylate oligomers. PMID:17459451

Kong, Lingjun; Lemley, Ann T



Oxidation of carbaryl in aqueous solution by membrane anodic fenton treatment.  


Carbaryl, a commonly used insecticide, was used in this study as a probe to investigate a new Fenton treatment technology, ion exchange membrane anodic Fenton treatment (membrane AFT). It was found that the degradation kinetics of carbaryl by membrane AFT obeys a previously published AFT model quite well. The NaCl (electrolyte) concentration in two half-cells was optimized for two kinds of membrane. Effects of the H(2)O(2)/Fe(2+) ratio and the Fenton reagent delivery rate were also investigated. The treatment efficiency for anion membrane AFT is higher than for salt-bridge AFT under the same operating conditions. Decreasing the delivery rate of Fenton reagents and increasing the treatment temperature also increase the treatment efficiency. The activation energy for carbaryl degradation by anion membrane AFT was estimated to be 14.7 kJ x mol(-1). 1-Naphthol, 1,4-naphthoquinone, and (phthalic acid-O-)yl N-methylcarbamate were detected by GC-MS as the degradation products of carbaryl by Fenton treatment. No decrease in carbaryl degradation rate was found during repeated use (100 times) of the anion exchange membrane. High and stable treatment efficiency can be achieved using an anion exchange membrane rather than a salt-bridge in the AFT system. Because of its effectiveness and convenience, the use of an ion exchange membrane as a substitute for the salt-bridge used in the previous AFT system has brought the AFT technology a major step closer to practical application. PMID:11929293

Wang, Qiquan; Lemley, Ann T



Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II.  


Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin. PMID:17618663

Kawiak, Anna; Piosik, Jacek; Stasilojc, Grzegorz; Gwizdek-Wisniewska, Anna; Marczak, Lukasz; Stobiecki, Maciej; Bigda, Jacek; Lojkowska, Ewa



Antibacterial and antioxidant activity of the secondary metabolites from in vitro cultures of Drosera aliciae.  


The objective of this research was to evaluate antioxidant as well as antibacterial properties of secondary metabolites obtained from Drosera aliciae plants grown in vitro and examine the mechanism of their antimicrobial action. Bactericidal activity of extracts from D. aliciae as well as pure ramentaceone (naphthoquinone) present in this plant were examined against human pathogenic strains both resistant and susceptible to antibiotics. Chloroform extract proved to be more effective than methanol preparation against all of the tested strains except for Pseudomonas aeruginosa isolates with the lowest minimal bactericidal concentration (MBC) values in the case of Staphylococcus aureus (25-50 mg fresh weight ml-1). The influence of D. aliciae extracts and ramentaceone on the synthesis of DNA, RNA or proteins in cultures of Enterococcus faecalis was estimated by measurement of incorporation of radioactive precursors: [3H]thymidine, [3H]uridine or [3H]leucine, respectively. Methanol extract from D. aliciae, except for a moderate effect on DNA synthesis, had no influence on RNA and protein synthesis. Chloroform preparation caused about a 75% decrease in [3H]uridine incorporation in comparison to control after 60 min and a significant reduction in DNA and protein synthesis (44% and 30% respectively). Ramentaceone also reduced DNA and RNA synthesis but less efficiently than chloroform extract and caused no changes in [3H]leucine incorporation. Methanol extract from D. aliciae proved to be an effective antioxidant in both the DPPH and FRAP assay with the activities exceeding those of well known antioxidants - flavonoids. Chloroform extract and ramentaceone showed no antioxidative properties. PMID:18782083

Krolicka, Aleksandra; Szpitter, Anna; Maciag, Monika; Biskup, Edyta; Gilgenast, Ewelina; Romanik, Grazyna; Kaminski, Marian; Wegrzyn, Grzegorz; Lojkowska, Ewa



Modeling Bimolecular Reactions and Transport in Porous Media Via Particle Tracking  

SciTech Connect

We use a particle-tracking method to simulate several one-dimensional bimolecular reactive transport experiments. In this numerical method, the reactants are represented by particles: advection and dispersion dominate the flow, and molecular diffusion dictates, in large part, the reactions. The particle/particle reactions are determined by a combination of two probabilities dictated by the physics of transport and energetics of reaction. The first is that reactant particles occupy the same volume over a short time interval. The second is the conditional probability that two collocated particles favorably transform into a reaction. The first probability is a direct physical representation of the degree of mixing in an advancing displacement front, and as such lacks empirical parameters except for the user-defined number of particles. This number can be determined analytically from concentration autocovariance, if this type of data is available. The simulations compare favorably to two physical experiments. In one, the concentration of product, 1,2-naphthoquinoe-4-aminobenzene (NQAB) from reaction between 1,2-naphthoquinone-4-sulfonic acid (NQS) and aniline (AN), was measured at the outflow of a column filled with glass beads at different times. In the other, the concentration distribution of reactants (CuSO_4 and EDTA^{4-}) and products (CuEDTA^{4-}) were quantified by snapshots of transmitted light through a column packed with cryloite sand. The thermodynamic rate coefficient in the latter experiment was 10^7 times greater than the former experiment, making it essentially instantaneous. When compared to the solution of the advection-dispersion-reaction equation (ADRE) with the well-mixed reaction coefficient, the experiments and the particle-tracking simulations showed on the order of 20% to 40% less overall product, which is attributed to poor mixing. The poor mixing also leads to higher product concentrations on the edges of the mixing zones, which the particle model simulates more accurately than the ADRE.

Dong Ding; David Benson; Amir Paster; Diogo Bolster



Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly - a mechanistic study of its antibacterial activity.  


The assembly of FtsZ plays a central role in construction of the cytokinetic Z-ring that orchestrates bacterial cell division. A naturally occurring naphthoquinone, plumbagin, is known to exhibit antibacterial properties against several types of bacteria. In this study, plumbagin was found to perturb formation of the Z-ring in Bacillus subtilis 168 cells and to cause elongation of these cells without an apparent effect on nucleoid segregation, indicating that it may inhibit FtsZ assembly. Furthermore, it bound to purified B. subtilis FtsZ (BsFtsZ) with a dissociation constant of 20.7 ± 5.6 ?m, and inhibited the assembly and GTPase activity of BsFtsZ in vitro. Interestingly, plumbagin did not inhibit either the assembly or GTPase activity of Escherichia coli FtsZ (EcFtsZ) in vitro. Using docking analysis, a putative plumbagin-binding site on BsFtsZ was identified, and the analysis indicated that hydrophobic interactions and hydrogen bonds predominate. Based on the in silico analysis, two variants of BsFtsZ, namely D199A and V307R, were constructed to explore the binding interaction of plumbagin and BsFtsZ. The effects of plumbagin on the assembly and GTPase activity of the variant BsFtsZ proteins in vitro indicated that the residues D199 and V307 may be involved in the binding of plumbagin to BsFtsZ. The results suggest that plumbagin inhibits bacterial proliferation by inhibiting the assembly of FtsZ, and provide insight into the binding site of plumbagin on BsFtsZ, which may help in the design of potent FtsZ-targeted antibacterial agents. PMID:23841620

Bhattacharya, Anusri; Jindal, Bhavya; Singh, Parminder; Datta, Anindya; Panda, Dulal



Anaerobic Respiration of Escherichia coli in the Mouse Intestine ?  

PubMed Central

The intestine is inhabited by a large microbial community consisting primarily of anaerobes and, to a lesser extent, facultative anaerobes, such as Escherichia coli, which we have shown requires aerobic respiration to compete successfully in the mouse intestine (S. A. Jones et al., Infect. Immun. 75:4891-4899, 2007). If facultative anaerobes efficiently lower oxygen availability in the intestine, then their sustained growth must also depend on anaerobic metabolism. In support of this idea, mutants lacking nitrate reductase or fumarate reductase have extreme colonization defects. Here, we further explore the role of anaerobic respiration in colonization using the streptomycin-treated mouse model. We found that respiratory electron flow is primarily via the naphthoquinones, which pass electrons to cytochrome bd oxidase and the anaerobic terminal reductases. We found that E. coli uses nitrate and fumarate in the intestine, but not nitrite, dimethyl sulfoxide, or trimethylamine N-oxide. Competitive colonizations revealed that cytochrome bd oxidase is more advantageous than nitrate reductase or fumarate reductase. Strains lacking nitrate reductase outcompeted fumarate reductase mutants once the nitrate concentration in cecal mucus reached submillimolar levels, indicating that fumarate is the more important anaerobic electron acceptor in the intestine because nitrate is limiting. Since nitrate is highest in the absence of E. coli, we conclude that E. coli is the only bacterium in the streptomycin-treated mouse large intestine that respires nitrate. Lastly, we demonstrated that a mutant lacking the NarXL regulator (activator of the NarG system), but not a mutant lacking the NarP-NarQ regulator, has a colonization defect, consistent with the advantage provided by NarG. The emerging picture is one in which gene regulation is tuned to balance expression of the terminal reductases that E. coli uses to maximize its competitiveness and achieve the highest possible population in the intestine.

Jones, Shari A.; Gibson, Terri; Maltby, Rosalie C.; Chowdhury, Fatema Z.; Stewart, Valley; Cohen, Paul S.; Conway, Tyrrell



Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats  

PubMed Central

Background There is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells. Methodology/Principal Findings Shikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. Conclusions/Significance Shikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.

Csikasz, Robert I.; Dehvari, Nodi; Shabalina, Irina G.; Hutchinson, Dana S.; Wilcke, Mona; Ostenson, Claes-Goran; Bengtsson, Tore



Discovery of Potent Small-Molecule Inhibitors of Multidrug-Resistant Plasmodium falciparum Using a Novel Miniaturized High-Throughput Luciferase-Based Assay ? †  

PubMed Central

Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by Plasmodium falciparum. Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites, which necessitates the discovery of new drugs. To identify new antimalarials, we developed an automated 384-well plate screening assay using P. falciparum parasites that stably express cytoplasmic firefly luciferase. After initial optimization, we tested two different types of compound libraries: known bioactive collections (Library of Pharmacologically Active Compounds [LOPAC] and the library from the National Institute of Neurological Disorders and Stroke [NINDS]) and a library of uncharacterized compounds (ChemBridge). A total of 12,320 compounds were screened at 5.5 ?M. Selecting only compounds that reduced parasite growth by 85% resulted in 33 hits from the combined bioactive collection and 130 hits from the ChemBridge library. Fifteen novel drug-like compounds from the bioactive collection were found to be active against P. falciparum. Twelve new chemical scaffolds were found from the ChemBridge hits, the most potent of which was a series based on the 1,4-naphthoquinone scaffold, which is structurally similar to the FDA-approved antimalarial atovaquone. However, in contrast to atovaquone, which acts to inhibit the bc1 complex and block the electron transport chain in parasite mitochondria, we have determined that our new 1,4-napthoquinones act in a novel, non-bc1-dependent mechanism and remain potent against atovaquone- and chloroquine-resistant parasites. Ultimately, this study may provide new probes to understand the molecular details of the malaria life cycle and to identify new antimalarials.

Lucumi, Edinson; Darling, Claire; Jo, Hyunil; Napper, Andrew D.; Chandramohanadas, Rajesh; Fisher, Nicholas; Shone, Alison E.; Jing, Huiyan; Ward, Stephen A.; Biagini, Giancarlo A.; DeGrado, William F.; Diamond, Scott L.; Greenbaum, Doron C.



Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents.  


Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion. PMID:22536197

Wink, Michael; Ashour, Mohamed L; El-Readi, Mahmoud Zaki



Regulation of Arabidopsis SHY2/IAA3 protein turnover.  


Auxin/indole acetic acid (Aux/IAA) proteins regulate transcriptional responses to the plant hormone auxin. Gain-of-function mutations in the Arabidopsis SHORT HYPOCOTYL 2 (SHY2/IAA3) gene encoding an Aux/IAA protein increase steady-state levels of SHY2/IAA3 protein and decrease auxin responses, indicating that SHY2/IAA3 negatively regulates auxin signaling. These shy2 mutations also cause ectopic light responses, suggesting that SHY2/IAA3 may promote light signaling. Auxin regulates turnover of the related Auxin-resistant (AXR)2/IAA7 and AXR3/IAA17 proteins by increasing their interaction with the Skp1-Cdc53/cullin-F-box (SCFTIR1) E3 ubiquitin ligase complex. To investigate whether SHY2/IAA3 is regulated similarly, we have used a turnover assay to reveal that axr1 and transport inhibitor resistant (tir)1 mutations affecting SCFTIR1 decrease SHY2/IAA3 turnover. In pull-down assays, SHY2/IAA3 protein interacted with TIR1, the F-box component of SCFTIR1 and with the photoreceptor phytochrome B. Auxin stimulated SHY2/IAA3 interaction with TIR1, whereas the shy2-2 gain-of-function mutation decreased this interaction. Light did not affect the interaction, suggesting that light regulates some other aspect of Aux/IAA gene or protein function. The chemical juglone (5-hydroxy-1,4-naphthoquinone) inhibited the interaction, suggesting that peptidyl-prolyl isomerization may mediate auxin-induced SHY2/IAA3 protein turnover. PMID:14617065

Tian, Qing; Nagpal, Punita; Reed, Jason W



Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 inhibition  

SciTech Connect

Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle and the arylation of intracellular nucleophiles. As the redox cycle is catalyzed by NADPH cytochrome P450 reductase, cytochrome P450 systems are expected to be related to the cytotoxicity induced by redox-cycling quinones. Thus, we investigated the relationship between cytochrome P450 systems and quinone toxicity for rat primary hepatocytes using an arylator, 1,4-benzoquinone (BQ), and a redox cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). The hepatocyte toxicity of both BQ and DMNQ increased in a time- and dose-dependent manner. Pretreatment with cytochrome P450 inhibitors, such as SKF-525A (SKF), ketoconazole and 2-methy-1,2-di-3-pyridyl-1-propanone, enhanced the hepatocyte toxicity induced by DMNQ but did not affect BQ-induced hepatocyte toxicity. The production of superoxide anion and the levels of glutathione disulfide and thiobarbituric-acid-reactive substances were increased by treatment with DMNQ, and SKF pretreatment further enhanced their increases. In addition, NADPH oxidation in microsomes was increased by treatment with DMNQ and further augmented by pretreatment with SKF, and a NADPH cytochrome P450 reductase inhibitor, diphenyleneiodonium chloride completely suppressed NADPH oxidations increased by treatment with either DMNQ- or DMNQ + SKF. Pretreatment with antioxidants, such as {alpha}-tocopherol, reduced glutathione, N-acetyl cysteine or an iron ion chelator deferoxamine, totally suppressed DMNQ- and DMNQ + SKF-induced hepatocyte toxicity. These results indicate that the hepatocyte toxicity of redox-cycling quinones is enhanced under cytochrome P450 inhibition, and that this enhancement is caused by the potentiation of oxidative stress.

Ishihara, Yasuhiro [Department of Biology, Graduate School of Science, Osaka University, Osaka 532-8686 (Japan); Shiba, Dai [Department of Biology, Graduate School of Science, Osaka University, Osaka 532-8686 (Japan); Shimamoto, Norio [Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1, Shido, Sanuki, Kagawa 769-2193 (Japan)]. E-mail:



[Intratumoral administration of biological preparations--recommendation for integrative medicine].  


The antitumor effect of biological preparations was examined in a double grafted tumor system. PSK is a hot water extract of cultured mycelia from Coliolus versicolor. Its protein content is about 38% and the main glycoside portion of PSK is beta-D-glucan. Lentinan is purified from fruit bodies of Lentinus edodes and is a beta-1, 3-glucan. Cepharanthin is an extract from the root of Stephania cepharantha HAYATA, consisting of 4 kinds of biscoclaurine alkaloids. TAHEEBO tea is a hot water extract of Tabebuia avellanedae, the active ingredient of which is naphthoquinones. If protein-bound polysaccharides were to be used in Western medicine, these polysaccharides would be purified, but purified beta-glucan loses its beneficial effects. Similarly, when raw Cepharanthin is purified to isolate its active ingredient (an alkaloid cepharanthine), its anti-tumor effect is weakened. Clear IAP induction was observed in serum of mice treated with extracts of Coliolus versicolor and Stephania cepharantha. However, IAP induction was not observed in the serum of mice treated with purified beta-glucan or purified alkaloid. This suggests that macrophages may recognize extracts but not purified substances. In Western medicine, purified substances with known chemical structures are recognized as drugs, but overdoses of these drugs are toxic to the body, thus adverse reactions are always an issue. In Chinese medicine, mixtures containing several crude drugs are recognized as drugs, whose active ingredients are not identified. In integrative medicine, drugs are extracts that contain active ingredients with known structures and functions. We propose a Japanese version of integrative medicine which is neither Western nor Chinese. PMID:11707968

Ebina, T



Affinity and activity of non-native quinones at the QB site of bacterial photosynthetic reaction centers.  


Purple, photosynthetic reaction centers from Rhodobacter sphaeroides bacteria use ubiquinone (UQ10) as both primary (QA) and secondary (QB) electron acceptors. Many quinones reconstitute QA function, while a few will act as QB. Nine quinones were tested for their ability to bind and reconstitute QA and QB functions. Only ubiquinone (UQ) reconstitutes both functions in the same protein. The affinities of the non-native quinones for the QB site were determined by a competitive inhibition assay. The affinities of benzoquinones, naphthoquinone (NQ), and 2-methyl-NQ for the QB site are 7 ± 3 times weaker than that at QA site. However, di-ortho-substituted NQs and anthraquinone bind tightly to the QA site (K d ? 200 nM), and ?1,000 times more weakly to the QB site, perhaps setting a limit on the size of the site. With a low-potential electron donor, 2-methyl, 3-dimethylamino-1,4-NQ, (Me-diMeAm-NQ) at QA, QB reduction is 260 meV, more favorable than with UQ as QA. Electron transfer from Me-diMeAm-NQ at the QA site to NQ at the QB site can be detected. In the QB site, the NQ semiquinone is estimated to be ?60-100 meV higher in energy than the UQ semiquinone, while in the QA site, the semiquinone energy level is similar or lower with NQ than with UQ. Thus, the NQ semiquinone is more stable in the QA than in the QB site. In contrast, the native UQ semiquinone is ?60 meV lower in energy in the QB than in the QA site, stabilizing forward electron transfer from QA to QB. PMID:23715773

Zhang, Xinyu; Gunner, M R



Development of Enantioselective Synthetic Routes to (-)-Kinamycin F and (-)-Lomaiviticin Aglycon  

PubMed Central

The development of enantioselective synthetic routes to (–)-kinamycin F (9) and (–)-lomaiviticin aglycon (6) is described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a ?-trimethylsilylmethyl-?,?-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39?37), and diazo transfer (37?53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the ?-trimethylsilylmethyl-?,?-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer, provided the advanced diazofluorene 63, which was elaborated to (–)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C2-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid–dichloromethane) to form the chain isomer of lomaiviticin aglycon 98, which cyclizes to (–)-lomaiviticin aglycon (6, 39–41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%, Table 2); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%, Table 1). We establish that dimeric diazofluorenes undergo hydrodediazotization 3-fold faster then related monomeric diazofluorenes (Table 6). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC50 = 500 nM).

Woo, Christina M.; Gholap, Shivajirao L.; Lu, Liang; Kaneko, Miho; Li, Zhenwu; Ravikumar, P. C.; Herzon, Seth B.



Deuterium-labeled phylloquinone has tissue-specific conversion to menaquinone-4 among Fischer 344 male rats.  


Phylloquinone (PK) is converted into menaquinone-4 (MK-4) via side chain removal-addition. Stable isotope use is an effective approach to identify the tissue location of this conversion, which is currently unknown. Following a 14-d PK-deficient diet, male Fischer 344 rats (8 mo; n = 15) were fed 1.6 mg deuterium-labeled PK (L-PK) per kg diet for 0 (control), 1 d (PK-1d), and 7 d (PK-7d). Both L-PK and deuterium-labeled MK-4 (L-MK-4) were detected in tissues in PK-1d and PK-7d, although the results varied. Whereas some tissues had an overall increase in MK-4 in response to L-PK, total brain, testes, and fat MK-4 concentrations did not. In contrast, L-MK-4 concentrations increased in all 3 tissues. The deuterium label was found only on the L-MK-4 naphthoquinone ring, confirming the need for side chain removal for the formation of MK-4. Labeled menadione (MD) was detected in urine and serum in PK-1d and PK-7d, confirming its role as an intermediate. A Caco-2 cell monolayer model was used to study the role of the enterocytes in the conversion process. Neither MK-4 nor MD was detected in Caco-2 cells treated with PK. However, when Caco-2 cells were treated with MD, MK-4 was formed. Similarly, MK-4 was formed in response to MD-treated 293T kidney cells, but not HuH7 liver cells. These data demonstrate that MK-4 is the predominant form of vitamin K in multiple tissues, but there appears to be a tissue-specific regulation for the conversion of PK to MK-4. PMID:22437559

Al Rajabi, Ala; Booth, Sarah L; Peterson, James W; Choi, Sang Woon; Suttie, John W; Shea, M Kyla; Miao, Benchun; Grusak, Michael A; Fu, Xueyan



Glucocorticoids induce long-lasting effects in neural stem cells resulting in senescence-related alterations.  


Alterations in intrauterine programming occurring during critical periods of development have adverse consequences for whole-organ systems or individual tissue functions in later life. In this paper, we show that rat embryonic neural stem cells (NSCs) exposed to the synthetic glucocorticoid dexamethasone (Dex) undergo heritable alterations, possibly through epigenetic mechanisms. Exposure to Dex results in decreased NSC proliferation, with no effects on survival or differentiation, and changes in the expression of genes associated with cellular senescence and mitochondrial functions. Dex upregulates cell cycle-related genes p16 and p21 in a glucocorticoid receptor(GR)-dependent manner. The senescence-associated markers high mobility group (Hmg) A1 and heterochromatin protein 1 (HP1) are also upregulated in Dex-exposed NSCs, whereas Bmi1 (polycomb ring finger oncogene) and mitochondrial genes Nd3 (NADH dehydrogenase 3) and Cytb (cytochrome b) are downregulated. The concomitant decrease in global DNA methylation and DNA methyltransferases (Dnmts) suggests the occurrence of epigenetic changes. All these features are retained in daughter NSCs (never directly exposed to Dex) and are associated with a higher susceptibility to oxidative stress, as shown by the increased occurrence of apoptotic cell death on exposure to the redox-cycling reactive oxygen species (ROS) generator 2,3-dimethoxy-1-naphthoquinone (DMNQ). Our study provides novel evidence for programming effects induced by glucocorticoids (GCs) on NSCs and supports the idea that fetal exposure to endogenous or exogenous GCs is likely to result in long-term consequences that may predispose to neurodevelopmental and/or neurodegenerative disorders. PMID:21368868

Bose, R; Moors, M; Tofighi, R; Cascante, A; Hermanson, O; Ceccatelli, S



Functional anatomy of scent glands in Paranemastoma quadripunctatum (Opiliones, Dyspnoi, Nemastomatidae).  


The morphological organization and functional anatomy of prosomal defensive (scent) glands in Paranemastoma quadripunctatum, a representative of the dyspnoid harvestmen, was investigated by means of histological semithin sections, software-based 3D-reconstruction and scanning electron microscopy. Scent glands comprise large, hollow sacs on either side of the prosoma, each of these opening to the outside via one orifice (ozopore) immediately above coxa I. In contrast to the situation known from laniatorean, cyphophthalmid and some eupnoid Opiliones, ozopores are not exposed but hidden in a depression (atrium), formed by a dorsal integumental fold of the carapace and the dorsal parts of coxae I. Glandular sacs are connected to ozopores via a short duct which is equipped with a specific closing mechanism in its distal part: A layer of modified epidermal cells forms a kind of pad-like tissue, surrounding the duct like a valve. Several muscles attached to the anterior parts of the glandular reservoir and to the epithelial pad may be associated with ozopore-opening. The actual mechanism of secretion discharge seems to be highly unusual and may be hypothesized on the basis of corroborating data from behavioral observations, scent gland anatomy and secretion chemistry as follows: Enteric fluid is considered to be directed towards the ozopores via cuticular grooves in the surface of the coxapophyses of legs I. Then, the fluid is sucked into the anterior part of the scent gland reservoirs by the action of dorsal dilator muscles that widen the reservoir and produce a short-term negative pressure. After dilution/solution of the naphthoquinone-rich scent gland contents, a secretion-loaded fluid is thought to be discharged with the help of transversal compressor muscles. This is the first detailed study on the functional anatomy of scent glands and the mechanisms of secretion discharge in the Dyspnoi. PMID:21618269

Schaider, Miriam; Komposch, Christian; Stabentheiner, Edith; Raspotnig, Günther



Potential of herbs in skin protection from ultraviolet radiation.  


Herbs have been used in medicines and cosmetics from centuries. Their potential to treat different skin diseases, to adorn and improve the skin appearance is well-known. As ultraviolet (UV) radiation can cause sunburns, wrinkles, lower immunity against infections, premature aging, and cancer, there is permanent need for protection from UV radiation and prevention from their side effects. Herbs and herbal preparations have a high potential due to their antioxidant activity, primarily. Antioxidants such as vitamins (vitamin C, vitamin E), flavonoids, and phenolic acids play the main role in fighting against free radical species that are the main cause of numerous negative skin changes. Although isolated plant compounds have a high potential in protection of the skin, whole herbs extracts showed better potential due to their complex composition. Many studies showed that green and black tea (polyphenols) ameliorate adverse skin reactions following UV exposure. The gel from aloe is believed to stimulate skin and assist in new cell growth. Spectrophotometer testing indicates that as a concentrated extract of Krameria triandra it absorbs 25 to 30% of the amount of UV radiation typically absorbed by octyl methoxycinnamate. Sesame oil resists 30% of UV rays, while coconut, peanut, olive, and cottonseed oils block out about 20%. A "sclerojuglonic" compound which is forming from naphthoquinone and keratin is the reaction product that provides UV protection. Traditional use of plant in medication or beautification is the basis for researches and making new trends in cosmetics. This review covers all essential aspects of potential of herbs as radioprotective agents and its future prospects. PMID:22279374

Kora?, Radava R; Khambholja, Kapil M



Seasonal nutrient dynamics in the Anacostia River (D.C., USA): geochemistry and hydrocarbon biomarkers  

NASA Astrophysics Data System (ADS)

The seasonal biogeochemistry of the urban Anacostia River (Washington D.C. USA) was investigated. Chemical parameters examined include: inorganics (Ca, Mg, Na, S, K, P, NO3, NH4, PO4, B, Ba, Ni, Co); fatty acids and other hydrocarbons; C, N and S stable isotopes; and other water chemistry indicators (hardness, salinity, alkalinity, soluble salts, SAR, TDS). Between April and July 2010, water and sediment were sampled from three tidal freshwater sites along the Anacostia River (UP, MID, and DWN). Two of the selected sites, UP and DWN, are located next to a combined sewage outflow. Water column nutrient analysis shows increasing availability of ammonium (NH4) and nitrate (NO3) at all sites between April and July. At MID, the site showing the highest rates of nutrient growth over the sampling period, NH4 concentrations increase from 0.13 to 1.49 µg/L and NO3 concentrations increase from 0.71 to 2.88 mg/L. A marked NO3 pulse is observed at the DWN site in early May; NO3 concentrations jump from 0.68 to 3.36 mg/L between April 5 and May 6, decreasing to 1.22 mg/L by May 20. Unlike UP and MID, which show NH4 and NO3 increasing concurrently, this NO3 pulse at DWN is accompanied with a decline in NH4 levels, suggestive of an allochthonous NO3 source. Forthcoming stable isotope data are expected to characterize the source of such nitrogen inputs, as well as organic material, throughout the year. Preliminary GC-MS analysis of isolated fatty acids does not explicitly suggest bacterial or higher plant dominance in the spring; however, some notable compounds were identified, such as the PAH fluoranthene, naphthoquinone, and testosterone, as well as a number of cholesterols and other steroids. Higher proportions of bacterial fatty acid biomarkers are expected during the summer. Principle Component Analysis (PCA) of the chemistry data suggests geochemical variables, rather than nutrients, are the driving forces of observed trends. PCA, along with fatty acid characterization and nutrient analysis, is expected to demonstrate an increasing role of bacterial production and nutrient variables later in the season, while stable isotope values will facilitate organic material source identification.

Sarraino, S.; Frantz, D. E.; Macavoy, S. E.



NapGH components of the periplasmic nitrate reductase of Escherichia coli K-12: location, topology and physiological roles in quinol oxidation and redox balancing.  

PubMed Central

Nap (periplasmic nitrate reductase) operons of many bacteria include four common, essential components, napD, napA, napB and napC (or a homologue of napC ). In Escherichia coli there are three additional genes, napF, napG and napH, none of which are essential for Nap activity. We now show that deletion of either napG or napH almost abolished Nap-dependent nitrate reduction by strains defective in naphthoquinone synthesis. The residual rate of nitrate reduction (approx. 1% of that of napG+ H+ strains) is sufficient to replace fumarate reduction in a redox-balancing role during growth by glucose fermentation. Western blotting combined with beta-galactosidase and alkaline phosphatase fusion experiments established that NapH is an integral membrane protein with four transmembrane helices. Both the N- and C-termini as well as the two non-haem iron-sulphur centres are located in the cytoplasm. An N-terminal twin arginine motif was shown to be essential for NapG function, consistent with the expectation that NapG is secreted into the periplasm by the twin arginine translocation pathway. A bacterial two-hybrid system was used to show that NapH interacts, presumably on the cytoplasmic side of, or within, the membrane, with NapC. As expected for a periplasmic protein, no NapG interactions with NapC or NapH were detected in the cytoplasm. An in vitro quinol dehydrogenase assay was developed to show that both NapG and NapH are essential for rapid electron transfer from menadiol to the terminal NapAB complex. These new in vivo and in vitro results establish that NapG and NapH form a quinol dehydrogenase that couples electron transfer from the high midpoint redox potential ubiquinone-ubiquinol couple via NapC and NapB to NapA.

Brondijk, T Harma C; Nilavongse, Arjaree; Filenko, Nina; Richardson, David J; Cole, Jeffrey A



Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models  

SciTech Connect

A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p pharmacokinetic and 2 harmacokinetic 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.

Bogen, K T



Recent acquisitions on chemotherapy and chemoprophylaxis of malaria.  


The most recent acquisitions on chemotherapy and chemoprophylaxis of malaria are reviewed. With regard to chemotherapy, candidate antimalarial compounds have been divided into four groups, according to their stages of development. Mefloquine and the combination of mefloquine with sulfadoxine/pyrimethamine belong to the first group: they have completed clinical trials and have been registered in several countries for routine clinical use. The second group is characterized by chemical compounds which are in an advanced stage of development, including clinical trials. The compounds considered in this group are: a) the 9-phenanthrenemethanols, among which halofantrine is the most promising one; b) the sesquiterpene lactones such as Qinghaosu, artemether, artesunate, artesunic acid and arteether which must be further tested in order to find more effective drug regimens capable of eliminating recrudescences and for the completion of toxicity studies; c) pyronaridine, which appears to be a promising antimalarial, effective also against chloroquine-resistant P. falciparum, but still requiring further investigations on resistance and cross-resistance, as well as its pharmacokinetics, tolerability and bioavailability; d) enpiroline, another promising compound, which needs to be further studied in Phase II and Phase III investigations with naturally acquired malaria. The third group is composed of seven chemical classes of compounds that are in an advanced pre-clinical development, namely: the 4-aminoquinolines, such as dabechin, piperaquine, hydroxypiperaquine, tripiperaquine, dichlor-quinazine and the Mannich base compounds, the 8-aminoquinolines, the 4-quinolinemethanols, the quinolones, the naphthoquinones, the quinazolines and the dihydrotriazines. Among the many antimalarial compounds of interest, which can be considered at the moment as leads for further studies, only the acridandione derivatives such as floxacrine, the antibiotics, antifungal agents or their metabolites, plant substances such as Yingzhaosu A and quassinoids have been mentioned. Malaria chemoprophylaxis, especially in chloroquine-resistant P. falciparum areas, has become a real problem. The attempts to secure protection under these circumstances with the utilization of amodiaquine, the combination of sulfadoxine/pyrimethamine (Fansidar), sulfalene/pyrimethamine (Metakelfin), of pyrimethamine/dapsone (Maloprim), with or without chloroquine, had to be abandoned or to be used with caution in view of the severe complications following the weekly administration of these drugs. The combination of chloroquine with proguanil or chlorproguanil, which could be recommended on theoretical bases, did not meet the expectations when tested in the field. (ABSTRACT TRUNCATED AT 400 WORDS) PMID:2698608

Onori, E; Majori, G



Structural-Functional Characterization and Physiological Significance of Ferredoxin-NADP+ Reductase from Xanthomonas axonopodis pv. citri  

PubMed Central

Xanthomonas axonopodis pv. citri is a phytopathogen bacterium that causes severe citrus canker disease. Similar to other phytopathogens, after infection by this bacterium, plants trigger a defense mechanism that produces reactive oxygen species. Ferredoxin-NADP+ reductases (FNRs) are redox flavoenzymes that participate in several metabolic functions, including the response to reactive oxygen species. Xanthomonas axonopodis pv. citri has a gene (fpr) that encodes for a FNR (Xac-FNR) that belongs to the subclass I bacterial FNRs. The aim of this work was to search for the physiological role of this enzyme and to characterize its structural and functional properties. The functionality of Xac-FNR was tested by cross-complementation of a FNR knockout Escherichia coli strain, which exhibit high susceptibility to agents that produce an abnormal accumulation of •O2-. Xac-FNR was able to substitute for the FNR in E. coli in its antioxidant role. The expression of fpr in X. axonopodis pv. citri was assessed using semiquantitative RT-PCR and Western blot analysis. A 2.2-fold induction was observed in the presence of the superoxide-generating agents methyl viologen and 2,3-dimethoxy-1,4-naphthoquinone. Structural and functional studies showed that Xac-FNR displayed different functional features from other subclass I bacterial FNRs. Our analyses suggest that these differences may be due to the unusual carboxy-terminal region. We propose a further classification of subclass I bacterial FNRs, which is useful to determine the nature of their ferredoxin redox partners. Using sequence analysis, we identified a ferredoxin (XAC1762) as a potential substrate of Xac-FNR. The purified ferredoxin protein displayed the typical broad UV-visible spectrum of [4Fe-4S] clusters and was able to function as substrate of Xac-FNR in the cytochrome c reductase activity. Our results suggest that Xac-FNR is involved in the oxidative stress response of Xanthomonas axonopodis pv. citri and performs its biological function most likely through the interaction with ferredoxin XAC1762.

Delprato, Maria Laura; Ceccarelli, Eduardo A.; Orellano, Elena G.



Bioactive compounds from northern plants.  


Northern conditions are characterised by long days with much light and low temperatures during the growing season. It has been chimed that herbs and berries grown in the north are stronger tasting compared to those of southern origin. The compounds imparting aroma and color to berries and herbs are secondary metabolites which in plants mostly act as chemical means of defense. Recently, the production of secondary metabolites using plant cells has been the subject of expanding research. Light intensity, photoperiod and temperature have been reported to influence the biosynthesis of many secondary metabolites. Native wild aromatic and medicinal plant species of different families are being studied to meet the needs of raw material for the expanding industry of e.g., health-promoting food products known as nutraceutics. There are already a large number of known secondary compounds produced by plants, but the recent advances in modern extraction and analysis should enable many more as yet unknown compounds to be found, characterised and utilised. Rose root (Rhodiola rosea) is a perennial herbaceous plant which inhabits mountain regions throughout Europe, Asia and east coastal regions of North America. The extract made from the rhizomes acts as a stimulant like the Ginseng root. Roseroot has been categorized as an adaptogen and is reported to have many pharmacological properties. The biologically active components of the extract are salitroside tyrosol and cinnamic acid glycosides (rosavin, rosarin, rosin). Round-leaved sundew (Drosera rotundifolia L.) has circumboreal distribution. It inhabits nutrient-poor, moist and sunny areas such as peat bogs and wetlands. Sundew leaves are collected from the wild-type for various medicinal preparations and can be utilized in treating e.g., as an important "cough-medicine" for different respiratory diseases. The antimicrobial activity of extracts of aerial parts against various bacteria has been investigated. Drosera produces various secondary metabolites. The most abundant, among these compounds, are the naphthoquinones. Bilberry (Vaccinium myrtillus) is a characteristic field layer species in boreal forests. Bilberry and other northern Vaccinium species, berries and leaves, contain high amounts of phenolic compounds. Bilberries are known for its exceptionally high amounts ofanthocyanins with powerful antioxidant capacity. They have been shown to possess beneficial health effects, like having a protective role in cardiovascular diseases and cancer. Many flavonoids also seem to have antiviral, antibacterial, antifungal and antiallergenic properties. The effect of ingested cranberry (V. oxycoccus) juice has been shown to prevent urinary tract infections in women. PMID:21520706

Hohtola, Anja



[The chemotherapy of Chagas disease].  


To date, Chagas disease has defied all attempts to develop an efficient and safe chemotherapy. Drugs effective on T. cruzi as trypanocidal agents may be classified as (a) drugs of extensive clinical use: Nifurtimox and Benznidazole; (b) drugs of restricted clinical use: azoles (e.g. Ketoconazole, Econazole; Miconazole); Amphotericin B; Allopurinol, Allopurinol ribosides and Primaquine; (d) drugs effective on T. cruzi and in experimental Chagas disease (murine model): alkyllysophospholipids; 5-amino-imidazole-4-carboxamides; bisbenzyl-isoquinolines; cruzipain (crucein) inhibitors; Gossipol; phenothiazines; d) drugs effective in vitro without other reported effects, acridines, actinomycin D, Crystal Violet (gentian violet), diterpenes (Mikania obtusata); N,N'-dimethyl-2-propen-1-amine, epoxidienthiol carbamates, Fe-chelators, guanyl hydrazones, o-naphthoquinones (beta-lapachone); quinoids (miconidine; tingenone); Olivacine, phenazine methosulfate, phenoxi-phenoxyl drugs, Proadifen, pyridinium azolate betaines, sesquiterpenes (Lychophora sp), sesquiterpene lactones, tetrahydrocarbazoles, DL-alpha-trifluoromethylarginine, triphenylmetane dyes. It is generally agreed that Nifurtimox and Benznidazole (a) are effective on acute Chagas' disease, but may not be effective in the chronic phase; (b) their effect depends on the susceptibility of T. cruzi strains to the drug; (c) they produce adverse effects in patients that may prevent prolonged treatments; they are genotoxic and produce biochemical damage in the mammalian tissues. Redox-cycling of Nifurtimox and Benznidazolee generates "reactive oxygen species" which explain the biological effects. At variance with the mammalian host, T. cruzi is deficient in antioxidant enzymes which are essential to prevent oxidative damage. Azoles are effective inhibitors of T. cruzi growth in vitro and in vivo since they inhibit sterol C14-delta 24(25) demethylase, an enzyme catalysing ergosterol production. Azoles reduce parasitemia and extend the survival of infected mice but do not produce parasitological cure and their clinical effectiveness is questionable. Allopurinol allopurinol ribosides and related compounds inhibit T. cruzi hypoxantine-guanine ribosyl transferase, thus preventing the synthesis of adenylic and guanylic acids and also DNA. They reduce parasitemia and negativize xenodiagnosis but these effects may not be permanent, which invalidates their clinical use. Cysteine-protease inhibitors recognize T. cruzi protease (cruzipain, crucein) active site, thus allowing a covalent linkage with the inhibitor. These peptide inhibitors are effective in acute and chronic murine models. Phenothiazines inhibit trypanothione reductase and a specially favoured fit is a small 2-substitued 2-chloro and 2-trifluoromethyl with a remote hydrophobic patch. The essential phenotiazine nucleus can adopt more than one inhibitory orientation in its binding site. Phenothiazines are promising trypanocidal agents for the treatment of Chagas' disease. The methodology for developing new drugs for the treatment of Chagas' disease is discussed. PMID:10668258

Stoppani, A O



Search for constituents with neurotrophic factor-potentiating activity from the medicinal plants of paraguay and Thailand.  


20 medicinal plants of Paraguay and 3 medicinal plants of Thailand were examined on nerve growth factor (NGF)-potentiating activities in PC12D cells. The trail results demonstrated that the methanol extracts of four plants, Verbena littoralis, Scoparia dulcis, Artemisia absinthium and Garcinia xanthochymus, markedly enhanced the neurite outgrowth induced by NGF from PC12D cells. Furthermore, utilizing the bioactivity-guided separation we successfully isolated 32, 4 and 5 constituents from V. littoralis, S. dulcis and G. xanthochymus, respectively, including nine iridoid and iridoid glucosides (1-9), two dihydrochalcone dimers (10 and 11), two flavonoids and three flavonoid glycosides (12-16), two sterols (17 and 18), ten triterpenoids (19-28), five xanthones (29-33), one naphthoquinone (34), one benzenepropanamide (35), four phenylethanoid glycosides (36-39) and two other compounds (40 and 41). Among which, 15 compounds (1-4, 10-11, 14-18, 29-31 and 34) were new natural products. The results of pharmacological trails verified that littoralisone (1), gelsemiol (5), 7a-hydroxysemperoside aglucone (6), verbenachalcone (10), littorachalcone (11), stigmast-5-ene 3beta,7alpha,22alpha-triol (18), ursolic acid (19), 3beta-hydroxyurs-11-en-28,13beta-olide (24), oleanolic acid (25), 2alpha,3beta-dihydroxyolean-12-en-28-oic acid (26), 1,4,5,6-tetrahydroxy-7,8-di(3-methylbut-2-enyl)xanthone (29), 1,2,6-trihydroxy-5-methoxy-7-(3-methylbut-2-enyl)xanthone (30), 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-butenyl)xanthone (31), 12b-hydroxy-des-D-garcigerrin A (32), garciniaxanthone E (33) and (4R)-4,9-dihydroxy-8-methoxy-alpha-lapachone (34) elicited marked enhancement of NGF-mediated neurite outgrowth in PC12D cells. These substances may contribute to the basic study and the medicinal development for the neurodegenerative disorder. PMID:15235225

Li, Yushan; Ohizumi, Yasushi



Naphthalene distributions and human exposure in Southern California  

NASA Astrophysics Data System (ADS)

The regional distribution of, and human exposure to, naphthalene are investigated for Southern California. A comprehensive approach is taken in which advanced models are linked for the first time to quantify population exposure to the emissions of naphthalene throughout Southern California. Naphthalene is the simplest and most abundant of the polycyclic aromatic hydrocarbons found in polluted urban environments, and has been detected in both outdoor and indoor air samples. Exposure to high concentrations of naphthalene may have adverse health effects, possibly causing cancer in humans. Among the significant emission sources are volatilization from naphthalene-containing products, petroleum refining, and combustion of fossil fuels and wood. Gasoline and diesel engine exhaust, with related vaporization from fuels, are found to contribute roughly half of the daily total naphthalene burden in Southern California. As part of this study, the emission inventory for naphthalene has been verified against new field measurements of the naphthalene-to-benzene ratio in a busy traffic tunnel in Los Angeles, supporting the modeling work carried out here. The Surface Meteorology and Ozone Generation (SMOG) airshed model is used to compute the spatial and temporal distributions of naphthalene and its photooxidation products in Southern California. The present simulations reveal a high degree of spatial variability in the concentrations of naphthalene-related species, with large diurnal and seasonal variations as well. Peak naphthalene concentrations are estimated to occur in the early morning hours in the winter season. The naphthalene concentration estimates obtained from the SMOG model are employed in the Regional Human Exposure (REHEX) model to calculate population exposure statistics. Results show average hourly naphthalene exposures in Southern California under summer and winter conditions of 270 and 430 ng m -3, respectively. Exposure to significantly higher concentrations may occur for individuals close to local sources, or in naphthalene "hotspots" revealed by simulations and observations. Such levels of naphthalene exposure may be used to gauge the potential health impacts of long-term naphthalene exposure. Results are also given for the distributions of 1,4-naphthoquinone, a naphthalene reaction product that may have significant health effects.

Lu, Rong; Wu, Jun; Turco, Richard P.; Winer, Arthur M.; Atkinson, Roger; Arey, Janet; Paulson, Suzanne E.; Lurmann, Fred W.; Miguel, Antonio H.; Eiguren-Fernandez, Arantzazu


Dimeric Fe (II, III) complex of quinoneoxime as functional model of PAP enzyme: Mössbauer, magneto-structural and DNA cleavage studies  

NASA Astrophysics Data System (ADS)

Purple acid phosphatase, ( PAP), is known to contain dinuclear Fe2 + 2, + 3 site with characteristic Fe + 3 ? Tyr ligand to metal charge transfer in coordination. Phthiocoloxime (3-methyl-2-hydroxy-1,4-naphthoquinone-1-oxime) ligand L, mimics (His/Tyr) ligation with controlled and unique charge transfers resulting in valence tautomeric coordination with mixed valent diiron site in model compound Fe-1: [?-OH-Fe2 + 2, + 3 ( o-NQCH3ox) ( o-NSQCH3ox)2 (CAT) H2O]. Fe-2: [Fe + 3( o-NQCH3ox) ( p-NQCH3ox)2]2 a molecularly associated dimer of phthiocoloxime synthesized for comparison of charge transfer. 57Fe Mössbauer studies was used to quantitize unusual valences due to ligand in dimeric Fe-1 and Fe-2 complexes which are supported by EPR and SQUID studies. 57Fe Mössbauer spectra for Fe-1 at 300 K indicates the presence of two quadrupole split asymmetric doublets due to the differences in local coordination geometries of [Fe + 3]A and [Fe + 2]B sites. The hyperfine interaction parameters are ? A = 0.152, (? E Q)A = 0.598 mm/s with overlapping doublet at ? B = 0.410 and (? E Q)B = 0.468 mm/s. Due to molecular association tendency of ligand, dimer Fe-2 possesses 100% Fe + 3(h.s.) hexacoordinated configuration with isomer shift ? = 0.408 mm/s. Slightly distorted octahedral symmetry created by NQCH3ox ligand surrounding Fe + 3(h.s.) state generates small field gradient indicated by quadrupole split ? E Q = 0.213 mm/s. Decrease of isomer shifts together with variation of quadrupole splits with temperature in Fe-1 dimer compared to Fe-2 is result of charge transfers in [Fe2 + 2, + 3 SQ] complexes. EPR spectrum of Fe-1 shows two strong signals at g 1 = 4.17 and g 2 = 2.01 indicative of S = 3/2 spin state with an intermediate spin of Fe + 3(h.s.) configuration. SQUID data of ? _m^{corr} .T were best fitted by using HDVV spin pair model S = 2, 3/2 resulting in antiferromagnetic exchange ( J = -13.5 cm - 1 with an agreement factor of R = 1.89 × 10 - 5). The lower J value of antiferromagnetic exchange leads to Fe+3?-(OH) Fe + 2 bridging in Fe-1 dimer instead of ?-oxo bridge. The intermolecular association through H-bonds may lead to weakly coupled antiferromagnetic interaction between two Fe-2 molecules having Fe + 3(h.s.) centers. Using S = 5/2, 5/2 spin pair model we obtained best-fitted parameters such as J = -12.4 cm - 1, g = 2.3 with R = 3.58 × 10 - 5. Synthetic strategy results in non-equivalent iron sites in Fe-1 dimer analogues to PAP enzyme hence its reconstitution results in pUC-19 DNA cleavage activity, as physiological functionality of APase. It is compared with nuclease activity of Fe-2 RAPase.

Salunke-Gawali, Sunita; Ahmed, Khursheed; Varret, François; Linares, Jorge; Zaware, Santosh; Date, Sadgopal; Rane, Sandhya