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1

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

1999-01-01

2

Conformational analysis of chloroalkyl derivatives of 1,4-naphthoquinone  

E-print Network

rights reserved. Keywords: Dipole moment; Kerr constant; NMR spectra; 1,4-Naphthoquinone derivative July 1999 Abstract Studies of Kerr effect and 1 H and 13 C NMR spectra of 2-substituted 3-g conformations, namely, Kerr effect and NMR. Both Kerr effect and NMR are widely used in order to determine

3

STABILITY OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE OXIDE, 1,2-NAPHTHOQUINONE, AND 1,4-NAPHTHOQUINONE  

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...

4

Novel naphthoquinone derivatives and evaluation of their trypanocidal and leishmanicidal activities.  

PubMed

Herein, we report the synthesis of 12 new naphthoquinone derivatives, 6 substituted 1,4-naphthoquinones and 6 heterocycle-fused naphthoquinones, as well as evaluation of their trypanocidal and leishmanicidal activities. Compounds 11a and 13a were active against the amastigote stage of T. cruzi and showed low cytotoxic effects. With respect to leishmanicidal assays, all compounds were inactive against the promastigote stages of L. chagasi and L. braziliensis. PMID:25370790

Naujorks, Aline Alves Dos Santos; da Silva, Adriano Olímpio; Lopes, Rosangela da Silva; de Albuquerque, Sérgio; Beatriz, Adilson; Marques, Maria Rita; de Lima, Dênis Pires

2015-01-14

5

Inhibition of 2-p-mercaptophenyl-1,4- naphthoquinone on human platelet function  

Microsoft Academic Search

As widely assumed, platelets and coagulation system heavily influence the pathogenesis and progression of cardiovascular diseases. Some 1,4-naphthoquinone derivatives, such as vitamin K3, have been reported to increase the synthesis of coagulation proteins. In this study, we examine how 2-p-mercaptophenyl -1,4-naphthoquinone (NTP), a newly synthesized 1,4-naphthoquinone derivative, affects the platelet function in humans. A tapered parallel plate chamber which provided

Ai Yu Shen; Mei Han Huang; Che-Ming Teng; Jong Shyan Wang

1999-01-01

6

Preparations of anthraquinone and naphthoquinone derivatives and their cytotoxic effects.  

PubMed

Chrysophanol and 1,8-di-O-hexylchrysophanol derivatives having nucleic acid bases at position 5 were synthesized. Furthermore, derivatives of menadione substituted at position 11 (type A naphthoquinone derivatives) or methylmenadione substituted at position 7 (type B naphthoquinone derivatives) modified with nucleic acid bases, amines and thiocyano, selenocyano or thioacetyl groups were synthesized. The cytotoxic effects of these derivatives on HCT 116 cells, which poorly express P-glycoprotein (P-gp), and Hep G2 cells, which stably express P-gp, were evaluated by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results were compared with those obtained using 5-fluorouracil (5-FU), which has been used clinically. Several of these derivatives exhibited markedly higher potent cytotoxic effects not only on HCT cancer cells but also Hep G2 cancer cells as compared with 5-FU. PMID:21372410

Cui, Xing-Ri; Saito, Ryota; Kubo, Takatsugu; Kon, Daijiro; Hirano, Yuich; Saito, Setsuo

2011-01-01

7

1,4-naphthoquinones: from oxidative damage to cellular and inter-cellular signaling.  

PubMed

Naphthoquinones may cause oxidative stress in exposed cells and, therefore, affect redox signaling. Here, contributions of redox cycling and alkylating properties of quinones (both natural and synthetic, such as plumbagin, juglone, lawsone, menadione, methoxy-naphthoquinones, and others) to cellular and inter-cellular signaling processes are discussed: (i) naphthoquinone-induced Nrf2-dependent modulation of gene expression and its potentially beneficial outcome; (ii) the modulation of receptor tyrosine kinases, such as the epidermal growth factor receptor by naphthoquinones, resulting in altered gap junctional intercellular communication. Generation of reactive oxygen species and modulation of redox signaling are properties of naphthoquinones that render them interesting leads for the development of novel compounds of potential use in various therapeutic settings. PMID:25232709

Klotz, Lars-Oliver; Hou, Xiaoqing; Jacob, Claus

2014-01-01

8

Comparison of antimicrobial activities of naphthoquinones from Impatiens balsamina.  

PubMed

Lawsone (1), lawsone methyl ether (2), and methylene-3,3'-bilawsone (3) are the main naphthoquinones in the leaf extracts of Impatiens balsamina L. (Balsaminaceae). Antimicrobial activities of these three naphthoquinones against dermatophyte fungi, yeast, aerobic bacteria and facultative anaerobic and anaerobic bacteria were evaluated by determination of minimal inhibitory concentrations (MICs) and minimal bactericidal or fungicidal concentrations (MBCs or MFCs) using a modified agar dilution method. Compound 2 showed the highest antimicrobial activity. It showed antifungal activity against dermatophyte fungi and Candida albicans with the MICs and MFCs in the ranges of 3.9-23.4 and 7.8-23.4?µg?mL(-1), respectively, and also had some antibacterial activity against aerobic, facultative anaerobic and anaerobic bacteria with MICs in the range of 23.4-93.8, 31.2-62.5 and 125?µg?mL(-1), respectively. Compound 1 showed only moderate antimicrobial activity against dermatophytes (MICs and MFCs in the ranges of 62.5-250 and 125-250?µg?mL(-1), respectively), but had low potency against aerobic bacteria, and was not active against C. albicans and facultative anaerobic bacteria. In contrast, 3 showed significant antimicrobial activity only against Staphylococus epidermidis and Bacillus subtilis (MIC and MBC of 46.9 and 93.8?µg?mL(-1), respectively). PMID:21895457

Sakunphueak, Athip; Panichayupakaranant, Pharkphoom

2012-01-01

9

Two new dimeric naphthoquinones with neuraminidase inhibitory activity from Lithospermum erythrorhizon.  

PubMed

The crude methanol extract of roots of Lithospermum erythrorhizon was subjected to successive chromatographic fractionation which afforded two new dimeric naphthoquinone derivatives shikometabolin E (2) and shikometabolin F (3) as well as one known compound shikometabolin A (1). The structures of compounds 1-3 were elucidated by using UV, MS, 1D and 2D NMR spectroscopic analysis. The two new dimeric naphthoquinone derivatives showed significant neuraminidase inhibitory activities. PMID:25190151

Yang, Yanqin; Zhao, Dapeng; Yuan, Kailong; Zhou, Guojun; Wang, Yu; Xiao, Yanmeng; Wang, Chenxu; Xu, Jingwei; Yang, Wei

2014-09-01

10

Modulation of Basophils' Degranulation and Allergy-Related Enzymes by Monomeric and Dimeric Naphthoquinones  

PubMed Central

Allergic disorders are characterized by an abnormal immune response towards non-infectious substances, being associated with life quality reduction and potential life-threatening reactions. The increasing prevalence of allergic disorders demands for new and effective anti-allergic treatments. Here we test the anti-allergic potential of monomeric (juglone, menadione, naphthazarin, plumbagin) and dimeric (diospyrin and diosquinone) naphthoquinones. Inhibition of RBL-2H3 rat basophils' degranulation by naphthoquinones was assessed using two complementary stimuli: IgE/antigen and calcium ionophore A23187. Additionally, we tested for the inhibition of leukotrienes production in IgE/antigen-stimulated cells, and studied hyaluronidase and lipoxidase inhibition by naphthoquinones in cell-free assays. Naphthazarin (0.1 µM) decreased degranulation induced by IgE/antigen but not A23187, suggesting a mechanism upstream of the calcium increase, unlike diospyrin (10 µM) that reduced degranulation in A23187-stimulated cells. Naphthoquinones were weak hyaluronidase inhibitors, but all inhibited soybean lipoxidase with the most lipophilic diospyrin, diosquinone and menadione being the most potent, thus suggesting a mechanism of competition with natural lipophilic substrates. Menadione was the only naphthoquinone reducing leukotriene C4 production, with a maximal effect at 5 µM. This work expands the current knowledge on the biological properties of naphthoquinones, highlighting naphthazarin, diospyrin and menadione as potential lead compounds for structural modification in the process of improving and developing novel anti-allergic drugs. PMID:24587235

Pinho, Brígida R.; Sousa, Carla; Valentão, Patrícia; Oliveira, Jorge M. A.; Andrade, Paula B.

2014-01-01

11

Biflorin: an o-naphthoquinone of clinical significance.  

PubMed

Biflorin is an o-naphthoquinone with proven cytotoxic effects on tumor cells showing antimicrobial, antitumor and antimutagenic activities. Biflorin is an isolated compound taken from the roots of the plant Capraria biflora L. (Schrophulariaceae), indigenous of the West Indies and South America, which is located in temperate or tropical areas. This compound has shown to be strongly active against grampositive and alcohol-acid-resistant bacteria. It has been efficient in inhibiting the proliferation tumor cell lines CEM, HL-60, B16, HCT-8 and MCF-7. Recently, SK-Br3 cell line was treated with biflorin showing important cytotoxic effects. In this article, information related to the first structural characterization studies are presented, as well as the latest reports concerning the biological activity of this molecule. PMID:25317728

Wisintainer, Gabrielle G N S; Simões, Evelyne R B; Lemos, Telma L G; Moura, Sidnei; Souza, Luciana G S; Fonseca, Aluisio M; Moraes, Manoel Odorico; Pessoa, Claudia; Roesch-Ely, Mariana; Henriques, João A P

2014-10-14

12

Inhibitory Effects of J78, a Newly Synthesized 1,4Naphthoquinone Derivative, on Experimental Thrombosis and Platelet Aggregation  

Microsoft Academic Search

Several compounds with the backbone of 1,4-naphthoquinone chemical structure have been reported to display antiplatelet and antithrombotic activities, indicating that this congener compound may be a new source in the antithrombotic drug development. In the present study, the possible antiplatelet activity and antithrombotic efficacy of J78 (2-chloro-3-[2?-bromo, 4?-fluoro- phenyl]-amino-8-hydroxy-1,4-naphthoquinone), a newly synthesized 1,4-naphthoquinone derivative, were examined. Orally administered J78 (50,

Yong-Ri Jin; Chung-Kyu Ryu; Chang-Kiu Moon; Mi-Ra Cho; Yeo-Pyo Yun

2004-01-01

13

Changes in cellular thiol content and intracellular Zn(2+) level by 1,4-naphthoquinone in rat thymocytes.  

PubMed

1,4-Naphthoquinone is an active metabolite of naphthalene and it is also found in diesel exhaust particles. It is known to cause oxidative stress. In this study, we characterized 1,4-naphthoquinone-mediated cytotoxicity and its effects on the levels of non-protein thiols and intracellular Zn(2+) in rat thymocytes (thymic lymphocytes) by using 5-chloromethylfluorescein (5-CMF) fluorescence and FluoZin-3 fluorescence, respectively. Low concentrations of 1,4-naphthoquinone (0.3?M) increased the intensity of 5-CMF fluorescence, which is used to measure non-protein thiols. In contrast, 5-CMF intensity decreased at higher concentrations (1-3?M) of 1,4-naphthoquinone. Removal of intracellular Zn(2+) attenuated the 1,4-naphthoquinone-induced augmentation of 5-CMF fluorescence. Additionally, 1,4-naphthoquinone (0.3-3?M) increased FluoZin-3 fluorescence, which is used to assess intracellular Zn(2+), in a concentration-dependent manner. The augmentation of FluoZin-3 fluorescence by 1,4-naphthoquinone was due to the release of intracellular Zn(2+), because the removal of extracellular Zn(2+) did not affect the augmentation of FluoZin-3 fluorescence. These results suggest that sublethal concentrations of 1,4-naphthoquinone (0.3-1?M) affect the cellular levels of non-protein thiols and intracellular Zn(2+). The difference in the observed decrease in cellular thiol content due to 1,4-naphthoquinone treatment and increase due to Zn(2+) release following 1,4-naphthoquinone treatment likely confers the change in cellular thiol content. Further, the increase in intracellular Zn(2+) concentration after 1,4-naphthoquinone exposure may change the activity of thymocytes because thymulin, a thymus-specific hormone, requires Zn(2+) for its biological activity. PMID:25168851

Fukunaga, Eri; Ishida, Shiro; Oyama, Yasuo

2014-08-26

14

MEASUREMENT OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE-1,2-OXIDE, 1,2-NAPHTHOQUINONE AND 1,4-NAPHTHOQUINONE AFTER ADMINISTRATION OF NAPHTHALENE TO F344 RATS  

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 ...

15

Effect of hydroxy substituent on the prooxidant action of naphthoquinone compounds.  

PubMed

Prooxidant activity of naphthoquinone compounds was analyzed by lipid peroxidation, and the formation of base adduct in DNA. Naphthoquinones with electron-repelling hydroxyl group in the benzene moiety such as juglone and shikonin of lower concentrations stimulated the microsomal lipid peroxidation, but lawsone and lapachol with hydroxyl group in the quinone moiety did not enhance the formation of lipid peroxides. Naphthoquinone-dependent lipid peroxidation was closely related to the enhancement of Fe(2+) autooxidation. Treatment of DNA with juglone a representative of 5-hydroxylated naphthoquinone stimulated the formation of 8-hydroxy-2'-deoxyguanosine, whereas lawsone and lapachol showed negligible formation of DNA base adduct. ESR spectra showed that juglone can form semiquinone radical in the presence of ferrous ion, but lawsone cannot. Biological toxicity of juglone with the potent electron-repelling group at 5-position may be due to the reactive oxygen species formed by semiquinone radical, but naphthoquinone compounds with an electron-repelling group in the quinone moiety, lawsone shows weak toxicity with only a little ability producing reactive oxygen species by the negligible formation of semiquinone. PMID:19961919

Murakami, Keiko; Haneda, Miyako; Iwata, Shouko; Yoshino, Masataka

2010-04-01

16

Simultaneous determination of naphthoquinone derivatives in Boraginaceous herbs by high-performance liquid chromatography.  

PubMed

A high-performance liquid chromatographic method using diode-array detection (HPLC-DAD) has been developed for the simultaneous quantification of eight naphthoquinone derivatives namely shikonin, acetylshikonin, deoxyshikonin, beta-acetoxyisovalerylshikonin, isobutylshikonin, beta,beta-dimethylacrylshikonin, 2-methyl-n-butyrylshikonin and isovalerylshikonin in nine species of the Boraginaceae family. These species, coming from different areas of China, are all used as interchangeable sourcing plants for the Chinese Materia Medica known as "Zicao", and are Arnebia euchroma (Royle) Johnston., A. guttata Bunge, Lithospermum erythrorhizon Sieb. et Zucc., Onosma paniculatum Bur. et Franch., O. exsertum Hemsl., O. confertum W.W. Smith, O. hookerii Clarke var. longiflorum Duthie, O. hookerii Clarke and O. waltonii Duthic. Quantification of the eight naphthoquinones in all the Zicao samples are reported and compared with each other. Furthermore, two positional isomers, 2-methyl-n-butyrylshikonin and isovalerylshikonin, were successfully separated and quantified for the first time in the present study. The results showed that, besides the three officially used species (namely, A. euchroma, A. guttata and L. erythrorhizon) that were listed in Chinese pharmacopoeia as interchangeable sourcing plants for Zicao, other six species of Onosma used by native peoples in Tibet and Yunnan Province also contain various types and considerable amounts of naphthoquinones and that O. waltonii contains the most. Therefore, these species of Onosma could be developed as new sources of naphthoquinones. The entire analytical procedure is reproducible and suitable for the quantification of naphthoquinones in all related Boraginaceous plants for quality assessment purposes. PMID:17723649

Hu, Yani; Jiang, Zhihong; Leung, Kelvin Sze-Yin; Zhao, Zhongzhen

2006-09-01

17

Synthesis and biological evaluation of novel ferrocene-naphthoquinones as antiplasmodial agents.  

PubMed

This work deals with the synthesis and evaluation of new compounds designed by combination of 1,4-naphthoquinone and ferrocene fragments in a 3-ferrocenylmethyl-2-hydroxy-1,4-naphthoquinone arrangement. A practical coupling reaction between 2-hydroxy-1,4-naphthoquinone and ferrocenemethanol derivatives has been developed. This procedure can be carried out "on-water", at moderate temperatures and without auxiliaries or catalysts, with moderate to high yields. The synthesized derivatives have shown significant in vitro antiplasmodial activity against chloroquine-sensitive and resistant Plasmodium falciparum strains and it has been shown that this activity is not related to the inhibition of biomineralization of ferriprotoporphyrin IX. Binding energy calculations and docking of these compounds to cytochrome b in comparison with atovaquone have been performed. PMID:24211630

García-Barrantes, Pedro M; Lamoureux, Guy V; Pérez, Alice L; García-Sánchez, Rory N; Martínez, Antonio R; San Feliciano, Arturo

2013-01-01

18

THz spectra of 1,4-naphthoquinones and its four derivatives  

NASA Astrophysics Data System (ADS)

Recently some naphthoquinone derivatives have been found with anticancer or other therapeutic properties, but also have some negative side effects. Numerous research projects have been conducted to investigate their properties and therapeutic mechanisms. With Terahertz Time-Domain Spectroscopy (THz-TDS), we have successfully obtained THz spectra of 1,4-naphthoquinone and its four derivatives in a series of naphthazarin - juglone - 1,4-naphthoquinone - menadione - plumbagin, in the range between 0.2 and 2.4~2.8 THz. Although these molecules are almost identical to each other, they have very distinctive THz spectra so that they can be identified much more easily than using conventional spectroscopy. We have comparatively analyzed their THz spectra, and found some possible correlations between THz spectra and molecular structures. These THz spectra cannot only be used as spectral fingerprint, but also provide us their conformational properties that can be used in study of their interaction with biomolecules to reveal their pharmaceutical mechanisms.

Wang, Weining; Li, Hongqi; Luo, Xiang; Zeng, Xiaoni

2008-03-01

19

[Detection of the anti-cancer biological effect of naphthoquinone pigment-LIII].  

PubMed

Naphthoquinone pigment-LIII, an extract from Arnebia euchroma, could apparently inhibit the proliferation of stomach cancer cell line and esophagus cancer cell line. At the effective concentration of 5 micrograms/ml, the mitotic index and growth curve declined without showing any damage to human normal cells. At 5-10 micrograms/ml, the colony efficiency of cancer cells became significantly low. The anti-cancer effect of Naphthoquinone pigment-LIII might be related to its role of influencing the amount of RNA and ultrastructure of cancer cells which was discussed in this paper. PMID:2208424

Lu, G; Liao, J

1990-07-01

20

5-Hydroxy-1,4-naphthoquinone (juglone) and 2-hydroxy-1,4-naphthoquinone (lawsone) influence on jack bean urease activity: Elucidation of the difference in inhibition activity.  

PubMed

The aim of this study was elucidation of the difference in inhibition influence of 5-hydroxy-1,4-naphthoquinone (juglone) and 2-hydroxy-1,4-naphthoquinone (lawsone) on jack bean urease activity. It was found that juglone acted as a strong, time and concentration dependent inactivator of urease. On the contrary, lawsone showed an inconsiderable inhibition influence. The reactivation of juglone modified urease showed the participation of reversible and irreversible contribution in the inactivation. In the presence of an excess of DTT, urease inactivated by juglone regained 70% of its activity. The reversible inactivation was attributed to oxidation of the essential urease thiols by reactive oxygen species (ROS) realizing during reduction of juglone to seminaphthoquinone. Presence of hydrogen peroxide in the incubation system was proved by direct determination and by application of catalase. The irreversible contribution in the inhibition was assumed as an arylation of urease thiol groups by juglone. The insignificant urease inhibition by lawsone was concluded as an effect of a low hydrogen peroxide generation and lawsone resistance for reaction with protein thiols. It was found that lawsone well reacted with l-cysteine, poorly with glutathione and hardly with urease thiols. The observed sequence was arranged according the rule the more complex thiol the less susceptible for reaction with lawsone. On the other hand, juglone displayed an excellent reactivity towards both thiols and urease. Thus, this indicated a significance of a steric hindrance which appeared when the hydroxyl group changing position from 5 in juglone (5-hydroxy-1,4-naphthoquinone) to 2 in lawsone (2-hydroxy-1,4-naphthoquinone). PMID:20202666

Kot, Miros?awa; Karcz, Waldemar; Zaborska, Wies?awa

2010-06-01

21

Reaction of beta-lapachone and related naphthoquinones with 2-mercaptoethanol: a biomimetic model of topoisomerase II poisoning by quinones.  

PubMed

1,2-Naphthoquinones, such as beta-lapachone, 4-alkoxy-1,2-naphthoquinones, and tetrahydrofuran-1,2-naphthoquinones, react rapidly with 2-mercaptoethanol in benzene to give 1,4-, 1,2-, 1,3- and 1,6-Michael-type adducts that are formed by the addition of the thiol group to the quinone ring. Menadione (2-methyl-1,4-naphthoquinone) reacts with the thiol reagent very slowly under the same reaction conditions. Although the formation of the adducts can be followed by 1H-NMR, attempts to isolate the adducts failed due to their retroconversion to the starting products. On addition of a Lewis acid, however, the adducts undergo cyclization reactions that give stable derivatives that can be isolated and characterized. Determination of the structures of the derivatives allowed for the identification of the adducts from which they originated. Thus, beta-lapachone and 2,3-dinordunnione underwent 1,4- and 1,2-Michael type additions to the quinone ring, while 4-pentyloxy-1,2-naphthoquinone underwent two simultaneous Michael additions to the quinone ring of the naphthoquinone. Menadione underwent a single 1,3-addition. The alkylation rates of the thiol group of 2-mercaptoethanol by the naphthoquinones parallel the naphthoquinones efficiencies in inducing DNA cleavage through DNA-bound topoisomerase II. These results support our hypothesis that the cytotoxic effect of the naphthoquinones derive, at least in part, from their alkylation of exposed thiol residues on the topoisomerase II-DNA complex. PMID:9620443

Neder, K; Marton, L J; Liu, L F; Frydman, B

1998-05-01

22

Extension of Lifespan in C. elegans by Naphthoquinones That Act through Stress Hormesis Mechanisms  

PubMed Central

Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap‘n’collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway. PMID:21765926

Wilson, Mark A.; Yu, Quian-Sheng; Wood, William H.; Zhang, Yongqing; Becker, Kevin G.; Greig, Nigel H.; Mattson, Mark P.; Camandola, Simonetta; Wolkow, Catherine A.

2011-01-01

23

Selective binding of naphthoquinone derivatives to serum albumin proteins and their effects on cytotoxicity.  

PubMed

Naphthoquinone derivatives such as lapachol, plumbagin, dichloroallyl lawsone show anticancer activity and generally cytotoxicity measurements are carried out in presence of bovine serum albumin; so understanding on the ability of serum albumin binding with such derivatives are essential. We have investigated cytotoxicity and serum albumin binding of a series of structurally related naphthoquinone derivatives. Substrate dependency and high selectivity in binding of naphthoquinone tethered carboxylic acids or pyridines with bovine serum albumin (BSA) and human serum albumin (HSA) are observed. For example, the binding constant of BSA with 3-(1,4-dihydro-2-methyl-1,4-dioxonaphthalen-3yl-thio)propanoic acid is ?594 times higher than 3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-amino)benzoic acid; whereas 4-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-amino)benzoic acid shows ?367 times higher binding constant than the latter compound. The BSA weakly bind to pyridine tethered naphthoquinones, whereas HSA does not binds with them. The binding constant of HSA with 2-(1,4-dihydro-2-methyl-1,4-dioxonaphthalene-3-ylthio)benzoic acid is 134 times higher than the HSA binding constant with 2,2'-(1,4-dihydro-1,4-dioxo-naphthalen-2,3-diylthio)dipropanoic acid. Among the naphthoquinone carboxylic acids, the 3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-amino)benzoic acid binds selectively to BSA, but it does not bind to HSA. The 2-hydroxybenzoic acid or 4-mercaptobenzoic acid strongly binds to BSA. The binding of BSA with 4-hydroxybenzoic acid or 2-mercaptobenzoic acid are insignificant. We have not observed clear relationships of structure of naphthoquinone derivatives versus serum albumin binding, but could identify the compound having the best IC50 values of cytotoxicity among the twelve naphthoquinone compounds. The compound 3-(1,2-dihydro-1,2-dioxonaphthalen-4-yl-thio)propanoic acid in four cancer cell lines has IC50 values in the range 2.7-7.6?M. This compound also has optimum binding constant with BSA (35.042×10(3)Lmol(-1)) or HSA (21.427×10(3)Lmol(-1)). The cytotoxicity values of the compounds were influenced by concentration of BSA. PMID:24560625

Jali, Bigyan R; Kuang, Yuting; Neamati, Nouri; Baruah, Jubaraj B

2014-05-01

24

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)

1994-07-01

25

DT-diaphorase-catalysed reduction of 1,4-naphthoquinone derivatives and glutathionyl-quinone conjugates. Effect of substituents on autoxidation rates.  

PubMed Central

DT-diaphorase catalysed the reduction of 1,4-naphthoquinones with hydroxy, methyl, methoxy and glutathionyl substituents at the expense of reducing equivalents from NADPH. The initial rates of quinone reduction did not correlate with either the half-wave reduction potential (E1/2) value (determined by h.p.l.c. with electrochemical detection against an Ag/AgCl reference electrode) or the partition coefficient of the quinones. After their reduction by DT-diaphorase the 1,4-naphthoquinone derivatives autoxidized at distinct rates, the extent of which was influenced by the nature of the substituents. Thus for the 1,4-naphthoquinone series the following order of rate of autoxidation was found: 5-hydroxy-1,4-naphthoquinone greater than 3-glutathionyl-1,4-naphthoquinone greater than 5-hydroxy-3-glutathionyl-1,4-naphthoquinone greater than 1,4-naphthoquinone greater than 2-hydroxy-1,4-naphthoquinone. For the 2-methyl-1,4-naphthoquinone (menadione) series the following order was observed: 5-hydroxy-2-methyl-1,4-naphthoquinone greater than 3-glutathionyl-5-hydroxy-2-methyl-1,4-naphthoquinone greater than 3-glutathionyl-2-methyl-1,4-naphthoquinone greater than 2-methyl-1,4-naphthoquinone greater than 3-hydroxy-2-methyl-1,4-naphthoquinone. The autoxidized naphthohydroquinone derivatives were re-reduced by DT-diaphorase, thus closing a cycle of enzymic reduction in equilibrium autoxidation. This was expressed as an excess of NADPH oxidized over the initial concentration of quinone present as well as H2O2 formation. These findings demonstrate that glutathionyl conjugates of 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone and those of their respective 5-hydroxy derivatives are able to act as substrates for DT-diaphorase and that they also autoxidize at rates higher than those for the unsubstituted parent compounds. These results are discussed in terms of the cellular role of DT-diaphorase in the reduction of hydroxy- or glutathionyl-substituted naphthoquinones as well as the further conjugation of these hydroquinones with glucuronide or sulphate within the cellular milieu, thereby facilitating their disposal from the cells. PMID:2494985

Buffinton, G D; Ollinger, K; Brunmark, A; Cadenas, E

1989-01-01

26

1,4-Naphthoquinones as inducers of oxidative damage and stress signaling in HaCaT human keratinocytes.  

PubMed

Selected biological effects of 1,4-naphthoquinone, menadione (2-methyl-1,4-naphthoquinone) and structurally related quinones from natural sources--the 5-hydroxy-naphthoquinones juglone, plumbagin and the 2-hydroxy-naphthoquinones lawsone and lapachol--were studied in human keratinocytes (HaCaT). 1,4-naphthoquinone and menadione as well as juglone and plumbagin were highly cytotoxic, strongly induced reactive oxygen species (ROS) formation and depleted cellular glutathione. Moreover, they induced oxidative DNA base damage and accumulation of DNA strand breaks, as demonstrated in an alkaline DNA unwinding assay. Neither lawsone nor lapachol (up to 100 microM) were active in any of these assays. Cytotoxic and oxidative action was paralleled by stimulation of stress signaling: all tested quinones except lawsone and lapachol strongly induced phosphorylation of the epidermal growth factor receptor (EGFR) and the related ErbB2 receptor tyrosine kinase. EGFR activation by plumbagin, juglone and menadione was attenuated by a superoxide dismutase mimetic, indicating that ROS-related mechanisms contribute to EGFR activation by these naphthoquinones. PMID:20153715

Klaus, Viola; Hartmann, Tobias; Gambini, Juan; Graf, Peter; Stahl, Wilhelm; Hartwig, Andrea; Klotz, Lars-Oliver

2010-04-15

27

The study of naphthoquinones and their complexes with DNA by using Raman spectroscopy and surface enhanced Raman spectroscopy: new insight into interactions of DNA with plant secondary metabolites.  

PubMed

Naphthoquinones represent the group of plant secondary metabolites with cytotoxic properties based on their ability to generate reactive oxygen species and interfere with the processes of cell respiration. Due to this fact, the possible cytotoxic mechanisms on cellular and subcellular levels are investigated intensively. There are many targets of cytotoxic action on the cellular level; however, DNA is a critical target of many cytotoxic compounds. Due to the cytotoxic properties of naphthoquinones, it is necessary to study the processes of naphthoquinones, DNA interactions (1,4-naphthoquinone, binapthoquinone, juglone, lawsone, plumbagin), especially by using modern analytical techniques. In our work, the Raman spectroscopy was used to determine the possible binding sites of the naphthoquinones on the DNA and to characterize the bond of naphthoquinone to DNA. Experimental data reveals the relationships between the perturbations of structure-sensitive Raman bands and the types of the naphthoquinones involved. The modification of DNA by the studied naphthoquinones leads to the nonspecific interaction, which causes the transition of B-DNA into A-DNA conformation. The change of the B-conformation of DNA for all measured DNA modified by naphthoquinones except plumbagin is obvious. PMID:25045679

Vaverkova, Veronika; Vrana, Oldrich; Adam, Vojtech; Pekarek, Tomas; Jampilek, Josef; Babula, Petr

2014-01-01

28

Increased production of naphthoquinones in Impatiens balsamina root cultures by elicitation with methyl jasmonate.  

PubMed

Impatiens balsamina root cultures were treated with yeast extract (YE), Candida albicans homogenate (CAH), Trichophyton rubrum homogenate (TRH), chitosan (CHI) and methyl jasmonate (MJ). Different elicitors, depending on concentrations used exerted differential effects on the production of the three main naphthoquinones, lawsone (2-hydroxy-1,4-naphthoquinone), lawsone methyl ether and methylene-3,3'-bilawsone. Treatment with MJ (400microM) was capable of increasing production of lawsone, and lawsone methyl ether up to 8.6- and 11.3-fold higher, respectively, compared to the level in untreated cultures. Treatment of 21-day-old root cultures with 300microM MJ for 36h resulted in the production of 10.0, 0.78 and 0.23mg/g DW of lawsone, its methyl ether and methylene-3,3'-bilawsone, respectively. Such levels are sufficient for commercial production. PMID:20620051

Sakunphueak, Athip; Panichayupakaranant, Pharkphoom

2010-11-01

29

Anticancer activity and SAR studies of substituted 1,4-naphthoquinones  

PubMed Central

In this paper, we report the structure–activity relationship studies of substituted 1,4-naphthoquinones for its anticancer properties. 1,4-Naphthoquinone, Juglone, Menadione, Plumbagin and LLL12.1 were used as lead molecules to design PD compounds. Most of the PD compounds showed improved antiproliferative activity in comparison to the lead molecule in prostate (DU-145), breast (MDA-MB-231) and colon (HT-29) cancer cell lines. PD9, PD10, PD11, PD13, PD14 and PD15 were found to be the most potent compound with an IC50 value of 1–3 ?M in all cancer cell lines. Fluorescent polarization assay was employed to study the inhibition of STAT3 dimerization by PD compounds. PD9 and PD18 were found to be potent STAT3 dimerization inhibitors. PMID:23791367

Bhasin, Deepak; Chettiar, Somsundaram N.; Etter, Jonathan P.; Mok, May; Li, Pui-Kai

2015-01-01

30

A highly diverse spectrum of naphthoquinone derivatives produced by the endophytic fungus Biatriospora sp. CCF 4378.  

PubMed

A strain of Biatriospora sp. CCF 4378 was tested for the production of secondary metabolites under submerged fermentation conditions. Eleven compounds were isolated from the culture broth, and the structures of these compounds were determined using HRMS, NMR and X-ray analysis. In addition to six known naphthoquinone derivatives, i.e. ascomycone A, ascomycone B, 6-deoxyfusarubine, 6-deoxyanhydrofusarubine, herbarine and balticol A, one derivative of 2-azaanthraquinone, 6-deoxybostrycoidine, was also identified. Four new natural pyranonaphthoquinones were found, and these natural products were pleorubrin A, pleorubrin B, pleorubrin C and pleorubrin D. The toxicity on human cell lines of the crude naphthoquinone fraction and pure 6-deoxybostrycoidin, ascomycone B, pleorubrin B and 6-deoxyfusarubin was tested. Ascomycone B and 6-deoxyfusarubin elicited rapid cytotoxicity at micromolar concentrations. PMID:25416512

Stod?lková, Eva; Man, Petr; Kuzma, Marek; Cerný, Jan; Císa?ová, Ivana; Kubátová, Alena; Chudí?ková, Milada; Kola?ík, Miroslav; Flieger, Miroslav

2014-11-22

31

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

PubMed

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

2007-12-01

32

Simultaneous determination of naphthoquinone derivatives in Boraginaceous herbs by high-performance liquid chromatography  

Microsoft Academic Search

A high-performance liquid chromatographic method using diode-array detection (HPLC-DAD) has been developed for the simultaneous quantification of eight naphthoquinone derivatives namely shikonin, acetylshikonin, deoxyshikonin, ?-acetoxyisovalerylshikonin, isobutylshikonin, ?,?-dimethylacrylshikonin, 2-methyl-n-butyrylshikonin and isovalerylshikonin in nine species of the Boraginaceae family. These species, coming from different areas of China, are all used as interchangeable sourcing plants for the Chinese Materia Medica known as “Zicao”,

Yani Hu; Zhihong Jiang; Kelvin Sze-Yin Leung; Zhongzhen Zhao

2006-01-01

33

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.  

PubMed

Abstract This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the ?-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol. PMID:25431148

Moreira, Diogo R M; de Sá, Matheus S; Macedo, Taís S; Menezes, Maria N; Reys, José Rui M; Santana, Antônio E G; Silva, Thaissa L; Maia, Gabriela L A; Barbosa-Filho, José M; Camara, Celso A; da Silva, Tania M S; da Silva, Katia N; Guimaraes, Elisalva T; Dos Santos, Ricardo R; Goulart, Marília O F; Soares, Milena B P

2014-11-28

34

Synthetic 1,4-pyran naphthoquinones are potent inhibitors of dengue virus replication.  

PubMed

Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays. PMID:24376541

da Costa, Emmerson C B; Amorim, Raquel; da Silva, Fernando C; Rocha, David R; Papa, Michelle P; de Arruda, Luciana B; Mohana-Borges, Ronaldo; Ferreira, Vitor F; Tanuri, Amilcar; da Costa, Luciana J; Ferreira, Sabrina B

2013-01-01

35

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests  

PubMed Central

This study evaluated the antifungal activities of synthetic naphthoquinones against opportunistic and dermatophytic fungi and their preliminary mechanisms of action. The minimum inhibitory concentrations (MICs) of four synthetic naphthoquinones for 89 microorganisms, including opportunistic yeast agents, dermatophytes and opportunistic filamentous fungi, were determined. The compound that exhibited the best activity was assessed for its action against the cell wall (sorbitol test), for interference associated with ergosterol interaction, for osmotic balance (K+ efflux) and for membrane leakage of substances that absorb at the wavelength of 260 nm. All tested naphthoquinones exhibited antifungal activity, and compound IVS320 (3a,10b-dihydro-1H-cyclopenta [b] naphtho [2,3-d] furan-5,10-dione)-dione) demonstrated the lowest MICs across the tested species. The MIC of IVS320 was particularly low for dermatophytes (values ranging from 5–28 ?g/mL) and Cryptococcus spp. (3–5 ?g/mL). In preliminary mechanism-of-action tests, IVS320 did not alter the fungal cell wall but did cause problems in terms of cell membrane permeability (efflux of K+ and leakage of substances that absorb at 260 nm). This last effect was unrelated to ergosterol interactions with the membrane. PMID:24998949

2014-01-01

36

Synthetic 1,4-Pyran Naphthoquinones Are Potent Inhibitors of Dengue Virus Replication  

PubMed Central

Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays. PMID:24376541

da Costa, Emmerson C. B.; Amorim, Raquel; da Silva, Fernando C.; Rocha, David R.; Papa, Michelle P.; de Arruda, Luciana B.; Mohana-Borges, Ronaldo; Ferreira, Vitor F.; Tanuri, Amilcar

2013-01-01

37

Naphthoquinone Derivative PPE8 Induces Endoplasmic Reticulum Stress in p53 Null H1299 Cells  

PubMed Central

Endoplasmic reticulum (ER) plays a key role in synthesizing secretory proteins and sensing signal function in eukaryotic cells. Responding to calcium disturbance, oxidation state change, or pharmacological agents, ER transmembrane protein, inositol-regulating enzyme 1 (IRE1), senses the stress and triggers downstream signals. Glucose-regulated protein 78 (GRP78) dissociates from IRE1 to assist protein folding and guard against cell death. In prolonged ER stress, IRE1 recruits and activates apoptosis signal-regulating kinase 1 (ASK1) as well as downstream JNK for cell death. Naphthoquinones are widespread natural phenolic compounds. Vitamin K3, a derivative of naphthoquinone, inhibits variant tumor cell growth via oxygen uptake and oxygen stress. We synthesized a novel naphthoquinone derivative PPE8 and evaluated capacity to induce ER stress in p53 null H1299 and p53 wild-type A549 cells. In H1299 cells, PPE8 induced ER enlargement, GRP78 expression, and transient IER1 activation. Activated IRE1 recruited ASK1 for downstream JNK phosphorylation. IRE1 knockdown by siRNA attenuated PPE8-induced JNK phosphorylation and cytotoxicity. Prolonged JNK phosphorylation may be involved in PPE8-induced cytotoxicity. Such results did not arise in A549 cells, but p53 knockdown by siRNA restored PPE8-induced GRP78 expression and JNK phosphorylation. We offer a novel compound to induce ER stress and cytotoxicity in p53-deficient cancer cells, presenting an opportunity for treatment.

Lien, Jin-Cherng; Lu, Te-Jung; Tseng, Chih-Hsiang; Sung, Ping-Jyun; Lee, Hong-Zin; Kuo, Yueh-Hsiung; Lu, Te-Ling

2015-01-01

38

Resonance Raman and infrared spectral studies on radical anions of model photosynthetic reaction center quinones (naphthoquinone derivatives).  

PubMed

Quinones play a vital role in the processes of electron transfer in bacterial photosynthetic reaction centers. It is of interest to investigate photochemical reactions involving quinones with a view to elucidate structure-function relationships in biological processes. Resonance Raman and FTIR spectra of electrochemically generated radical anions of 2-methyl-1,4-naphthoquinone, and 2-methyl-3-phytyl-1,4-naphthoquinone, also known as Vitamin K3 and Vitamin K1, respectively, (model compound for QA in Rhodopseudomonas viridis, a bacterial photosynthetic reaction center) have been reported. The same study has also been extended to 1,4-naphthoquinone for comparison. The vibrational assignments were carried out on the basis of comparison with our earlier time resolved resonance Raman studies on photochemically generated radical anions of 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (Balakrishnan et al., J. Phys. Chem., 100, (1996), 16472-16478). These in vitro results have been compared with the reported vibrational spectral data under in vivo conditions. PMID:9745901

Balakrishnan, G; Babaei, A; McQuillan, A J; Umapathy, S

1998-08-01

39

Anomalous Appearance of ?[C(2)=C(3)] Frequencies in IR Spectra of 1,4-Naphthoquinone Hydroxy Derivatives  

NASA Astrophysics Data System (ADS)

Absorption bands in the carbonyl range 1750-1500 cm-1 of the IR spectrum of 2,3-dihydroxy-1,4-naphthoquinone and some of its derivatives were assigned based on calculations of normal mode frequencies using the B3LYP/cc-pVTZ method for isolated molecules and the polarized continuum model taking into account the influence of weakly and moderately polar solvents (CCl4, CDCl3, and CH2Cl2). It was shown that the frequency of the quinone C(2)=C(3) stretching vibration for 2,3-OH- and 2,5,8-OH-1,4-naphthoquinones (2-OH-naphthazarins) was 50-60 cm-1 higher than that of the carbonyl stretching vibration. The frequency difference reached 100 cm-1 for 2,3,5,8-OH-1,4-naphthoquinones (2,3-OH-naphthazarins).

Glazunov, V. P.; Berdyshev, D. V.

2014-09-01

40

Activity of 10 naphthoquinones, including parvaquone (993C) and menoctone, in cattle artificially infected with Theileria parva.  

PubMed

Ten naphthoquinones, including parvaquone (993C) (Clexon; Wellcome) and menoctone, were tested for activity in cattle artificially infected with Theileria parva, the causative organism of East Coast fever (ECF). Parvaquone cured all 14 cattle treated with a single dose of 20 mg/kg intramuscularly and all five treated twice with 10 mg/kg intramuscularly. Menoctone cured seven of 10 cattle treated with a single dose of 5 mg/kg intramuscularly. Of 25 untreated control cattle, 22 died of ECF. None of the remaining eight naphthoquinones was as active as parvaquone. Three esters of active naphthoquinones, designed as 'prodrugs' of their parent compounds, showed little or no activity in infected cattle despite being highly active in vitro against T parva. These results were instrumental in the selection of parvaquone for development as the first specifically active remedy for ECF. PMID:6665318

McHardy, N; Hudson, A T; Morgan, D W; Rae, D G; Dolan, T T

1983-11-01

41

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. PMID:22777178

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

2012-01-01

42

Synthesis of new 9-hydroxy-?- and 7-hydroxy-?-pyran naphthoquinones and cytotoxicity against cancer cell lines.  

PubMed

A synthetic method to obtain ?- and ?-pyran naphthoquinones 10 and 11 with a hydroxyl substituent on the aromatic ring was developed. Two series of ?- and ?-pyran naphthoquinones were obtained from the 8-hydroxy-lawsone, and their anticancer properties were evaluated against four tumor cell lines. In general, the new compounds displayed good activity, possibly indicating that these compounds have increased pro-oxidant capacity. The 9-hydroxy-?-lapachone and 7-hydroxy-?-lapachone analogues of the natural products ?-lapachone and ?-lapachone were successfully produced by this methodology. PMID:21487631

da Rocha, David R; de Souza, Ana C G; Resende, Jackson A L C; Santos, Wilson C; dos Santos, Evelyne A; Pessoa, Cláudia; de Moraes, Manoel O; Costa-Lotufo, Letícia V; Montenegro, Raquel C; Ferreira, Vitor F

2011-06-01

43

Antitumor agents. 89. Psychorubrin, a new cytotoxic naphthoquinone from Psychotria rubra and its structure-activity relationships.  

PubMed

A new naphthoquinone, isolated from the alcoholic extract of Psychotria rubra, exhibited significant cytotoxicity in the KB cell assay (ED50 = 3.0 micrograms/mL). Spectral data was used to assign the structure of psychorubrin as 2. Naphthoquinone derivatives 6, 8, 13, and 14 were prepared and exhibited superior cytotoxic activity to that of psychorubrin. All were potential Michael acceptors whose conjugation had been extended. However, when a hydrophilic hydroxy group was present in such compounds, reduced in vitro activity was observed. PMID:3669007

Hayashi, T; Smith, F T; Lee, K H

1987-11-01

44

1,4-Naphthoquinone Cations as Antiplasmodial Agents: Hydroxy-, Acyloxy-, and Alkoxy-Substituted Analogues  

PubMed Central

Cations of hydroxy-substituted 1,4-naphthoquinones were synthesized and evaluated as antiplasmodial agents against Plasmodium falciparum. The atovaquone analogues were found to be inactive as antagonists of parasite growth, which was attributed to ionization of the acidic hydroxyl moiety. Upon modification to an alkoxy substituent, the antiplasmodial activity was restored in the sub-100 nM range. Optimal inhibitors were found to possess IC50 values of 17.4–49.5 nM against heteroresistant P. falciparum W2. PMID:24936235

2012-01-01

45

5-Chloro-8-hydr­oxy-6-methyl-1,4-naphthoquinone  

PubMed Central

The mol­ecule of the title compound, C11H7ClO3, is planar, with a maximum deviation of 0.0383?(10)?Å from the naphthoquinone plane. An intra­molecular O—H?O hydrogen bond generates an S(6) ring motif. The crystal packing is stabilized by inter­molecular C—H?O hydrogen bonds. Short intra­molecular Cl?O [2.8234?(8)?Å] and O?O [2.5530?(11)?Å], and inter­molecular Cl?Cl [3.2777?(3)?Å] contacts further stabilize the crystal structure. PMID:21582583

Tan, Daniel Teoh-Chuan; Osman, Hasnah; Kamaruddin, Azlina Harun; Jebas, Samuel Robinson; Fun, Hoong-Kun

2009-01-01

46

Antiplatelet and antithrombotic activities of CP201, a newly synthesized 1,4-naphthoquinone derivative  

Microsoft Academic Search

The antiplatelet and antithrombotic activities of a newly synthesized CP201, 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone on human platelet aggregation in vitro and murine pulmonary thrombosis in vivo were examined. In addition, the antiplatelet activity of CP201 involved in calcium-signaling cascade was also investigated. CP201 showed concentration-dependent inhibitory effects on platelet aggregation induced by collagen and thrombin, with IC50 values of 4.1±0.3 and 4.6±0.4 ?M,

Yong-Ri Jin; Kyung-Ae Hwang; Mi-Ra Cho; Soo-Yeon Kim; Jin-Ho Kim; Chung-Kyu Ryu; Dong-Ju Son; Young-Hyun Park; Yeo-Pyo Yun

2004-01-01

47

Application of MEKC and monolithic CEC for the analysis of bioactive naphthoquinones in Eleutherine americana.  

PubMed

Two microscale separation techniques for the analysis of bioactive naphthoquinones in Eleutherine americana were developed and validated. By MEKC four compounds (eleuthoside B, isoeleutherin, eleutherol and eleutherinoside A) could be determined in plant extracts using an aqueous electrolyte solution composed of 25 mM sodium tetraborate, 50 mM sodium cholate and 20% THF. CEC on a polymeric methacrylate-based monolith with strong cationic properties showed promising results, as it additionally enabled the separation of two enantiomers, eleutherin and isoeleutherin. The mobile phase for CEC experiments comprised 3 mM ammonium formate in a mixture of ACN and water. At an applied voltage of -25 kV, all five markers were baseline separated in less than 12 min. Both methods were successfully validated for linearity (MEKC: R(2) > or = 0.999; CEC: R(2) > or = 0.997), sensitivity (MEKC: LOD = 4-5 microg/mL; CEC: LOD=2-8 microg/mL), accuracy (MEKC: 96.5-102.7% recovery; CEC: 97.1-103.5% recovery) and precision (MEKC: sigma(rel) < or = 2.43%; CEC: sigma(rel) < or = 2.21%). The quantitative analysis of naphthoquinone derivatives in several E. americana samples showed that both methods are suitable for practical applications, because the results were well comparable to those obtained by established techniques such as HPLC. PMID:19862752

Ganzera, Markus; Nischang, Ivo; Siegl, Christian; Senzenberger, Birgit; Svec, Frantisek; Stuppner, Hermann

2009-11-01

48

Luminescence of 1,4-naphthoquinone and the vitamin K system in Shpolskii matrices at 4 K  

NASA Astrophysics Data System (ADS)

This work investigates the high-resolution phosphorescence spectra of 1,4-naphthoquinone and the vitamin K system in Shpolskii solvents at 4 K. The quasi-linear vibronic bands are discussed with regard to spectral assignments and polarization data. The effect of non-totally symmetric vibrations is also discussed.

Vo-Dinh, Tuan; Wild, Urs P.

49

Naphthoquinone spiroketals and organic extracts from the endophytic fungus Edenia gomezpompae as potential herbicides.  

PubMed

From the fermentation mycelium of the endophytic fungus Edenia gomezpompae were obtained several phytotoxic compounds including two new members of the naphthoquinone spiroketal family, namely, palmarumycin EG1 (1) and preussomerin EG4 (4). In addition, preussomerins EG1-EG3 (7-9) and palmarumycins CP19 (2), CP17 (3), and CP2 (6), as well as ergosta-4,6,8(14),22-tetraen-3-one (5), were obtained. Compounds 2, 3, and 5 are new to this species. The structures of palmarumycins CP19 (2) and CP17 (3) were unambiguously determined by X-ray analysis. The isolates and mycelium organic extracts from four morphological variants of E. gomezpompae caused significant inhibition of seed germination, root elongation, and seedling respiration of Amaranthus hypochondriacus, Solanum lycopersicum, and Echinochloa crus-galli. The treatments also affected respiration on intact mitochondria isolated from spinach. PMID:24689520

Macías-Rubalcava, Martha L; Ruiz-Velasco Sobrino, M Emma; Meléndez-González, Claudio; Hernández-Ortega, Simón

2014-04-23

50

Investigation of the cumulative tissue doses of naphthoquinones in human serum using protein adducts as biomarker of exposure.  

PubMed

Both 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are reactive metabolites of naphthalene that are thought to be responsible for the naphthalene-induced cytotoxicity and genotoxicity. The aim of this study was to investigate the cumulative tissue dose of 1,2-NPQ and 1,4-NPQ in human serum derived from blood donors in Taiwan via measurements of albumin adducts by a methodology, which employs trifluoroacetic acid anhydride and methanesulfonic acid to selectively cleave cysteinyl adducts on proteins. Both 1,2-NPQ and 1,4-NPQ adducts were detected in all male and female subjects (n=22). The median levels of 1,2-NPQ adduct in human subjects were estimated to be 268 (range 139-857) and 203 (range 128-1352) (pmol/g) in male (n=11) and female (n=11) subjects, respectively. In contrast, the median levels of 1,4-NPQ adduct were estimated to be 45.0 (range 22.0-117) and 38.9 (range 21.5-172) (pmol/g) in male and female subjects, respectively. We noticed that levels of 1,2-NPQ adduct were significantly correlated with those of 1,4-NPQ adduct (correlation coefficient r=0.643, p<0.01). Results from in vitro experiments confirmed that the production of naphthoquinones-derived adducts on serum albumin increased with increased concentration of naphthoquinones (0-100 microM). Linear relationships were observed over the range of concentration. Time-course experiments suggested that both 1,2-NPQ and 1,4-NPQ-derived adducts rapidly reached maximum values at 10 min mark and remained constant thereafter. The reaction rate constant analyses indicated that the second-order rate constants, representing in vitro reactions between naphthoquinones and cysteine residues of serum albumin, were estimated to be 0.0044/0.0002L(gprotein)(-1)h(-1), respectively. Overall, the cumulative tissue doses of 1,4-NPQ (217-316 nM h) in male and female subjects were approximately 3-fold greater than those of 1,2-NPQ (76-98 nM h) in the study population. The initial concentrations of serum 1,2-NPQ and 1,4-NPQ in the study population were estimated to be between 145-188 and 807-1175 nM, respectively. We conclude that the relatively large amounts of naphthoquinones present in human serum may point to toxicological consequences. PMID:19505452

Lin, Po-Hsiung; Chen, Dar-Ren; Wang, Tzu-Wen; Lin, Chia-Hua; Chuang, Ming-Chieh

2009-09-14

51

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.

2003-12-01

52

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. PMID:23350008

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

2013-01-01

53

The cytotoxic effects of 5-OH-1,4-naphthoquinone and 5,8-diOH-1,4-naphthoquinone on doxorubicin-resistant human leukemia cells (HL-60).  

PubMed

The effect of 5-OH-1,4-naphthoquinone and 5,8-diOH-1,4-naphthoquinone, two quinones highly reactive with oxygen, was studied on HL-60 and HL-60R cells. The multidrug resistance developed by the doxorubicin-resistant HL-60 cell line did not prevent the cytotoxic effect of these compounds, at clinically relevant concentrations. An increase in cellular defenses against oxygen radicals seemed to be one of the features developed by HL-60R, since the homogenate from this cell line had only 65% of the ability of the original cell line to form oxygen radicals during doxorubicin reduction. This result may be explained in part by the slight increase in superoxide dismutase and DT-diaphorase enzymatic activities. PMID:1635381

Segura-Aguilar, J; Jönsson, K; Tidefelt, U; Paul, C

1992-01-01

54

Synthesis, leishmanicidal activity and theoretical evaluations of a series of substituted bis-2-hydroxy-1,4-naphthoquinones.  

PubMed

A series of eight substituted bis-2-hydroxy-1,4-naphthoquinone derivatives was synthesized through lawsone condensation with various aromatic and aliphatic aldehydes under mild acidic conditions. The title compounds were evaluated for antileishmanial activity in vitro against Leishmania amazonensis and Leishmania braziliensis promastigotes; six compounds showed good activity without significant toxic effects. The compound with the highest activity was used for an in vivo assay with Leishmania amazonensis. PMID:25247686

de Araújo, Morgana V; de Souza, Patricia S O; de Queiroz, Aline C; da Matta, Carolina B B; Leite, Anderson Brandão; da Silva, Amanda Evelyn; de França, José A A; Silva, Tania M S; Camara, Celso A; Alexandre-Moreira, Magna S

2014-01-01

55

A study on the properties and reactivity of naphthoquinone-cobalt(III) prototypes for bioreductive prodrugs.  

PubMed

Our group has recently initiated a study on the development of new prototypes for bioreductive prodrugs, based on Co(III) complexes with the ligand 2,2'-bis(3-hydroxy-1,4-naphthoquinone), H2bhnq. The focus of this work is to investigate the dissociation of bhnq(-2) from the complex upon reduction, and the effects of pH, redox potential, oxygen concentration and nature of the auxiliary ligands on this reaction. The bhnq(2-) ligand is a "non-cytotoxic" agent that was chosen as a probe for the reactivity studies due to its suitable chromophoric properties, at the same time that it resembles more cytotoxic naphthoquinones relevant for cancer therapy. In this way, two Co(III) complexes [Co(bhnq)(L1)]BF4·H2O (1) and [Co(bhnq)(L2)]BF4·H2O (2) (L1=N,N'-bis(pyridin-2-ylmethyl)ethylenediamine and L2=N,N'-dimethyl-N,N'-bis(pyridin-2-ylmethyl)ethylenediamine) were synthesized and fully characterized. The gallium analogs [Ga(bhnq)(L1)]NO3·3H2O (3) and [Ga(bhnq)(L2)]NO3·3H2O (4) were also prepared for helping with the assignments of the redox properties of the cobalt complexes and the structure of 2. Cyclic voltammetry analysis revealed a pH-independent quasi-reversible Co(III)/Co(II) process at -0.22 and -0.08V vs NHE for 1 and 2, respectively. An O2-dependent dissociation of bhnq(2-) was observed for the reaction of 1 with ascorbic acid. For 2, the dissociation of bhnq(2-) was found to be independent on the concentration of O2 and faster than in 1, with little influence of the pH on both complexes. The difference in reactivity between 1 and 2 and their redox properties, among other factors, suggests that 1 undergoes redox cycling, pointed out as a key feature for a prodrug to achieve hypoxic selectivity. PMID:24326134

Bustamante, Francisco L S; Miranda, Fabio S; Castro, Frederico A V; Resende, Jackson A L C; Pereira, Marcos D; Lanznaster, Mauricio

2014-03-01

56

Design, synthesis, and biological testing of novel naphthoquinones as substrate-based inhibitors of the quinol/fumarate reductase from Wolinella succinogenes.  

PubMed

Novel naphthoquinones were designed, synthesized, and tested as substrate-based inhibitors against the membrane-embedded protein quinol/fumarate reductase (QFR) from Wolinella succinogenes, a target closely related to QFRs from the human pathogens Helicobacter pylori and Campylobacter jejuni. For a better understanding of the hitherto structurally unexplored substrate binding pocket, a structure-activity relationship (SAR) study was carried out. Analogues of lawsone (2-hydroxy-1,4-naphthoquinone 3a) were synthesized that vary in length and size of the alkyl side chains (3b-k). A combined study on the prototropic tautomerism of 2-hydroxy-1,4-naphthoquinones series indicated that the 1,4-tautomer is the more stable and biologically relevant isomer and that the presence of the hydroxyl group is crucial for inhibition. Furthermore, 2-bromine-1,4-naphthoquinone (4a-c) and 2-methoxy-1,4-naphthoquinone (5a-b) series were also discovered as novel and potent inhibitors. Compounds 4a and 4b showed IC50 values in low micromolar range in the primary assay and no activity in the counter DT-diaphorase assay. PMID:24251984

Nasiri, Hamid Reza; Madej, M Gregor; Panisch, Robin; Lafontaine, Michael; Bats, Jan W; Lancaster, C Roy D; Schwalbe, Harald

2013-12-12

57

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

PubMed

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

2009-09-01

58

Synthesis and SAR study of novel anticancer and antimicrobial naphthoquinone amide derivatives.  

PubMed

A series of novel naphthoquinone amide derivatives of the bioactive quinones, plumbagin, juglone, menadione and lawsone, with various amino acids were synthesized. The compounds were characterized by (1)H NMR, (13)C NMR, Mass, IR and elemental analysis. All the compounds were evaluated for their anticancer activity against HeLa and SAS cancer cell lines and 3D-QSAR indicated the presence of electron donating group near sulphur enhanced the activity against HeLa cells. Among the derivatives synthesized, compounds 11f, 10a, 10b and 10g were the most active with IC50 values of 16, 12, 14 and 24.5 ?M, respectively. The analogues were also screened for antimicrobial activity against two human bacterial pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative Pseudomonas aeruginosa and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA). Among the synthesized compounds, 8g, 10g and 11g exhibited maximum antibacterial activity towards MRSA and antifungal activity against FRCA in well diffusion method. PMID:24913712

Sreelatha, Thonthula; Kandhasamy, Subramani; Dinesh, Raghu; Shruthy, Suresh; Shweta, Sinha; Mukesh, Doble; Karunagaran, Devarajan; Balaji, Ravichandran; Mathivanan, Narayanasamy; Perumal, Paramasivan Thirumalai

2014-08-01

59

Surface enhanced Raman spectral studies of 2-bromo-1,4-naphthoquinone.  

PubMed

Silver nanoparticles have been synthesized by a simple and inexpensive solution combustion method with urea as fuel. The structural and morphology of the silver nanoparticles were investigated through X-ray powder diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersion Spectra (EDS) techniques. Structural and morphological results confirmed the nanocrystalline nature of the silver nanoparticles. Density Functional Theory (DFT) calculations were also performed to study the ground and excited state behavior of 2-bromo-1,4-naphthoquinone (2-BrNQ) and 2-BrNQ on silver nanoparticles. Surface-Enhanced Raman Scattering (SERS) spectra of 2-BrNQ adsorbed on silver nanoparticles were investigated. The CO, CH in-plane bending and CBr stretching modes were enhanced in SERS spectrum with respect to normal Raman spectrum. The spectral analysis reveals that the 2-BrNQ adsorbed 'stand-on' orientation on the silver surface. Density Functional Theory (DFT) calculations are also performed to study the vibrational features of 2-BrNQ molecule and 2-BrNQ molecule on silver surface. PMID:25481490

Geetha, K; Umadevi, M; Sathe, G V; Vanelle, P; Terme, T; Khoumeri, O

2015-03-01

60

2,3-DIPHENYL-1,4-NAPHTHOQUINONE: A POTENTIAL CHEMOTHERAPEUTIC AGENT AGAINST TRYPANOSOMA CRUZI  

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. PMID:18788881

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

2010-01-01

61

Proteomics Analyses of Bacillus subtilis after Treatment with Plumbagin, a Plant-Derived Naphthoquinone.  

PubMed

Abstract Infectious diseases and increasing antibiotic resistance among diverse classes of microbes are global health concerns and a prime focus of omics systems science applications in novel drug discovery. Plumbagin is a plant-derived naphthoquinone, a natural product that exhibits antibacterial activity against gram-positive bacteria. In the present study, we investigated the antimicrobial effects of plumbagin against Bacillus subtilis using two complementary proteomics techniques: two-dimensional electrophoresis (2-DE) and isobaric tag for relative and absolute quantification (iTRAQ). Comparative quantitative proteomics analysis of plumbagin treated and untreated control samples identified differential expression of 230 proteins (1% FDR, 1.5 fold-change and ?2 peptides) in B. subtilis after plumbagin treatment. Pathway analysis involving the differentially expressed proteins suggested that plumbagin effectively increases heme and protein biosynthesis, whereas fatty acid synthesis was significantly reduced. Gene expression and metabolic activity assays further corroborated the proteomics findings. We anticipate that plumbagin blocks the cell division by altering the membrane permeability required for energy generation. This is the first report, to the best of our knowledge, offering new insights, at proteome level, for the putative mode(s) of action of plumbagin and attendant cellular targets in B. subtilis. The findings also suggest new ways forward for the modern omics-guided drug target discovery, building on traditional plant medicine. PMID:25562197

Reddy, Panga Jaipal; Ray, Sandipan; Sathe, Gajanan J; Prasad, T S Keshava; Rapole, Srikanth; Panda, Dulal; Srivastava, Sanjeeva

2015-01-01

62

Synthesis and Biological Activity of New Thiopyrano[2,3-d]thiazoles Containing a Naphthoquinone Moiety  

PubMed Central

Novel 11-substituted 3,11-dihydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]-thiazole-2,5,10-triones 4a–i were synthesized in 75–90% yields via the hetero-Diels-Alder reaction of 5-arylidene-4-thioxo-2-thiazolidinones with 1,4-naphthoquinone. The synthesized compounds were evaluated for their antineoplastic and antimycobacterial activities. A moderate selectivity against melanoma cancer cells (GI50 (UACC-257-melanoma) = 0.22 ?M) was demonstrated for 4i, whereas derivatives 4a, 4c, 4g, and 4h showed promising antimycobacterial activity at a low toxicity level. PMID:23833711

Atamanyuk, Dmytro; Zimenkovsky, Borys; Atamanyuk, Vasyl; Nektegayev, Ihor; Lesyk, Roman

2013-01-01

63

Effects of donor plants and plant growth regulators on naphthoquinone production in root cultures of Impatiens balsamina  

Microsoft Academic Search

The effects of type of explant (leaves and roots), donor plants, and plant growth regulators on naphthoquinone (NQ) production\\u000a of Impatiens balsamina L. root cultures were evaluated. The root cultures were initiated in liquid Gamborg’s B5 medium supplemented with 0.1 mg l?1 ?-naphthaleneacetic acid (NAA), 0.1 mg l?1 kinetin (Kn) and 1.0 mg l?1 6-benzyladenine (BA). The present investigation indicated that the root cultures established from

Athip Sakunphueak; Pharkphoom Panichayupakaranant

2010-01-01

64

Toward the total synthesis of hygrocin B and divergolide C: construction of the naphthoquinone-azepinone core.  

PubMed

A highly regioselective Diels-Alder approach toward the bioactive natural products hygrocin B and divergolide C is presented. The route uses an unusual benzoquinone-azepinone dienophile prepared in 8 steps from ethyl 8-methoxy-1-naphthoate, by a route which includes, as key steps, a Birch alkylation and a Beckmann rearrangement of a tetralone oxime, both of which are demonstrated on multigram scale. The naphthoquinone-azepinone core is suitably functionalized for addition of the ansa-chain, found in the natural products. PMID:24661134

Nawrat, Christopher C; Kitson, Russell R A; Moody, Christopher J

2014-04-01

65

1,4-Naphthoquinone, a pro-oxidant, suppresses immune responses via KEAP-1 glutathionylation.  

PubMed

Low levels of oxidative stress have been shown to activate Nrf-2, an important anti-inflammatory transcription factor, by us and also by several other investigators. Earlier we showed that pro-oxidants protect normal lymphocytes against radiation injury by activating Nrf-2. In the present study, we have investigated the effect of oxidative stress on immune responses and delineated the underlying mechanism. Hydrogen peroxide, tert-butylhydroquinone and 1,4-naphthoquinone (NQ) inhibited mitogen induced proliferation of lymphocytes. NQ also inhibited mitogen (Concanavalin A) induced cytokine secretion by murine T cells and lipopolysaccharide induced release of cytokines, nitric oxide and cyclooxygenase-2 expression by macrophages. NQ modulated cellular redox by decreasing GSH/GSSG ratio and the immunosuppressive effects of NQ were significantly abrogated by thiol containing antioxidants and not by non-thiol antioxidants. This redox perturbation led to activation of Nrf-2 pathway and inhibition of NF-?B. NQ treatment increased total protein S-thiolation, induced glutathionylation of KEAP-1 protein and decreased IKK? levels in lymphocytes. Molecular docking studies revealed that NQ can disrupt KEAP-1/Nrf-2 interaction by directly blocking the binding site of Nrf-2 in the KEAP-1 protein. Further, inhibitors of Nrf-2 and HO-1 abrogated the anti-inflammatory effects of NQ. T cells isolated from spleen and gut associated lymphoid tissue of NQ administered mice also showed suppression of NF-?B activation and were hyporesponsive to mitogenic stimulation. These results demonstrate that pro-oxidants modulate inflammatory and immune responses via oxidative stress mediated KEAP-1 glutathionylation and IKK? degradation. PMID:24406247

Gambhir, Lokesh; Checker, Rahul; Thoh, Maikho; Patwardhan, R S; Sharma, Deepak; Kumar, Mukesh; Sandur, Santosh K

2014-03-01

66

Substituted 3?acyl?2?phenylamino?1,4?naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death.  

PubMed

Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3?acyl?2?phenylamino?1,4?naphthoquinones (DPB1?DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor?bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 µM) and DPB6 was the least cytotoxic one (EC50 56 µM). The 1,4?naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4?naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA?ethidium bromide complexes. Cell death of MCF7 cells induced by 3?acyl?2?phenylamino?1,4?naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4?naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4?naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%). PMID:24756411

Farias, Mirelle Sifroni; Pich, Claus Tröger; Kviecinski, Maicon Roberto; Bucker, Nádia Cristina Falcão; Felipe, Karina Bettega; Da Silva, Fabiana Ourique; Günther, Tânia Mara Fisher; Correia, João Francisco; Ríos, David; Benites, Julio; Valderrama, Jaime A; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

2014-07-01

67

A small library of synthetic di-substituted 1, 4-naphthoquinones induces ROS-mediated cell death in murine fibroblasts.  

PubMed

Synthesis of compound libraries and their concurrent assessment as selective reagents for probing and modulating biological function continues to be an active area of chemical biology. Microwave-assisted solid-phase Dötz benzannulation reactions have been used to inexpensively synthesize 2, 3-disubstituted-1, 4-naphthoquinone derivatives. Herein, we report the biological testing of a small library of such compounds using a murine fibroblast cell line (L929). Assessment of cellular viability identified three categories of cytotoxic compounds: no toxicity, low/intermediate toxicity and high toxicity. Increased levels of Annexin-V-positive staining and of caspase 3 activity confirmed that low, intermediate, and highly toxic compounds promote cell death. The compounds varied in their ability to induce mitochondrial depolarization and formation of reactive oxygen species (ROS). Both cytotoxic and non-cytotoxic compounds triggered mitochondrial depolarization, while one highly cytotoxic compound did not. In addition, all cytotoxic compounds promoted increased intracellular ROS but the cells were only partially protected from compound-induced apoptosis when in the presence of superoxide dismutase, catalase, or ascorbic acid suggesting utilization of additional pro-death mechanisms. In summary, nine of twelve (75%) 1, 4-naphthoquinone synthetic compounds were cytotoxic. Although the mitochondria did not appear to be a central target for induction of cell death, all of the cytotoxic compounds induced ROS formation. Thus, the data demonstrate that the synthesis regime effectively created cytotoxic compounds highlighting the potential use of the regime and its products for the identification of biologically relevant reagents. PMID:25197824

Ramirez, Oscar; Motta-Mena, Laura B; Cordova, Amanda; Garza, Kristine M

2014-01-01

68

2-Chloro-1,4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent.  

PubMed

Abstract The ability of flavonoids to affect multiple key pathways of glucose toxicity, as well as to attenuate inflammation has been well documented. In this study, the inhibition of rat lens aldose reductase by 3,7-di-hydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxy-phenyl]-5-hydroxy-chromen-4-one (compound 1), was studied in greater detail in comparison with the parent quercetin (compound 2). The inhibition activity of 1, characterized by IC50 in low micromolar range, surpassed that of 2. Selectivity in relation to the closely related rat kidney aldehyde reductase was evaluated. At organ level in isolated rat lenses incubated in the presence of high glucose, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner, which indicated that 1 was readily taken up by the eye lens cells and interfered with cytosolic aldose reductase. In addition, compound 1 provided macroscopic protection of colonic mucosa in experimental colitis in rats. At pharmacologically active concentrations, compound 1 and one of its potential metabolite 2-chloro-3-hydroxy-[1,4]-naphthoquinone (compound 3) did not affect osmotic fragility of red blood cells. PMID:24666303

Milackova, Ivana; Prnova, Marta Soltesova; Majekova, Magdalena; Sotnikova, Ruzena; Stasko, Michal; Kovacikova, Lucia; Banerjee, Sreeparna; Veverka, Miroslav; Stefek, Milan

2015-02-01

69

A Small Library of Synthetic Di-Substituted 1, 4-Naphthoquinones Induces ROS-Mediated Cell Death in Murine Fibroblasts  

PubMed Central

Synthesis of compound libraries and their concurrent assessment as selective reagents for probing and modulating biological function continues to be an active area of chemical biology. Microwave-assisted solid-phase Dötz benzannulation reactions have been used to inexpensively synthesize 2, 3-disubstituted-1, 4-naphthoquinone derivatives. Herein, we report the biological testing of a small library of such compounds using a murine fibroblast cell line (L929). Assessment of cellular viability identified three categories of cytotoxic compounds: no toxicity, low/intermediate toxicity and high toxicity. Increased levels of Annexin-V-positive staining and of caspase 3 activity confirmed that low, intermediate, and highly toxic compounds promote cell death. The compounds varied in their ability to induce mitochondrial depolarization and formation of reactive oxygen species (ROS). Both cytotoxic and non-cytotoxic compounds triggered mitochondrial depolarization, while one highly cytotoxic compound did not. In addition, all cytotoxic compounds promoted increased intracellular ROS but the cells were only partially protected from compound-induced apoptosis when in the presence of superoxide dismutase, catalase, or ascorbic acid suggesting utilization of additional pro-death mechanisms. In summary, nine of twelve (75%) 1, 4-naphthoquinone synthetic compounds were cytotoxic. Although the mitochondria did not appear to be a central target for induction of cell death, all of the cytotoxic compounds induced ROS formation. Thus, the data demonstrate that the synthesis regime effectively created cytotoxic compounds highlighting the potential use of the regime and its products for the identification of biologically relevant reagents. PMID:25197824

Ramirez, Oscar; Motta-Mena, Laura B.; Cordova, Amanda; Garza, Kristine M.

2014-01-01

70

Synthesis of novel and diverse naphtho[1,2-b]furans by phosphine-catalyzed [3+2] annulation of activated 1,4-naphthoquinones and acetylenecarboxylates.  

PubMed

A new phosphine-catalyzed [3+2] annulation reaction between activated 1,4-naphthoquinones and acetylenecarboxylates is described. This reaction provides a facile and efficient route to a variety of biologically promising and novel naphtho[1,2-[Formula: see text

Xia, Likai; Somai Magar, Krishna Bahadur; Lee, Yong Rok

2015-02-01

71

Anti-proliferative actions of 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone in vascular smooth muscle cells  

SciTech Connect

Highlights: {yields} 2-Decylamino-DMNQ inhibited PDGF-BB-induced VSMC proliferation in a dose-dependent manner with no apparent cytotoxicity. {yields} 2-Decylamino-DMNQ inhibited PDGF-BB-induced phosphorylation of Erk1/2 and PLC{gamma}1. {yields} 2-Decylamino-DMNQ arrested a G{sub 0}/G{sub 1} cell cycle progression in association with pRb phosphorylation and PCNA expression. {yields} Both U0126, an Erk inhibitor, and U73122, a PLC{gamma} inhibitor, arrested a G{sub 0}/G{sub 1} phase of the cell cycle. -- Abstract: Naphthoquinone derivatives have been reported to possess various pharmacological activities, such as antiplatelet, anticancer, antifungal, and antiviral properties. In this study, we investigated the effects of a newly-synthesized naphthoquinone derivative, 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone (2-decylamino-DMNQ), on VSMC proliferation and examined the molecular basis of the underlying mechanism. In a dose-dependent manner, 2-decylamino-DMNQ inhibited PDGF-stimulated VSMC proliferation with no apparent cytotoxic effect. While 2-decylamino-DMNQ did not affect PDGF-R{beta} or Akt, it did inhibit the phosphorylation of Erk1/2 and PLC{gamma}1 induced by PDGF. Moreover, 2-decylamino-DMNQ suppressed DNA synthesis through the arrest of cell cycle progression at the G{sub 0}/G{sub 1} phase, including the suppression of pRb phosphorylation and a decrease in PCNA expression, which was related to the downregulation of cell cycle regulatory factors, such as cyclin D1/E and CDK 2/4. It was demonstrated that both U0126, an Erk1/2 inhibitor, and U73122, a PLC{gamma} inhibitor, increased the proportion of cells in the G{sub 0}/G{sub 1} phase of the cell cycle. Thus, these results suggest that 2-decylamino DMNQ has an inhibitory effect on PDGF-induced VSMC proliferation and the mechanism of this action is through cell cycle arrest at the G{sub 0}/G{sub 1} phase. This may be a useful tool for studying interventions for vascular restenosis in coronary revascularization procedures and stent implantation.

Lee, Jung-Jin [Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of) [Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of); Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Zhang, Wei-Yun; Yi, Hyoseok; Kim, Yohan; Kim, In-Su [Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of)] [Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of); Shen, Gui-Nan; Song, Gyu-Yong [Department of Medicinal Chemistry, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of)] [Department of Medicinal Chemistry, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of); Myung, Chang-Seon, E-mail: cm8r@cnu.ac.kr [Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of) [Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764 (Korea, Republic of); Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764 (Korea, Republic of)

2011-07-22

72

Surface Enhanced Raman Spectroscopic investigations of 2-bromo-3-methylamino-1,4-naphthoquinone on silver nanoparticles.  

PubMed

Surface Enhanced Raman Spectroscopic technique has been employed to investigate the orientation of 2-bromo-3-methylamino-1,4-naphthoquinone (BMANQ) on silver nanoparticles. Silver nanoparticles have been prepared by solution combustion method with citric acid as fuel. Silver nanoparticles were characterized by X-ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and Scanning Electron Microscopy (SEM). XRD and morphological results confirmed the nanocrystalline nature of the prepared silver nanoparticles. The observed intense CO stretching, CBr stretching and NH2 vibration suggests that the BMANQ molecule may be adsorbed in a 'stand-on' orientation to the silver surface. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy show that charge transfer occurs within the molecule. PMID:25468439

Geetha, K; Umadevi, M; Sathe, G V; Vanelle, P; Terme, T; Khoumeri, O

2014-11-01

73

Surface Enhanced Raman Spectroscopic investigations of 2-bromo-3-methylamino-1,4-naphthoquinone on silver nanoparticles  

NASA Astrophysics Data System (ADS)

Surface Enhanced Raman Spectroscopic technique has been employed to investigate the orientation of 2-bromo-3-methylamino-1,4-naphthoquinone (BMANQ) on silver nanoparticles. Silver nanoparticles have been prepared by solution combustion method with citric acid as fuel. Silver nanoparticles were characterized by X-ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and Scanning Electron Microscopy (SEM). XRD and morphological results confirmed the nanocrystalline nature of the prepared silver nanoparticles. The observed intense Cdbnd O stretching, Csbnd Br stretching and NH2 vibration suggests that the BMANQ molecule may be adsorbed in a 'stand-on' orientation to the silver surface. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy show that charge transfer occurs within the molecule.

Geetha, K.; Umadevi, M.; Sathe, G. V.; Vanelle, P.; Terme, T.; Khoumeri, O.

2015-02-01

74

Naphthoquinone-directed C-H annulation and C(sp³)-H bond cleavage: one-pot synthesis of tetracyclic naphthoxazoles.  

PubMed

One-pot synthesis of tetracyclic naphthoxazole derivatives from electron-deficient naphthoquinones and alkynes was achieved via Rh(III)-catalyzed C-H activation and C(sp(3))-H bond cleavage for the first time. This approach proceeds through a tandem cascade process involving substrate tautomerization, C-H activation, oxidative addition, cyclization, and aromatization. In addition, broad substrate scope, simple starting materials, and steric tolerance make this strategy of great practicality. PMID:24746121

Wang, Meining; Zhang, Chi; Sun, Li-Ping; Ding, Chunyong; Zhang, Ao

2014-05-16

75

One pot synthesis of poly(5-hydroxyl-1,4-naphthoquinone) stabilized gold nanoparticles using the monomer as the reducing agent for nonenzymatic electrochemical detection of glucose.  

PubMed

Monodispersed and highly stable gold nanoparticles with a diameter between 8 and 9nm were synthesized in a weakly alkaline medium by chemical reduction of AuCl4(-) using 5-hydroxyl-1,4-naphthoquinone, and stabilized by the simultaneously formed poly(hydroxyl-1,4-naphthoquinone). The electrochemical properties of the resultant poly(hydroxyl-1,4-naphthoquinone) stabilized gold nanoparticles (AuNQ NPs) and its electrocatalytic activity for glucose oxidation in alkaline media were then investigated using a range of techniques, including dc cyclic, rotating disk electrode and Fourier transformed large amplitude ac voltammetry. The results demonstrate that these AuNQ NP modified electrodes exhibit excellent catalytic activity toward glucose oxidation in the potential region where the premonolayer oxidation process occurs. The overall catalytic glucose oxidation process was found to be mass transport controlled under the experimental conditions employed, allowing measurements to be conducted with a high reproducibility. The AuNQ NP modified electrodes showed a high sensitivity of 183?AmM(-1)cm(-2) with a wide linear dynamic range of 0.5-50mM and a detection limit of 61?M. However, despite its excellent tolerance toward ascorbic acid, significant interference from uric acid was found with this AuNQ NP modified electrode. PMID:25542355

Cooray, M C Dilusha; Liu, Yuping; Langford, Steven J; Bond, Alan M; Zhang, Jie

2015-01-26

76

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.  

PubMed

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

2006-09-14

77

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

PubMed

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

2013-01-01

78

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

2012-12-01

79

Simple Spectrophotometric Method for Determination of Paroxetine in Tablets Using 1,2-Naphthoquinone-4-Sulphonate as a Chromogenic Reagent  

PubMed Central

Simple and rapid spectrophotometric method has been developed and validated for the determination of paroxetine (PRX) in tablets. The proposed method was based on nucleophilic substitution reaction of PRX with 1,2-naphthoquinone-4-sulphonate (NQS) in an alkaline medium to form an orange-colored product of maximum absorption peak (?max) at 488 nm. The stoichiometry and kinetics of the reaction were studied, and the reaction mechanism was postulated. Under the optimized reaction conditions, Beer's law correlating the absorbance (A) with PRX concentration (C) was obeyed in the range of 1–8 ?g mL?1. The regression equation for the calibration data was: A = 0.0031 + 0.1609 C, with good correlation coefficients (0.9992). The molar absorptivity (?) was 5.9 × 105 L mol?1 1 cm?1. The limits of detection and quantitation were 0.3 and 0.8 ?g mL?1, respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2%. The proposed method was successfully applied to the determination of PRX in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 97.17 ± 1.06 %. The results obtained by the proposed method were comparable with those obtained by the official method. PMID:20107559

Darwish, Ibrahim A.; Abdine, Heba H.; Amer, Sawsan M.; Al-Rayes, Lama I.

2009-01-01

80

Naphthoquinone-Dependent Generation of Superoxide Radicals by Quinone Reductase Isolated from the Plasma Membrane of Soybean[W  

PubMed Central

Using a tetrazolium-based assay, a NAD(P)H oxidoreductase was purified from plasma membranes prepared from soybean (Glycine max) hypocotyls. The enzyme, a tetramer of 85 kD, produces O2·? by a reaction that depended on menadione or several other 1,4-naphthoquinones, in apparent agreement with a classification as a one-electron-transferring flavoenzyme producing semiquinone radicals. However, the enzyme displayed catalytic and molecular properties of obligatory two-electron-transferring quinone reductases of the DT-diaphorase type, including insensitivity to inhibition by diphenyleneiodonium. This apparent discrepancy was clarified by investigating the pH-dependent reactivity of menadionehydroquinone toward O2 and identifying the protein by mass spectrometry and immunological techniques. The enzyme turned out to be a classical NAD(P)H:quinone-acceptor oxidoreductase (EC 1.6.5.2, formerly 1.6.99.2) that reduces menadione to menadionehydroquinone and subsequently undergoes autoxidation at pH ? 6.5. Autoxidation involves the production of the semiquinone as an intermediate, creating the conditions for one-electron reduction of O2. The possible function of this enzyme in the generation of O2·? and H2O2 at the plasma membrane of plants in vivo is discussed. PMID:18408044

Schopfer, Peter; Heyno, Eiri; Drepper, Friedel; Krieger-Liszkay, Anja

2008-01-01

81

Synthesis, spectral characterization, molecular structure and pharmacological studies of N'-(1, 4-naphtho-quinone-2yl) isonicotinohyWdrazide  

NASA Astrophysics Data System (ADS)

A simple and efficient procedure was employed for the synthesis of N'-(1,4-naphtho-quinone-2-yl) isonicotinohydrazide (NIH) by the reaction of 2-hydroxy-1,4-naphthaquinone (lawsone) and isonicotinoyl hydrazine in methanol using ultrasonic irradiation. Lawsone is the principal dye, isolated from the leaves of henna (Lawsonia inermis). Structural modification was done on the molecule aiming to get a more active derivative. The structure of the parent compound and the derivative was characterized by elemental analyses, infrared, electronic, 1H, 13C NMR and GC-MS spectra. The fluorescence spectral investigation of the compound was studied in DMSO and ethanol. Single crystal X-ray diffraction studies reveal that NIH crystallizes in monoclinic space group. The DNA cleavage study was monitored by gel electrophoresis method. The synthesized compound was found to have significant antioxidant activity against DPPH radical (IC50 = 58 ?M). The in vitro cytotoxic studies of the derivative against two human cancer cell lines MCF-7 (human breast cancer) and HCT-15 (human colon carcinoma cells) using MTT assay revealed that the compound exhibited higher cytotoxic activity with a lower IC50 value indicating its efficiency in killing the cancer cells even at low concentrations. These results suggest that the structural modifications performed on lawsone could be considered a good strategy to obtain a more active drug.

Kavitha Rani, P. R.; Fernandez, Annette; George, Annie; Remadevi, V. K.; Sudarsanakumar, M. R.; Laila, Shiny P.; Arif, Muhammed

2015-01-01

82

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.

83

Glyceraldehyde-3-phosphate dehydrogenase as a quinone reductase in the suppression of 1,2-naphthoquinone protein adduct formation.  

PubMed

1,2-Naphthoquinone (1,2-NQ) is electrophilic, and forms covalent bonds with protein thiols, but its two-electron reduction product 1,2-dihydroxynaphthalene (1,2-NQH(2)) is not, so enzymes catalyzing the reduction with reduced pyridine nucleotides as cofactors could protect cells from electrophile-based chemical insults. To assess this possibility, we examined proteins isolated from the 9000g supernatant from mouse liver for 1,2-NQ reductase activity using an HPLC assay procedure for the hydroquinone of 1,2-NQ and Cibacron Blue 3GA column chromatography and Western blot analysis with specific antibody to determine 1,2-NQ-bound proteins. Among the proteins with high affinities for pyridine nucleotides that also inhibited 1,2-NQ-protein adduct formation in the presence of NADH, a 37-kDa protein was found and identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using recombinant human GAPDH, we found that this glycolytic enzyme indeed catalyzes the two-electron reduction of 1,2-NQ accompanied by extensive NADH consumption under 20% oxygen conditions. When either 1,2-NQH(2) or 1,2-NQ was incubated with GAPDH in the presence of NADH, minimal covalent bonding to the enzyme occurred compared to that in its absence. These results indicate that GAPDH can inhibit 1,2-NQ-based electrophilic protein modification by conversion to the nonelectrophilic 1,2-NQH(2) via an NADH-dependent process. PMID:21963991

Miura, Takashi; Shinkai, Yasuhiro; Hirose, Reiko; Iwamoto, Noriko; Cho, Arthur K; Kumagai, Yoshito

2011-12-01

84

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).  

PubMed

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

2013-01-01

85

Potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Leishmania (L.) infantum: biological activity and structure-activity relationships.  

PubMed

Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis. PMID:25171058

Pinto, Erika G; Santos, Isabela O; Schmidt, Thomas J; Borborema, Samanta E T; Ferreira, Vitor F; Rocha, David R; Tempone, Andre G

2014-01-01

86

Molecular insights into human monoamine oxidase (MAO) inhibition by 1,4-naphthoquinone: evidences for menadione (vitamin K3) acting as a competitive and reversible inhibitor of MAO.  

PubMed

Monoamine oxidase (MAO) catalyzes the oxidative deamination of biogenic and exogenous amines and its inhibitors have therapeutic value for several conditions including affective disorders, stroke, neurodegenerative diseases and aging. The discovery of 2,3,6-trimethyl-1,4-naphthoquinone (TMN) as a nonselective and reversible inhibitor of MAO, has suggested 1,4-naphthoquinone (1,4-NQ) as a potential scaffold for designing new MAO inhibitors. Combining molecular modeling tools and biochemical assays we evaluate the kinetic and molecular details of the inhibition of human MAO by 1,4-NQ, comparing it with TMN and menadione. Menadione (2-methyl-1,4-naphthoquinone) is a multitarget drug that acts as a precursor of vitamin K and an inducer of mitochondrial permeability transition. Herein we show that MAO-B was inhibited competitively by 1,4-NQ (K(i)=1.4 ?M) whereas MAO-A was inhibited by non-competitive mechanism (K(i)=7.7 ?M). Contrasting with TMN and 1,4-NQ, menadione exhibited a 60-fold selectivity for MAO-B (K(i)=0.4 ?M) in comparison with MAO-A (K(i)=26 ?M), which makes it as selective as rasagiline. Fluorescence and molecular modeling data indicated that these inhibitors interact with the flavin moiety at the active site of the enzyme. Additionally, docking studies suggest the phenyl side groups of Tyr407 and Tyr444 (for MAO-A) or Tyr398 and Tyr435 (for MAO-B) play an important role in the interaction of the enzyme with 1,4-NQ scaffold through forces of dispersion as verified for menadione, TMN and 1,4-NQ. Taken together, our findings reveal the molecular details of MAO inhibition by 1,4-NQ scaffold and show for the first time that menadione acts as a competitive and reversible inhibitor of human MAO. PMID:22071524

Coelho Cerqueira, Eduardo; Netz, Paulo Augusto; Diniz, Cristiane; Petry do Canto, Vanessa; Follmer, Cristian

2011-12-15

87

Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships  

PubMed Central

Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis. PMID:25171058

Schmidt, Thomas J.; Borborema, Samanta E. T.; Ferreira, Vitor F.; Rocha, David R.; Tempone, Andre G.

2014-01-01

88

Oxidative phenylamination of 5-substituted 1-hydroxynaphthalenes to N-phenyl-1,4-naphthoquinone monoimines by air and light “on water”  

PubMed Central

Summary A number of N-phenyl-1,4-naphthoquinone monoimines 6–10 were prepared by on-water oxidative phenylamination of 1,5-dihydroxynaphthalene (1) and 5-acetylamino-1-hydroxynaphthalene (5) with oxygen-substituted phenylamines under aerobic conditions and either solar or green LED radiation, in the presence of rose bengal as singlet oxygen sensitizer. As compared to the conventional oxidative phenylamination procedures, this novel synthetic method offers the advantage of aerobic conditions “on water” instead of hazardous oxidant reagents currently employed in aqueous alcoholic media. PMID:25383115

Meléndez, Juan; Estela, Cynthia; Ríos, David; Espinoza, Luis; Brito, Iván; Valderrama, Jaime A

2014-01-01

89

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. PMID:22305461

2012-01-01

90

Trypanosoma cruzi mitochondrial swelling and membrane potential collapse as primary evidence of the mode of action of naphthoquinone analogues  

PubMed Central

Background Naphthoquinones (NQs) are privileged structures in medicinal chemistry due to the biological effects associated with the induction of oxidative stress. The present study evaluated the activities of sixteen NQs derivatives on Trypanosoma cruzi. Results Fourteen NQs displayed higher activity against bloodstream trypomastigotes of T. cruzi than benznidazole. Further assays with NQ1, NQ8, NQ9 and NQ12 showed inhibition of the proliferation of axenic epimastigotes and intracelulluar amastigotes interiorized in macrophages and in heart muscle cells. NQ8 was the most active NQ against both proliferative forms of T. cruzi. In epimastigotes the four NQs induced mitochondrial swelling, vacuolization, and flagellar blebbing. The treatment with NQs also induced the appearance of large endoplasmic reticulum profiles surrounding different cellular structures and of myelin-like membranous contours, morphological characteristics of an autophagic process. At IC50 concentration, NQ8 totally disrupted the ??m of about 20% of the parasites, suggesting the induction of a sub-population with metabolically inactive mitochondria. On the other hand, NQ1, NQ9 or NQ12 led only to a discrete decrease of TMRE + labeling at IC50 values. NQ8 led also to an increase in the percentage of parasites labeled with DHE, indicative of ROS production, possibly the cause of the observed mitochondrial swelling. The other three NQs behaved similarly to untreated controls. Conclusions NQ1, NQ8, NQ9 and NQ12 induce an autophagic phenotype in T. cruzi epimastigoted, as already observed with others NQs. The absence of oxidative stress in NQ1-, NQ9- and NQ12-treated parasites could be due to the existence of more than one mechanism of action involved in their trypanocidal activity, leaving ROS generation suppressed by the detoxification system of the parasite. The strong redox effect of NQ8 could be associated to the presence of the acetyl group in its structure facilitating quinone reduction, as previously demonstrated by electrochemical analysis. Further experiments using biochemical and molecular approaches are needed to better characterize ROS participation in the mechanism of action of these NQs. PMID:24004461

2013-01-01

91

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

2012-03-01

92

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

PubMed

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

2012-10-01

93

Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity.  

PubMed

Taking advantage of the structural features of natural products showing anti-trypanosomatid activity, we designed and synthesized a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives. The library was obtained following a parallel approach and using readily available synthons. All the derivatives showed inhibitory activity toward either Trypanosoma or Leishmania species, with 8, 10, and 16 being the most active compounds against Trypanosoma brucei rhodesiense, Leishmania donovani, and Trypanosoma cruzi cells (IC(50)=50nM, IC(50)=0.28microM, and IC(50)=1.26microM, respectively). PMID:18353643

Bolognesi, Maria Laura; Lizzi, Federica; Perozzo, Remo; Brun, Reto; Cavalli, Andrea

2008-04-01

94

Spectrophotometric study for the reaction between fluvoxamine and 1,2-naphthoquinone-4-sulphonate: Kinetic, mechanism and use for determination of fluvoxamine in its dosage forms  

NASA Astrophysics Data System (ADS)

Spectrophotometric study was carried out, for the first time, to investigate the reaction between the antidepressant fluvoxamine (FXM) and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 9), an orange-colored product exhibiting maximum absorption peak ( ?max) at 470 nm was produced. The kinetics of the reaction was investigated and its activation energy was found to be 2.65 kcal mol -1. Because of this low activation energy, the reaction proceeded easily. The stoichiometry of the reaction was determined and the reaction mechanism was postulated. This color-developing reaction was successfully employed in the development of simple and rapid spectrophotometric method for determination of FXM in its pharmaceutical dosage forms. Under the optimized reaction conditions, Beer's law correlating the absorbance ( A) with FXM concentration ( C) was obeyed in the range of 0.6-8 ?g ml -1. The regression equation for the calibration data was A = 0.0086 + 0.1348 C, with good correlation coefficient (0.9996). The molar absorptivity ( ?) was 5.9 × 10 4 l mol -1 cm -1. The limits of detection and quantification were 0.2 and 0.6 ?g ml -1, respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2%. The proposed method was successfully applied to the determination of FXM in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.47 ± 0.96%. The results obtained by the proposed method were comparable with those obtained by the official method. The proposed method is superior to all the previously reported spectrophotometric methods for determination of FXM in terms of its simplicity and sensitivity. The method is practical and valuable for its routine application in quality control laboratories for analysis of FXM.

Darwish, Ibrahim A.; Abdine, Heba H.; Amer, Sawsan M.; Al-Rayes, Lama I.

2009-05-01

95

Ferrocene and (arene)ruthenium(II) complexes of the natural anticancer naphthoquinone plumbagin with enhanced efficacy against resistant cancer cells and a genuine mode of action.  

PubMed

A series of ferrocene and (arene)ruthenium(II) complexes attached to the naturally occurring anticancer naphthoquinones plumbagin and juglone was tested for efficacy against various cancer cell lines and for alterations in the mode of action. The plumbagin ferrocene and (p-cymene)Ru(II) conjugates 1c and 2a overcame the multi-drug drug resistance of KB-V1/Vbl cervix carcinoma cells and showed IC50 (72 h) values around 1 ?M in growth inhibition assays using 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT). They were further investigated for their influence on the cell cycle of KB-V1/Vbl and HCT-116 colon carcinoma cells, on the generation of reactive oxygen species (ROS) by the latter cell line, for their substrate character for the P-glycoprotein drug eflux pump via the calcein-AM efflux assays, and for DNA affinity by the electrophoretic mobility shift assay (EMSA). The derivatives 1c and 2a increased the number of dead cancer cells (sub-G0/G1 fraction) in a dose- and time-dependent manner. ROS levels were significantly increased upon treatment with 1c and 2a. These compounds also showed a greater affinity to linear DNA than plumbagin. While plumbagin did not affect calcein-AM transport by P-glycoprotein the derivatives 1c and 2a exhibited a 50% or 80% inhibition of the P-glycoprotein-mediated calcein-AM efflux relative to the clinically established sensitizer verapamil. PMID:24907976

Spoerlein-Guettler, Cornelia; Mahal, Katharina; Schobert, Rainer; Biersack, Bernhard

2014-09-01

96

Early postnatal, but not late, exposure to chemical ambient pollutant 1,2-naphthoquinone increases susceptibility to pulmonary allergic inflammation at adulthood.  

PubMed

High diesel exhaust particle levels are associated with increased health effects; however, knowledge on the impact of its chemical contaminant 1,2-naphthoquinone (1,2-NQ) is limited. We investigated whether postnatal and adult exposures to 1,2-NQ influence allergic reaction and the roles of innate and adaptive immunity. Male neonate (6 days) and adult (56 days) C57Bl/6 mice were exposed to 1,2-NQ (100 nM; 15 min) for 3 days, and on day 59, they were sensitized and later challenged with ovalbumin (OVA). Airway hyper-responsiveness (AHR) and production of cytokines, immunoglobulin E (IgE) and leukotriene B4 (LTB4) were measured in the airways. Postnatal exposure to 1,2-NQ activated dendritic cells in splenocytes by increasing expressing cell surface molecules (e.g., CD11c). Co-exposure to OVA effectively polarized T helper (Th) type 2 (Th2) by secreting Th2-mediated cytokines. Re-stimulation with unspecific stimuli (PMA and ionomycin) generated a mixed Th1 (CD4(+)/IFN-?(+)) and Th17 (CD4(+)/IL-17(+)) phenotype in comparison with the vehicle-matched group. Postnatal exposure to 1,2-NQ did not induce eosinophilia in the airways at adulthood, although it evoked neutrophilia and exacerbated OVA-induced eosinophilia, Th2 cytokines, IgE and LTB4 production without affecting AHR and mast cell degranulation. At adulthood, 1,2-NQ exposure evoked neutrophilia and increased Th1/Th2 cytokine levels, but failed to affect OVA-induced eosinophilia. In conclusion, postnatal exposure to 1,2-NQ increases the susceptibility to antigen-induced asthma. The mechanism appears to be dependent on increased expression of co-stimulatory molecules, which leads to cell presentation amplification, Th2 polarization and enhanced LTB4, humoral response and Th1/Th2 cytokines. These findings may be useful for future investigations on treatments focused on pulmonary illnesses observed in children living in heavy polluted areas. PMID:24554396

Santos, Karen T; Florenzano, Juliana; Rodrigues, Leandro; Fávaro, Rodolfo R; Ventura, Fernanda F; Ribeiro, Marcela G; Teixeira, Simone A; Ferreira, Heloisa H A; Brain, Susan D; Damazo, Amílcar S; Zorn, Telma M; Câmara, Niels O; Muscará, Marcelo N; Peron, Jean Pierre; Costa, Soraia K

2014-08-01

97

Charge transfer interaction of 4-acetamidophenol (paracetamol) with 2,3-dichloro-1,4-naphthoquinone: A study in aqueous ethanol medium by UV-vis spectroscopic and DFT methods  

NASA Astrophysics Data System (ADS)

4-Acetamidophenol (paracetamol) is shown to form charge transfer complex with 2,3-dichloro1,4-naphthoquinone in aqueous ethanol media exhibiting the unusual 2:1 (paracetamol:quinone) stoichiometry. The complexation enthalpy and entropy have been estimated from the formation constant ( K) determined spectrophotometrically at five different temperatures. In aqueous ethanol mixtures of varying composition K increases with increasing dielectric constant of the medium. This has been rationalized by calculating the electronic charge distribution in paracetamol molecule and its conjugate base at the DFT/B3LYP/6-31++G(d,p) level. The theoretically calculated vertical ionization potential of paracetamol also agrees with reported experimental value.

Saha, Avijit; Tiwary, Amit S.; Mukherjee, Asok K.

2008-12-01

98

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.  

PubMed

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

2013-04-01

99

In Vitro Activity of 2-methoxy-1,4-naphthoquinone and Stigmasta-7,22-diene-3?-ol from Impatiens balsamina L. against Multiple Antibiotic-Resistant Helicobacter pylori  

PubMed Central

Infection with Helicobacter pylori is strongly associated with gastric cancer and gastric adenocarcinoma. WHO classified H. pylori as a group 1 carcinogen in 1994. Impatiens balsamina L. has been used as indigenous medicine in Asia for the treatment of rheumatism, fractures and fingernail inflammation. In this study, we isolated anti-H. pylori compounds from this plant and investigated their anti- and bactericidal activity. Compounds of 2-methoxy-1,4-naphthoquinone (MeONQ) and stigmasta-7,22-diene-3?-ol (spinasterol) were isolated from the pods and roots/stems/leaves of I. balsamina L., respectively. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for MeONQ were in the ranges of 0.156–0.625 and 0.313–0.625 ?g mL?1, respectively, and in the ranges of 20–80??g mL?1 both of MICs and MBCs for spinasterol against antibiotic (clarithromycin, metronidazole and levofloxacin) resistant H. pylori. Notably, the activity of MeONQ was equivalent to that of amoxicillin (AMX). The bactericidal H. pylori action of MeONQ was dose-dependent. Furthermore, the activity of MeONQ was not influenced by the environmental pH values (4–8) and demonstrated good thermal (121°C for 15 min) stability. MeONQ abounds in the I. balsamina L. pod at the level of 4.39% (w/w db). In conclusion, MeONQ exhibits strong potential to be developed as a candidate agent for the eradication of H. pylori infection. PMID:19773391

Wang, Yuan-Chuen; Li, Wan-Yu; Wu, Deng-Chyang; Wang, Jeh-Jeng; Wu, Cheng-Hsun; Liao, Jyun-Ji; Lin, Cheng-Kun

2011-01-01

100

Charge–transfer reaction of 2,3-dichloro-1,4-naphthoquinone with crizotinib: Spectrophotometric study, computational molecular modeling and use in development of microwell assay for crizotinib  

PubMed Central

The reaction of 2,3-dichloro-1,4-naphthoquinone (DCNQ) with crizotinib (CZT; a novel drug used for treatment of non-small cell lung cancer) was investigated in different solvents of varying dielectric constants and polarity indexes. The reaction produced a red-colored product. Spectrophotometric investigations confirmed that the reaction proceeded through charge–transfer (CT) complex formation. The molar absorptivity of the complex was found to be linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9567 and 0.9069, respectively. The stoichiometric ratio of DCNQ:CZT was found to be 2:1 and the association constant of the complex was found to be 1.07 × 102 l/mol. The kinetics of the reaction was studied; the order of the reaction, rate and rate constant were determined. Computational molecular modeling for the complex between DCNQ and CZT was conducted, the sites of interaction on CZT molecule were determined, and the mechanism of the reaction was postulated. The reaction was employed as a basis in the development of a novel 96-microwell assay for CZT in a linear range of 4–500 ?g/ml. The assay limits of detection and quantitation were 2.06 and 6.23 ?g/ml, respectively. The assay was validated as per the guidelines of the International Conference on Harmonization (ICH) and successfully applied to the analysis of CZT in its bulk and capsules with good accuracy and precision. The assay has high throughput and consumes a minimum volume of organic solvents thus it reduces the exposures of the analysts to the toxic effects of organic solvents, and significantly reduces the analysis cost.

Alzoman, Nourah Z.; Alshehri, Jamilah M.; Darwish, Ibrahim A.; Khalil, Nasr Y.; Abdel-Rahman, Hamdy M.

2014-01-01

101

2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity.  

PubMed

Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3'-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 20(4-c) proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs. PMID:11170645

Salmon-Chemin, L; Buisine, E; Yardley, V; Kohler, S; Debreu, M A; Landry, V; Sergheraert, C; Croft, S L; Krauth-Siegel, R L; Davioud-Charvet, E

2001-02-15

102

Redox cycling of 1,2-naphthoquinone by thioredoxin1 through Cys32 and Cys35 causes inhibition of its catalytic activity and activation of ASK1/p38 signaling.  

PubMed

1,2-Naphthoquinone (1,2-NQ) is an atmospheric chemical capable of (1) redox cycling with electron donors and (2) covalent modification of nucleophilic groups on proteins. In the present study, we investigated its interaction with the redox protein, thioredoxin1 (Trx1), which led to oxidative stress-dependent cell damage. In experiments with purified wild-type Trx1 and its double mutant (32S/35S Trx1), we found that incubation of Trx1 with 1,2-NQ resulted in a redox cycling reaction, generating superoxide and hydrogen peroxide involving Cys32 and Cys35 and an arylation reaction resulting in covalent modification of Lys85 together with a loss of Trx activity. A significant fraction of the lost Trx1 activity following interaction with 1,2-NQ was restored by dithiothreitol. Exposure of RAW264.7 cells to 1,2-NQ generated reactive oxygen species (ROS) and caused a decrease in Trx activity. Trx is a negative regulator of apoptosis signal-regulating kinase 1 (ASK1), and under the conditions of the experiment, 1,2-NQ activated ASK1 and p38, leading to PARP cleavage and apoptotic cell death that were blocked by pretreatment with polyethylene glycol-catalase. These results suggest that Trx1 readily undergoes oxidative modification by 1,2-NQ through the proximal thiols Cys32 and Cys35. It seems likely that ROS production concomitant with decline in cellular Trx activity plays a role in the activation of ASK1/p38 signaling to promote apoptotic cell death cause by 1,2-NQ exposure. PMID:22587396

Shinkai, Yasuhiro; Iwamoto, Noriko; Miura, Takashi; Ishii, Takeshi; Cho, Arthur K; Kumagai, Yoshito

2012-06-18

103

Plumbagin, a medicinal plant (Plumbago zeylanica)-derived 1,4-naphthoquinone, inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model.  

PubMed

We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of human prostate cancer (PCa) cells in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2 × 10(6)) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p. five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by bioluminescence imaging of live mice. PL-treatment significantly (p = 0.0008) inhibited the growth of orthotopic xenograft tumors. Results demonstrated a significant inhibition of metastasis into liver (p = 0.037), but inhibition of metastasis into the lungs (p = 0.60) and lymph nodes (p = 0.27) was not observed to be significant. These results were further confirmed by histopathology of these organs. Results of histopathology demonstrated a significant inhibition of metastasis into lymph nodes (p = 0.034) and lungs (p = 0.028), and a trend to significance in liver (p = 0.075). None of the mice in the PL-treatment group showed PCa metastasis into the liver, but these mice had small metastasis foci into the lymph nodes and lungs. However, control mice had large metastatic foci into the lymph nodes, lungs, and liver. PL-caused inhibition of the growth and metastasis of PC-3M cells accompanies inhibition of the expression of: 1) PKC?, pStat3Tyr705, and pStat3Ser727, 2) Stat3 downstream target genes (survivin and Bcl(xL)), 3) proliferative markers Ki-67 and PCNA, 4) metastatic marker MMP9, MMP2, and uPA, and 5) angiogenesis markers CD31 and VEGF. Taken together, these results suggest that PL inhibits tumor growth and metastasis of human PCa PC3-M-luciferase cells, which could be used as a therapeutic agent for the prevention and treatment of human PCa. PMID:23273564

Hafeez, Bilal Bin; Zhong, Weixiong; Fischer, Joseph W; Mustafa, Ala; Shi, Xudong; Meske, Louise; Hong, Hao; Cai, Weibo; Havighurst, Thomas; Kim, Kyungmann; Verma, Ajit K

2013-06-01

104

Plumbagin, a medicinal plant (Plumbago zeylanica) - derived 1,4-naphthoquinone, inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model  

PubMed Central

We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of prostate cancer (PCa) in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2X106) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by bioluminescence imaging of live mice. PL-treatment significantly (p=0.0008) inhibited the growth of orthotopic xenograft tumors. PCa metastasis into the liver, lungs and lymph nodes was determined by bioluminescence imaging and histopathology. Results demonstrated a significant inhibition of metastasis into liver (p=0.037), but inhibition of metastasis into the lungs (p=0.60) and liver (p=0.27) was not observed to be significant. These results were further confirmed by histopathology of these organs. Results of histopathology demonstrated a significant inhibition of metastasis into lymph nodes (p=0.034) and lungs (p=0.028), and a trend to significance in liver (p=0.075). None of the mice in the PL-treatment group showed PCa metastasis into the liver, but these mice had small metastasis foci into the lymph nodes and lungs. However, control mice had large metastatic foci into the lymph nodes, lungs, and liver. PL-caused inhibition of the growth and metastasis of PC-3M cells accompanies inhibition of the expression of: 1) PKC?, pStat3Tyr705, and pStat3Ser727, 2) Stat3 downstream target genes (survivin and BclxL), 3) proliferative markers Ki-67 and PCNA, 4) metastatic marker MMP9, MMP2, and uPA, and 5) angiogenesis markers CD31 and VEGF. Taken together, these results suggest that PL inhibits tumor growth and metastasis of human PCa PC3-M-luciferase cells, which could be used as a therapeutic agent for the prevention and treatment of human PCa. PL: Plumbagin, PCa: Prostate cancer. PMID:23273564

Hafeez, Bilal Bin; Zhong, Weixiong; Fischer, Joseph W.; Mustafa, Ala; Shi, Xudong Daniel; Meske, Louise; Hong, Hao; Cai, Weibo; Havighurst, Thomas; Kim, KyungMann; Verma, Ajit. K

2012-01-01

105

Pericyclic Reactions of Prenylated Naphthoquinones: Biomimetic  

E-print Network

benefits. For example, the Chinese medicinal plant Rubia cordifolia has yielded the achiral chromene bark of which is used to treat rheumatism and asthma in Chinese herbal medicine.4 Extracts from, astringents, and diuretics in Brazilian traditional medicine.5 Phytochemical investigations have yielded

Trauner, Dirk

106

Hydroxylated naphthoquinones as substrates for Escherichia coli anaerobic reductases.  

PubMed Central

We have used two hydroxylated naphthoquinol menaquinol analogues, reduced plumbagin (PBH2, 5-hydroxy-2-methyl-1,4-naphthoquinol) and reduced lapachol [LPCH2, 2-hydroxy-3-(3-methyl-2-butenyl)-1, 4-naphthoquinol], as substrates for Escherichia coli anaerobic reductases. These compounds have optical, solubility and redox properties that make them suitable for use in studies of the enzymology of menaquinol oxidation. Oxidized plumbagin and oxidized lapachol have well resolved absorbances at 419 nm (epsilon=3.95 mM-1. cm-1) and 481 nm (epsilon=2.66 mM-1.cm-1) respectively (in Mops/KOH buffer, pH 7.0). PBH2 is a good substrate for nitrate reductase A (Km=282+/-28 microM, kcat=120+/-6 s-1) and fumarate reductase (Km=155+/-24 microM, kcat=30+/-2 s-1), but not for DMSO reductase. LPCH2 is a good substrate for nitrate reductase A (Km=57+/-35 microM, kcat=68+/-13 s-1), fumarate reductase (Km=85+/-27 microM, kcat=74+/-6 s-1) and DMSO reductase (Km=238+/-30 microM, kcat=191+/-21 s-1). The sensitivity of enzymic LPCH2 and PBH2 oxidation to 2-n-heptyl-4-hydroxyquinoline N-oxide inhibition is consistent with their oxidation occurring at sites of physiological quinol binding. PMID:9576848

Rothery, R A; Chatterjee, I; Kiema, G; McDermott, M T; Weiner, J H

1998-01-01

107

5-Hydr­oxy-8-nitro-1,4-naphthoquinone  

PubMed Central

The title compound, C10H5NO5, features an intra­molecular O—H?O hydrogen bond, forming a six-membered ring with an S(6) ring motif. The nitro group makes a dihedral angle of 71.66?(5)° with the plane of the benzene ring to which it is bound. The two rings are almost coplanar, with a dihedral angle of 4.44?(5)°. Short inter­molecular distances between the centroids of the six-membered rings [3.7188?(6)–3.8299?(6)?Å] indicate the existence of ?–? inter­actions. The inter­esting features of the crystal structure are the short inter­molecular O?O and O?N inter­actions. The crystal packing is stabilized by intra­molecular O—H?O and inter­molecular C—H?O (×3) hydrogen bonds, and C—H?? inter­actions. PMID:21203231

Tan, Daniel Teoh-Chuan; Osman, Hasnah; Kamaruddin, Azlina Harun; Kia, Reza; Fun, Hoong-Kun

2008-01-01

108

Naphthoquinones as broad spectrum biocides for treatment of ship's ballast water: Toxicity to phytoplankton and bacteria  

Microsoft Academic Search

Current UN International Maritime Organization legislation mandates the phased introduction of ballast water treatment technologies capable of complying with rigorous standards related to removal of waterborne organisms. Doubts concerning mechanical treatments at very high ballasting rates have renewed interest in chemical treatment for very large vessels. High removal rates for biota require broad spectrum biocides that are safe to transport

D. A. Wright; R. Dawson; S. J. Cutler; H. G. Cutler; C. E. Orano-Dawson; E. Graneli

2007-01-01

109

Substituent-enabled oxidative dehydrogenative cross-coupling of 1,4-naphthoquinones with alkenes.  

PubMed

A Rh-catalyzed oxidative dehydrogenative cross-coupling of 1,4-naphthquinones with alkenes was achieved by using a substituent-enabled C(sp(2))-H functionalization (SEF) strategy. The method shows high functional group tolerance, broad substrate scope, and great potential for further functional transformations. PMID:25075553

Zhang, Chi; Wang, Meining; Fan, Zhoulong; Sun, Li-Ping; Zhang, Ao

2014-08-15

110

Naphthoquinones from Onosma paniculata induce cell-cycle arrest and apoptosis in melanoma Cells.  

PubMed

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. PMID:22530779

Kretschmer, Nadine; Rinner, Beate; Deutsch, Alexander J A; Lohberger, Birgit; Knausz, Heike; Kunert, Olaf; Blunder, Martina; Boechzelt, Herbert; Schaider, Helmut; Bauer, Rudolf

2012-05-25

111

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. PMID:22530779

2012-01-01

112

New cytotoxic furoquinones obtained from terpenyl-1,4-naphthoquinones and 1,4-anthracenediones  

Microsoft Academic Search

A series of new furoterpenyl-1,4-naphtho(anthra)quinones have been prepared via oxidative cyclization of the corresponding 2-hydroxy-3-butenyl-1,4-naphtho(anthra)quinones. Depending on the reaction conditions the 1,2-quinones or the 1,4-quinones were obtained. Several new furo-1,4-anthraquinones were also obtained by condensation of 2,3-dichloroquinones with 1,3-dicarbonyls. The compounds synthesized have been evaluated for their cytotoxicity against neoplastic cell lines, some of them being effective below the micromolar

José M. Miguel del Corral; M. Angeles Castro; Alaide B. Oliveira; Simone A. Gualberto; Carmen Cuevas; Arturo San Feliciano

2006-01-01

113

Electrochemical properties of substituted 2-methyl-1,4-naphthoquinones: redox behavior predictions.  

PubMed

In the context of the investigation of drug-induced oxidative stress in parasitic cells, electrochemical properties of a focused library of polysubstituted menadione derivatives were studied by cyclic voltammetry. These values were used, together with compatible measurements from literature (quinones and related compounds), to build and evaluate a predictive structure-redox potential model (quantitative structure-property relationship, QSPR). Able to provide an online evaluation (through Web interface) of the oxidant character of quinones, the model is aimed to help chemists targeting their synthetic efforts towards analogues of desired redox properties. PMID:25556761

Elhabiri, Mourad; Sidorov, Pavel; Cesar-Rodo, Elena; Marcou, Gilles; Lanfranchi, Don Antoine; Davioud-Charvet, Elisabeth; Horvath, Dragos; Varnek, Alexandre

2015-02-16

114

Methylations of Tryptophan-Modified Naphthoquinone Affect Its Inhibitory Potential toward A Aggregation  

E-print Network

(A) is the hallmark of Alzheimer's disease (AD). Small molecules inhibiting A can be valuable for treating AD. INTRODUCTION Alzheimer's disease (AD), a progressive neurodegenerative disorder for which there is no cure or effective treatment, is the leading cause of dementia in aged humans. AD has been estimated

Caflisch, Amedeo

115

In vitro induction of erythrocyte phosphatidylserine translocation by the natural naphthoquinone shikonin.  

PubMed

Shikonin, the most important component of Lithospermum erythrorhizon, has previously been shown to exert antioxidant, anti-inflammatory, antithrombotic, antiviral, antimicrobial and anticancer effects. The anticancer effect has been attributed to the stimulation of suicidal cell death or apoptosis. Similar to the apoptosis of nucleated cells, erythrocytes may experience eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include the increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide formation. The present study explored whether Shikonin stimulates eryptosis. To this end, Fluo 3 fluorescence was measured to quantify [Ca2+]i, forward scatter to estimate cell volume, annexin V binding to identify phosphatidylserine-exposing erythrocytes, hemoglobin release to determine hemolysis and antibodies to quantify ceramide abundance. As a result, a 48 h exposure of human erythrocytes to Shikonin (1 µM) significantly increased [Ca2+]i, increased ceramide abundance, decreased forward scatter and increased annexin V binding. The effect of Shikonin (1 µM) on annexin V binding was significantly blunted, but not abolished by the removal of extracellular Ca2+. In conclusion, Shikonin stimulates suicidal erythrocyte death or eryptosis, an effect at least partially due to the stimulation of Ca2+ entry and ceramide formation. PMID:24828755

Lupescu, Adrian; Bissinger, Rosi; Jilani, Kashif; Lang, Florian

2014-05-01

116

Isolation and chemopreventive evaluation of novel naphthoquinone compounds from Alkanna tinctoria  

PubMed Central

Botanically derived natural products have recently become an attractive source of new chemotherapeutic agents. To explore active anti-colorectal cancer compounds, we performed phytochemical studies on Alkanna tinctoria and isolated eight quinone compounds. Using different spectrum 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 based on extensive spectroscopic evidence including high-resolution mass spectrometry and NMR spectra. The antiproliferative effects of these eight compounds on HCT-116 and SW-480 human colorectal cancer cells were determined by the MTS method. Cell cycle and apoptosis were determined using flow cytometry. Enzymatic activities of caspases were determined by 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, while 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

2013-01-01

117

Synthesis and Biological Evaluation of Naphthoquinone Analogs as a Novel Class of Proteasome Inhibitors  

PubMed Central

Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the ?5 and ?6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the ?6 subunit. PMID:20621484

Lawrence, Harshani R.; Kazi, Aslamuzzaman; Luo, Yunting; Kendig, Robert; Ge, Yiyu; Jain, Sanjula; Daniel, Kenyon; Santiago, Daniel; Guida, Wayne C.; Sebti, Saïd M.

2012-01-01

118

Allan, Hong and Stoltz Supporting Information Expedient Synthesis of 3-Hydroxyisoquinolines and 2-Hydroxy-1,4-naphthoquinones  

E-print Network

, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California and back-filled with argon. Tetrahydrofuran (7.5 mL) was added and the suspension was heated to 65 °C for 3

Stoltz, Brian M.

119

Biopolymeric film containing bioactive naphthoquinone (shikonin) in combined therapy of inflammatory destructive lesions in the buccal mucosa.  

PubMed

Clinical morphological efficiency of local application of a new biopolymeric film was studied. The film was based on methylcellulose derivatives and contained shikonin (preparation of plant origin) and its esters isolated from Lithospermum erythrorhizon L. cell culture. Combined therapy of 30 patients (34-72 years) with erosive ulcerative lichen planus and leukoplakia of the buccal mucosa was carried out. Local application of the new drug led to more rapid pain relief, epithelialization of the inflammatory destructive foci in the buccal mucosa, and reduced the intensity of morphological signs of lesions in the studied patient population. PMID:24319756

Zagorodnyaya, E B; Oskol'skii, G I; Basharov, A Ya; Lushnikova, E L; Nepomnyashchikh, L M; Zagorodnii, A S

2013-12-01

120

Vasorelaxation induced by a new naphthoquinone-oxime is mediated by NO-sGC-cGMP pathway.  

PubMed

It has been established that oximes cause endothelium-independent relaxation in blood vessels. In the present study, the cardiovascular effects of the new oxime 3-hydroxy-4-(hydroxyimino)-2-(3-methylbut-2-enylnaphtalen-1(4H)-one (Oxime S1) derived from lapachol were evaluated. In normotensive rats, administration of Oxime S1 (10, 15, 20 and 30 mg/Kg, i.v.) produced dose-dependent reduction in blood pressure. In isolated aorta and superior mesenteric artery rings, Oxime S1 induced endothelium-independent and concentration-dependent relaxations (10(-8) M to 10(-4) M). In addition, Oxime S1-induced vasorelaxations were attenuated by hydroxocobalamin or methylene blue in aorta and by PTIO or ODQ in mesenteric artery rings, suggesting a role for the nitric oxide (NO) pathway. Additionally, Oxime S1 (30 and 100 µM) significantly increased NO concentrations (13.9 ± 1.6 nM and 17.9 ± 4.1 nM, respectively) measured by nitric oxide microsensors. Furthermore, pre-contraction with KCl (80 mM) prevented Oxime S1-derived vasorelaxation in endothelium-denuded aortic rings. Of note, combined treatment with potassium channel inhibitors also reduced Oxime S1-mediated vasorelaxation suggesting a role for potassium channels, more precisely Kir, Kv and KATP channels. We observed the involvement of BKCa channels in Oxime S1-induced relaxation in mesenteric artery rings. In conclusion, these data suggest that the Oxime S1 induces hypotension and vasorelaxation via NO pathway by activating soluble guanylate cyclase (sGC) and K+ channels. PMID:25006785

Dantas, Bruna P V; Ribeiro, Thaís P; Assis, Valéria L; Furtado, Fabíola F; Assis, Kívia S; Alves, Jeziane S; Silva, Tania M S; Camara, Celso A; França-Silva, Maria S; Veras, Robson C; Medeiros, Isac A; Alencar, Jacicarlos L; Braga, Valdir A

2014-01-01

121

Dabbing and shooting of benzo- and naphthoquinone secretions: Defensive strategies of bark-inhabiting aleocharine (col.: Staphylinidae) and tenebrionid (col.: Tenebrionidae) beetle larvae  

Microsoft Academic Search

The abdominal glands of three bark-inhabiting larvae of generaBolitochara, Leptusa (Staphylinidae), andHypophloeus (Tenebrionidae) were studied chemically and morphologically. Behavior of the larvae indicated that secretion is emitted only after severe disturbance of the larvae. These mechanical contacts may also occur incidentally with coinhabiting nonpredatory arthropods when the beetle larvae move within small interstices under bark. Depending on the species, the

Konrad Dettner

1993-01-01

122

DISCRIMINATING REDOX CYCLING AND ARYLATION PATHWAYS OF REACTIVE CHEMICAL TOXICITY IN TROUT HEPATOCYTES  

EPA Science Inventory

The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl-1,4-naphthoquinone (MNQ), 1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ), which redox cycle or arlyate in mammalian cells, was determined in isolated trout (Oncorhynchus mykiss) hepatocytes. Mor...

123

DIFFERENTIATING MECHANISMS OF REACTIVE CHEMICAL TOXICITY IN ISOLATED TROUT HEPATOCYTES  

EPA Science Inventory

The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl 1,4-naphthoquinone (MNQ ),1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ), which redox cycle or arlyate in mammalian cells, was determined in isolated trout (Oncorhynchus mykiss) hepatocytes. Mor...

124

Naturally Occurring Hydroxy Napthoquinones and Their Iron Complexes as Modulators of Radiation Induced Lipid Peroxidation in Synaptosomes  

PubMed Central

The modulation of radiation induced lipid peroxidation in synaptosomes by iron (II) and iron (III) complexes of two naturally occurring and therapeutically relevant naphthoquinones viz. 5,hydroxy-1,4 naphthoquinone; juglone and 2,hydroxy-1,4 naphthoquinone; lawsone, have been studied. At lower concentrations the complexes enhance lipid peroxidation predominantly through redox cycling as observed for Fe(II)- juglonate while at higher concentrations the complexes tend to limit lipid peroxidation through fast recombinations. PMID:18475800

Kumbhar, A. S.; Jitender; Kale, R. K.

1997-01-01

125

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.  

PubMed

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

2012-11-01

126

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  

NASA Astrophysics Data System (ADS)

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)Cl2]·3H2O and [Ni(L)Cl2]·4H2O complexes, computed using fluorescent enhancement data, were found to be 0.6, 1.5 and 0.9 × 108 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-, NO3-, H2PO4- and CN- in acetonitrile.

Madhupriya, Selvaraj; Elango, Kuppanagounder P.

2012-11-01

127

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

PubMed

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. PMID:24106678

Sperandeo, Norma R; Faudone, Sonia N

2013-01-01

128

Reaction of (2-amino-5,10,15,20-tetraphenylporphyrinato)nickel(II) with quinones  

Microsoft Academic Search

(2-Amino-5,10,15,20-tetraphenylporphyrinato)nickel(II) reacts with 1,4-benzoquinone, 1,4-naphthoquinone and 2-hydroxy-1,4-naphthoquinone, in the presence of a catalytic amount of sulfuric acid, to afford new porphyrin–quinone dyads and ?-extended heterocyclic-fused porphyrin derivatives.

Cristina M. A. Alonso; Maria G. P. M. S. Neves; Augusto C. Tomé; Artur M. S. Silva; José A. S. Cavaleiro

2005-01-01

129

Natural Product Inhibitors of Hsp90: Potential Leads for Drug Discovery  

E-print Network

, our group was able to conduct a high-throughput screen that resulted in the identification of several Hsp90 inhibitors that contained a 1,4-naphthoquinone scaffold. From this, a library of naphthoquinones was synthesized. To further probe structure...

Amolins, Michael Wayne

2009-07-09

130

Synthesis, electrochemical and spectral properties of some ?-N-quinonyl amino acids  

Microsoft Academic Search

Summary.   Four series of ?-N-quinonyl amino acids were synthesized by Michael-like additions. The quinones include 2-phenylthio-1,4-benzoquinone, 1,4-naphthoquinone,\\u000a 2-methyl-1,4-naphthoquinone and 2,3-dichloro-1,4-naphthoquinone. These modified amino acids can be used for post chain assembly\\u000a modifications of biologically active peptides, which target the quinonic drug to a cancer damaged area. The electron-transfer\\u000a capabilities of the modified amino acids were probed by cyclic voltammetry measurements.

S. Bittner; S. Gorohovsky; J. Y. Becker

2002-01-01

131

Preparative production of spinochrome E, a pigment of different sea urchin species.  

PubMed

A concise route to spinochrome E (1) (2,3,5,6,7,8-hexahydroxy-1,4-naphthoquinone), a pigment isolated from sea urchins of different species, has been developed starting from either commercially available 5,8-dihydroxy-1,4-naphthoquinone (11) or 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (12). The protocol involves 3 steps, the chlorination of either 11 or 12 to tetrachloronaphthazarin (13), the total nucleophilic substitution of the chlorine atoms in 13 by methoxy groups, and hydrolysis of tetramethyl ether14; this makes possible the preparation of the target compound in overall yields from 41 to 46%. PMID:25230502

Shestak, Olga P; Anufriev, Victor Ph; Novikov, Vyacheslav L

2014-07-01

132

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

1981-01-01

133

EFFICIENT SYNTHESIS OF CYTOTOXIC FURONAPHTHOQUINONE NATURAL PRODUCTS  

Microsoft Academic Search

An efficient synthesis of furonaphthoquinone natural products 1 and 4 has been carried out starting from 2-hydroxy-1, 4-naphthoquinone (10) and 2,3-dimethoxy-1,3-butadiene (11) in the presence of CAN.

Yong Rok Lee; Byung So Kim

2001-01-01

134

40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste  

Code of Federal Regulations, 2013 CFR

...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

2013-07-01

135

40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste  

Code of Federal Regulations, 2014 CFR

...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

2014-07-01

136

In vitro Activation of heme oxygenase-2 by menadione and its analogs  

PubMed Central

Background Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure–activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy. Methods Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and ?2, respectively, as well as recombinant, human heme oxygenase-2. Results Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and ?3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, ?-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase. Conclusions These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties. PMID:24533775

2014-01-01

137

Hydrogen peroxide formation in a surrogate lung fluid by transition metals and quinones present in particulate matter.  

PubMed

Inhaled ambient particulate matter (PM) causes adverse health effects, possibly by generating reactive oxygen species (ROS), including hydrogen peroxide (HOOH), in the lung lining fluid. There are conflicting reports in the literature as to which chemical components of PM can chemically generate HOOH in lung fluid mimics. It is also unclear which redox-active species are most important for HOOH formation at concentrations relevant to ambient PM. To address this, we use a cell-free, surrogate lung fluid (SLF) to quantify the initial rate of HOOH formation from 10 transition metals and 4 quinones commonly identified in PM. Copper, 1,2-naphthoquinone, 1,4-naphthoquinone, and phenanthrenequinone all form HOOH in a SLF, but only copper and 1,2-naphthoquinone are likely important at ambient concentrations. Iron suppresses HOOH formation in laboratory solutions, but has a smaller effect in ambient PM extracts, possibly because organic ligands in the particles reduce the reactivity of iron. Overall, copper produces the majority of HOOH chemically generated from typical ambient PM while 1,2-naphthoquinone generally makes a small contribution. However, measured rates of HOOH formation in ambient particle extracts are lower than rates calculated from soluble copper by an average (±1?) of 44 ± 22%; this underestimate is likely due to either HOOH destruction by Fe or a reduction in Cu reactivity due to organic ligands from the PM. PMID:24857372

Charrier, Jessica G; McFall, Alexander S; Richards-Henderson, Nicole K; Anastasio, Cort

2014-06-17

138

Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC–UV and HPTLC analyses  

Technology Transfer Automated Retrieval System (TEKTRAN)

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 constit...

139

Quantum-chemical calculations and electron diffraction study of the equilibrium molecular structure of vitamin K3  

NASA Astrophysics Data System (ADS)

The equilibrium molecular structure of 2-methyl-1,4-naphthoquinone (vitamin K3) having C s symmetry is experimentally characterized for the first time by means of gas-phase electron diffraction using quantum-chemical calculations and data on the vibrational spectra of related compounds.

Khaikin, L. S.; Tikhonov, D. S.; Grikina, O. E.; Rykov, A. N.; Stepanov, N. F.

2014-05-01

140

DEFICIENCY IN PHYLLOQUINONE (VITAMIN K1) METHYLATION AFFECTS PRENYL QUINONE DISTRIBUTION PHOTOSYSTEM I ABUNDANCE AND ANTHOCYANIN ACCUMULATION IN THE ARABIDOPSIS AtmenG MUTANT  

Technology Transfer Automated Retrieval System (TEKTRAN)

Phylloquinone (vitamin K1) is synthesized in cyanobacteria and in chloroplasts of higher plants where it serves as electron carrier of photosystem I. The last step of phylloquinone synthesis in cyanobacteria is the methylation of 2-phytyl-1,4-naphthoquinone by the menG gene product. The gene encodin...

141

Compatibility studies of lapachol with pharmaceutical excipients for the development of topical formulations  

Microsoft Academic Search

Among naphthoquinones, lapachol and many heterocyclic derivatives have been investigated during the past years, mainly due to their antibacterial, antifungal and anticancer activities. Assessment of possible incompatibility between an active component (i.e. lapachol) and different excipients along with the evaluation of thermal stability are crucial parts of a normal study prior to the final formulation setting of a medicine. DSC

A. M. Lira; A. A. S. Araújo; I. D. J. Basílio; B. L. L. Santos; D. P. Santana; R. O. Macedo

2007-01-01

142

Antimicrobial Activity of Shikonin Preparations  

Microsoft Academic Search

Shikonin is a natural red naphthoquinone pigment synthesized in the roots of plants belonging to the Boraginaceae family. At present, a purified shikonin preparation is widely used in Japan for the production of medicinals, cosmetics, and some food products [1]. In Russia, shikonin enters into the antiinflammatory ointment and cream compositions used for the treatment of burns. Shikonin possesses a

T. B. Karyagina; V. G. Arzumanyan; T. V. Timchenko; D. I. Bairamashvili

2001-01-01

143

Three new compounds from Arnebia euchroma  

Microsoft Academic Search

A new naphthoquinone dimer, arnebiabinone (1), a new phenolic compound, ethyl 9-(2?,5?-dihydroxyphenyl) nonanoate (2), and a new natural product, octyl ferulate (3), were isolated from the EtOH extract of dried roots of Arnebia euchroma (Royle) Johnst. Their structures were elucidated on the basis of chemical reaction and spectral analysis.

Hong Liu; Yong-Sheng Jin; Yan Song; Xiang-Nan Yang; Xiao-Wei Yang; Dong-Sheng Geng; Hai-Sheng Chen

2010-01-01

144

Three new compounds from Arnebia euchroma.  

PubMed

A new naphthoquinone dimer, arnebiabinone (1), a new phenolic compound, ethyl 9-(2',5'-dihydroxyphenyl) nonanoate (2), and a new natural product, octyl ferulate (3), were isolated from the EtOH extract of dried roots of Arnebia euchroma (Royle) Johnst. Their structures were elucidated on the basis of chemical reaction and spectral analysis. PMID:20419539

Liu, Hong; Jin, Yong-Sheng; Song, Yan; Yang, Xiang-Nan; Yang, Xiao-Wei; Geng, Dong-Sheng; Chen, Hai-Sheng

2010-04-01

145

Vitamin K  

Technology Transfer Automated Retrieval System (TEKTRAN)

Vitamin K was identified in the early 1930’s when it was shown to be essential for normal blood coagulation. Phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone) found in green plants is the major source of the vitamin. Large amounts of menaquinones with lengthy side chains are also synthesized in...

146

Cytotoxic and Antimicrobial Constituents of the Bark of Diospyros maritima Collected in Two Geographical Locations in Indonesia  

E-print Network

Cytotoxic and Antimicrobial Constituents of the Bark of Diospyros maritima Collected in Two, Natural Products Laboratory, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North a new naphthoquinone derivative, (4S)-shinanolone (5), and a new natural product coumarin, 7,8-dimethoxy

Falkinham, Joseph

147

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

2008-01-01

148

Antitumor Activity of DMAKO-05, a Novel Shikonin Derivative, and Its Metabolism in Rat Liver Microsome.  

PubMed

The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug. PMID:25273027

Zhang, Xu; Wang, Ru-Bing; Zhou, Wen; Xiao, Sui; Meng, Qing-Qing; Li, Shao-Shun

2014-10-01

149

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

PubMed

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

2009-03-01

150

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

PubMed Central

Background Natural 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 several other cancer cells and their possible mode of action were investigated. Methodology/Findings The tested compounds were previously isolated from the Cameroonian medicinal plants Vismia laurentii (1, 3, 4, 5 and 6) and Newbouldia laevis (2). The preliminary cytotoxicity results allowed the selection of xanthone V1 and 2-acetylfuro-1,4-naphthoquinone, which were then tested on a panel of cancer cell lines. The study was also extended to the analysis of cell cycle distribution, apoptosis induction, caspase 3/7 activation and the anti-angiogenic properties of xanthone V1 and 2-acetylfuro-1,4-naphthoquinone. IC50 values around or below 4 µg/ml were obtained on 64.29% and 78.57% of the tested cancer cell lines for xanthone V1 and 2-acetylfuro-1,4-naphthoquinone, respectively. The most sensitive cell lines (IC50<1 µg/ml) were breast MCF-7 (to xanthone V1), cervix HeLa and Caski (to xanthone V1 and 2-acetylfuro-1,4-naphthoquinone), leukemia PF-382 and melanoma colo-38 (to 2-acetylfuro-1,4-naphthoquinone). The two compounds showed respectively, 65.8% and 59.6% inhibition of the growth of blood capillaries on the chorioallantoic membrane of quail eggs in the anti-angiogenic assay. Upon treatment with two fold IC50 and after 72 h, the two compounds induced cell cycle arrest in S-phase, and also significant apoptosis in CCRF-CEM leukemia cells. Caspase 3/7 was activated by xanthone V1. Conclusions/Significance The overall results of the present study provided evidence for the cytotoxicity of compounds xanthone V1 and 2-acetylfuro-1,4-naphthoquinone, and bring supportive data for future investigations that will lead to their use in cancer therapy. PMID:21886765

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

2011-01-01

151

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

PubMed

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

2010-01-01

152

Antibacterial activity of Tabebuia impetiginosa Martius ex DC (Taheebo) against Helicobacter pylori.  

PubMed

The growth-inhibiting activity of Tabebuia impetiginosa Martius ex DC dried inner bark-derived constituents against Helicobacter pylori ATCC 43504 was examined using paper disc diffusion and minimum inhibitory concentration (MIC) bioassays. The activity of the isolated compounds was compared to that of the commercially available anti-Helicobacter pylori agents, amoxicillin, metronidazole, and tetracycline. The biologically active components of Tabebuia impetiginosa dried inner bark (taheebo) were characterized by spectroscopic analysis as 2-(hydroxymethyl)anthraquinone, anthraquinone-2-carboxylic acid, and 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol). With the paper disc diffusion assay 2-(hydroxymethyl)anthraquinone exhibited strong activity against Helicobacter pylori ATCC 43504 at 0.01 mg/disc. Anthraquinone-2-carboxylic acid, lapachol and metronidazole were less effective, exhibiting moderate anti-Helicobacter pylori activity at 0.1 mg/disc. Amoxicillin and tetracycline were the most potent compounds tested, displaying very strong activity at 0.005 mg/disc. 2-(Hydroxymethyl)anthraquinone exhibited moderate activity at this dose. Tetracycline still had strong activity at 0.001 mg/disc while amoxicillin had little activity at this dose. In the MIC bioassay, 2-(hydroxymethyl)anthraquinone (2 microg/mL), anthraquinone-2-carboxylic acid (8 microg/mL), and lapachol (4 microg/mL) were more active than metronidazole (32 microg/mL) but less effective than amoxicillin (0.063 microg/mL) and tetracycline (0.5 microg/mL). The anti-Helicobacter pylori activity of seven 1,4-naphthoquinone derivatives (structurally related to lapachol), 1,4-naphthoquinone, 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin), 2-methyl-1,4-naphthoquinone (menadione), 2-hydroxy-1,4-naphthoquinone (lawsone), 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin), 5-hydroxy-1,4-naphthoquinone (juglone), and 2,3-dichloro-1,4-naphthoquinone (dichlone) was also evaluated using the paper disc assay. Menadione and plumbagin were the most potent compounds tested with the later still exhibiting very strong activity at 0.001 mg/disc. Menadione, juglone and tetracycline had strong activity at this low dose while the latter two compounds and amoxicillin had very strong activity at 0.005 mg/disc. Lawsone was unusual in that it had very strong activity at 0.1 and 0.05 mg/disc but weak activity at doses of 0.01 mg/disc and lower. Naphthazalin, lapachol and dichlone had similar activities while metronidazole had the lowest activity of all compounds tested. These results may be an indication of at least one of the pharmacological actions of taheebo. The Tabebuia impetiginosa dried inner bark-derived materials, particularly 2-(hydroxymethyl)anthraquinone, merit further study as potential Helicobacter pylori eradicating agents or lead compounds. PMID:16359837

Park, Byeoung-Soo; Lee, Hyun-Kyung; Lee, Sung-Eun; Piao, Xiang-Lan; Takeoka, Gary R; Wong, Rosalind Y; Ahn, Young-Joon; Kim, Jeong-Han

2006-04-21

153

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

PubMed

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

2003-10-01

154

Aqua­(4,4?-bipyridine-?N)bis­(1,4-dioxo-1,4-dihydronaphthalen-2-olato-?2 O 1,O 2)zinc 4,4?-bipyridine mono­solvate dihydrate  

PubMed Central

The reaction of 2-hy­droxy-1,4-naphtho­quinone and 4,4?-bipyridine with zinc acetate produced the title compound, [Zn(C10H5O3)2(C10H8N2)(H2O)]·C10H8N2·2H2O. The bond lengths and angles around the metal atom indicate a deviation from octa­hedral geometry. The two naphtho­quinone ligands coordinate in a cis fashion, with the 4,4?-bipyridine ligand and the water mol­ecules completing the coordination sphere of the metal atom. The asymmetric unit contains also one free 4,4?-bipyridine mol­ecule and two uncoordinated water mol­ecules. These mol­ecules make contacts with the complex through O—H?N and O—H?O hydrogen bonds, creating a layer two-dimensional network parallel to (121). PMID:22219743

Silva, Marcos M. P.; Carvalho, Lucas J.; Lanznaster, Maurício; Resende, Jackson A. L. C.

2011-01-01

155

Quinone-Enhanced Reduction of Nitric Oxide by Xanthine/Xanthine Oxidase  

PubMed Central

The quinones 1,4-naphthoquinone, methyl-1,4-naphthoquinone, tetramethyl-1,4-benzoquinone, 2,3-dimethoxy-5-methyl-1,4-benzoquinone, 2,6-dimethylbenzoquinone, 2,6-dimethoxybenzoquinone, and 9,10-phenanthraquinone enhance the rate of nitric oxide reduction by xanthine/xanthine oxidase in nitrogen-saturated phosphate buffer (pH 7.4). Maximum initial rates of NO reduction (Vmax) and the amount of nitrous oxide produced after 5 min of reaction increase with quinone one- and two-electron redox potentials measured in acetonitrile. One of the most active quinones of those studied is 9,10-phenanthraquinone with a Vmax value 10 times larger than that corresponding to the absence of quinone, under the conditions of this work. Because NO production is enhanced under hypoxia and under certain pathological conditions, the observations obtained in this work are very relevant to such conditions. PMID:19301825

Sanchez-Cruz, Pedro; Alegría, Antonio E.

2009-01-01

156

The correlation of cathodic peak potentials of vitamin K(3) derivatives and their calculated electron affinities. The role of hydrogen bonding and conformational changes.  

PubMed

2-methyl-1,4-naphtoquinone 1 (vitamin K(3), menadione) derivatives with different substituents at the 3-position were synthesized to tune their electrochemical properties. The thermodynamic midpoint potential (E(1/2)) of the naphthoquinone derivatives yielding a semi radical naphthoquinone anion were measured by cyclic voltammetry in the aprotic solvent dimethoxyethane (DME). Using quantum chemical methods, a clear correlation was found between the thermodynamic midpoint potentials and the calculated electron affinities (E(A)). Comparison of calculated and experimental values allowed delineation of additional factors such as the conformational dependence of quinone substituents and hydrogen bonding which can influence the electron affinities (E(A)) of the quinone. This information can be used as a model to gain insight into enzyme-cofactor interactions, particularly for enzyme quinone binding modes and the electrochemical adjustment of the quinone motif. PMID:19265668

Nasiri, Hamid Reza; Panisch, Robin; Madej, M Gregor; Bats, Jan W; Lancaster, C Roy D; Schwalbe, Harald

2009-06-01

157

-GAB and pH Dependence of the Electron Transfer from P+ in Rhodobacter sphaeroides Reaction Centers  

E-print Network

-G°AB and pH Dependence of the Electron Transfer from P+ QA - QB to P+ QAQB - in Rhodobacter+QA -QB and P+QAQB - states (-G°AB) and on the pH was measured using naphthoquinones with different RCs with ubiquinone as QA. The fast phase, 1, is pH independent from pH 6 to 11 while 2 slows above pH

Li, Jiali

158

Synthesis and pharmacological activity of diterpenylnaphthoquinone derivatives.  

PubMed

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

2011-01-01

159

Electrocoagulation of quinone pigments.  

PubMed

Some representative quinones, viz. one naphthoquinone (plumbagin) and five anthraquinones (alizarin, purpurin, chrysazin, emodin, and anthrarufin), were subjected to electrocoagulation. It was found that the rate and extent of coagulation of these compounds appears to correlate with the number and relative position of their phenolic substituent groups, and that all of the coagulated quinones could be recovered. Attempts were then made to electrochemically isolate three quinones, namely plumbagin, morindone and erythrolaccin, from natural sources. PMID:17971722

Chairungsi, Neeranuch; Jumpatong, Kanlaya; Suebsakwong, Patiwat; Sengpracha, Waya; Phutdhawong, Weerachai; Buddhasukh, Duang

2006-01-01

160

Quinones in plant plasma membranes — a missing link?  

Microsoft Academic Search

Summary The occurrence of a vitamin-K-like substance (naphthoquinone group) and flavins (flavin mononucleotide and flavin adenine dinucleotide) is demonstrated in plasma membranes isolated from maize (Zea mays L.) roots, on the basis of high-pressure liquid chromotography and spectral analysis. At least three NAD(P)H dehydrogenases could be purified to homogeneity from this plant material. Two of these proteins (25 and 30

S. Liithje; P. Van Gestelen; M. C. Córdoba-Pedregosa; J. A. González-Reyes; H. Asard; J. M. Villalba; M. Böttger

1998-01-01

161

The Pin 1 inhibitor juglone attenuates kidney fibrogenesis via Pin 1-independent mechanisms in the unilateral ureteral occlusion model  

Microsoft Academic Search

BACKGROUND: Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral

Shannon Reese; Aparna Vidyasagar; Lynn Jacobson; Zeki Acun; Stephane Esnault; Debra Hullett; James S Malter; Arjang Djamali

2010-01-01

162

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

1990-01-01

163

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). PMID:16786055

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

2006-01-01

164

Antitumor agents—CLXVII. Synthesis and structure-activity correlations of the cytotoxic anthraquinone 1,4-bis-(2,3-epoxypropylamino)-9,10-anthracenedione, and of related compounds  

Microsoft Academic Search

1,4-Bis-(2,3-epoxypropylamino)-9,10-anthracenedione (3) was synthesized in this laboratory and was found to be a potent antitumor agent. Derivatives of this compound containing anthraquinone, naphthoquinone, and quinone skeletons were also prepared and evaluated for in vitro cytotoxic activity in several cell lines. These molecules were designed as bifunctional antitumor agents with the potential to act as (1) intercalating agents due to their

Mary G. Johnson; Hiroshi Kiyokawa; Shohei Tani; Junko Koyama; Susan L. Morris-Natschke; Anthony Mauger; Margaret M. Bowers-Daines; Barry C. Lange; Kuo-Hsiung Lee

1997-01-01

165

Synthesis of new 2-vinylation products of indole via a Michael-type addition reaction with dimethyl acetylenedicarboxylate and their Diels-Alder reactivity as precursors of new carbazoles.  

PubMed

Reaction of 4,7-dihydroindole and dimethyl acetylenedicarboxylate provided a convenient route to functionalized 2-vinylindoles. Diels-Alder reactions of the 2-vinylindoles with naphthoquinone, p-benzoquinone, 1,2-dicyano-4,5-dichloroquinone, N-phenyltriazolinedione, and tetracyanoethylene were investigated to give [c]annelated 1,2-dihydro, 1,2,3,4-tetrahydro, and fully aromatized carbazoles. The structure and formation mechanism of both 2-vinylindoles and their cycloadduct are discussed. PMID:16995688

Cavdar, Hüseyin; Saraçoglu, Nurullah

2006-09-29

166

Total synthesis of mevashuntin.  

PubMed

The total synthesis of (±)-mevashuntin, a structurally unique naturally occurring pyrano-naphthoquinone-thiazolone, is described. The route is centered upon a late stage regioselective Diels-Alder reaction between two highly functionalized components, as well as an improved protocol for the one pot synthesis of benzothiazolones from ortho-bromoaryl isothiocyanates. The strategy results in a highly convergent route, providing access to the natural product in 11 steps from 3-(4-methoxyphenoxy)propanol and confirming its relative stereochemistry. PMID:22369640

Nawrat, Christopher C; Moody, Christopher J

2012-03-16

167

Juglone (5-hydroxy-1,4 napthoquinone) and soil nitrogen transformation interactions under a walnut plantation in southern Ontario, Canada  

Microsoft Academic Search

Juglone (5-hydroxy-1,4-naphthoquinone), a chemical substance produced by black walnut (Juglans nigra L.), inhibits the growth\\u000a and existence of some beneficial soil microorganisms, especially Frankia spp. isolate ArI3 and Rhizobium japonicum. However,\\u000a no studies to date have reported on the effect of juglone on soil ammonification and nitrification. A field study and laboratory\\u000a incubation study to investigate this were conducted. In

N. V. Thevathasans; A. M. Gordon; R. P. Voroney

1998-01-01

168

Seasonal changes of juglone potential in leaves of black walnut ( Juglans nigra L.)  

Microsoft Academic Search

The literature concerning the extraction and quantification of juglone (5-hydroxy-1,4-naphthoquinone) frequently fails to differentiate between juglone and its immediate precursors. The proposal that the term “juglone potential” be used to define the total concentration of juglone under an oxidative environment in walnut tissues is made. The juglone potential of a given tissue will more accurately reflect the allelopathic agent's presence

Kim D. Coder

1983-01-01

169

Sorption and desorption of pesticide in the octadecylsilyl-silica gel\\/water system by single microparticle injection and absorption microspectroscopy  

Microsoft Academic Search

The sorption and desorption processes of a pesticide between a single octadecylsilyl (ODS)-silica gel microparticle and the surrounding water phase were kinetically analyzed by absorption microspectroscopy combined with a single microparticle injection method. 2-Amino-3-chloro-1,4-naphthoquinone (quinoclamine) sorbed into the microparticle was completely desorbed into the water phase, and both the sorption and desorption processes could be analyzed by the intraparticle diffusion

Katsumi Chikama; Hiroshi Kakizaki; Kiyoharu Nakatani

2008-01-01

170

Identification, cloning and characterization of an aldo-keto reductase from Trypanosoma cruzi with quinone oxido-reductase activity.  

PubMed

Drugs currently used for treatment of Trypanosoma cruzi infection, the ethiological agent of Chagas' disease, have shown side effects and variable efficiency. With the aim to describe parasite enzymes involved in the mechanisms of action of trypanocidal drugs and since it has been reported that reductases are crucial in their metabolism, we attempted to identify novel NADPH-dependent oxido-reductases from T. cruzi. The percolation of a soluble fraction of epimastigote lysates through a Cibacron Blue-Sepharose column followed by elution by NADPH yielded a predominant protein with an apparent molecular weight of 32 kDa. This protein was identified by MALDI-TOF as an aldo-keto reductase (AKR) and hence denominated TcAKR. TcAKR was mainly localized in the cytosol and was also present in trypomastigote and amastigote lysates. The recombinant TcAKR (recTcAKR) showed NADPH-dependent reductase activity with the AKR substrates 4-nitrobenzaldehyde and 2-dihydroxyacetone. The saturation curves for both substrates were consistent with the Michaelis-Menten model. We also tested whether recTcAKR may reduce naphthoquinones (NQ), since many of these compounds have displayed important trypanocidal activity. recTcAKR reduced o-NQ (1,2-naphthoquinone, 9,10-phenanthrenquinone and beta-lapachone) with concomitant generation of free radicals but did not exhibit affinity for p-NQ (5-hydroxy-1,4-naphthoquinone, 2-hydroxy-1,4-naphthoquinone, alpha-lapachone and menadione). The substrate saturation curve with o-NQ fitted to a sigmoidal curve, suggesting that recTcAKR presents a cooperative behavior. In addition, three peaks assigned to monomers, dimers and tetramers were obtained when recTcAKR was submitted to a Superose 12 gel chromatography column. TcAKR is the first member of the AKR family described in T. cruzi. Our results indicate that this enzyme may participate in the mechanisms of action of trypanocidal drugs. PMID:20595031

Garavaglia, Patricia A; Cannata, Joaquín J B; Ruiz, Andrés M; Maugeri, Dante; Duran, Rosario; Galleano, Mónica; García, Gabriela A

2010-10-01

171

Selected phytotoxins and organic extracts from endophytic fungus Edenia gomezpompae as light reaction of photosynthesis inhibitors.  

PubMed

In a search for natural herbicides, we investigated the action mechanism of the naphthoquinone spiroketals, isolated from the endophytic fungus Edenia gomezpompae: preussomerins EG1 (1) and EG4 (2), and palmarumycins CP17 (3), and CP2 (4) on the photosynthesis light reactions. The naphthoquinone spiroketals 1-4 inhibited the ATP synthesis in freshly lysed spinach thylakoids from water to MV, and they also inhibited the non-cyclic electron transport in the basal, phosphorylating and uncoupled conditions from water to MV. Therefore, they act as Hill reaction inhibitors. The results suggested that naphthoquinone spiroketals 1-4 have two interactions and inhibition site on the PSII electron transport chain. The first one involves the water splitting enzyme inhibition; and, the second on the acceptor site of PSII in a similar way that herbicide Diuron, studied by polaroghaphy and corroborated by fluorescence of the chlorophyll a of PSII. The culture medium and mycelium organic extracts from four morphological variants of E. gomezpompae were phytotoxic, and the culture medium extracts were more potent than mycelium extracts. They also act as Hill reaction inhibitors. PMID:24911268

Macías-Rubalcava, Martha Lydia; Ruiz-Velasco Sobrino, María Emma; Meléndez-González, Claudio; King-Díaz, Beatriz; Lotina-Hennsen, Blas

2014-09-01

172

Characterization of Model Peptide Adducts with Reactive Metabolites of Naphthalene by Mass Spectrometry  

PubMed Central

Naphthalene is a volatile polycyclic aromatic hydrocarbon generated during combustion and is a ubiquitous chemical in the environment. Short term exposures of rodents to air concentrations less than the current OSHA standard yielded necrotic lesions in the airways and nasal epithelium of the mouse, and in the nasal epithelium of the rat. The cytotoxic effects of naphthalene have been correlated with the formation of covalent protein adducts after the generation of reactive metabolites, but there is little information about the specific sites of adduction or on the amino acid targets of these metabolites. To better understand the chemical species produced when naphthalene metabolites react with proteins and peptides, we studied the formation and structure of the resulting adducts from the incubation of model peptides with naphthalene epoxide, naphthalene diol epoxide, 1,2-naphthoquinone, and 1,4-naphthoquinone using high resolution mass spectrometry. Identification of the binding sites, relative rates of depletion of the unadducted peptide, and selectivity of binding to amino acid residues were determined. Adduction occurred on the cysteine, lysine, and histidine residues, and on the N-terminus. Monoadduct formation occurred in 39 of the 48 reactions. In reactions with the naphthoquinones, diadducts were observed, and in one case, a triadduct was detected. The results from this model peptide study will assist in data interpretation from ongoing work to detect peptide adducts in vivo as markers of biologic effect. PMID:22870282

Pham, Nathalie T.; Jewell, William T.; Morin, Dexter; Jones, A. Daniel; Buckpitt, Alan R.

2012-01-01

173

Development of a test system for screening toxic substances: a comparison using organic substances  

SciTech Connect

The purpose of this research was to develop a test system for screening toxic substances by predicting their aquatic ecosystem effects. The system studied was a static, one liter microcosm with a diverse species assemblage. The microcosm was composed of biotic inoculum, chemically defined medium and sediment. The biotic inoculum contained primary producers, grazers, carnivores and decomposers. Three different types of sediment were studied: sand, clay, and clay plus sand. Four organic chemicals: phenol, triethylene glycol (TEG), quinoline and naphthoquinone were evaluated with this test system. The toxicities of TEG, quinoline and naphthoquinone were compared for each sediment type. Toxicity was evaluated in terms of the chemical's effects on primary productivity and heterotrophic activity though other effects are also noted. Naphthoquinone concentration exhibited no correlation between ecosystem property values and therefore, could not be ranked. Phenol exhibited the greatest toxicity to net production immediately after the toxicant addition. Quinoline was most toxic to net production over the longer time scale. TEG exhibited the least toxicity to net production, however, TEG exhibited higher toxicity to heterotrophic activity than either quinoline or phenol. Although the type of sediment used in the microcosms did not change the relative toxicities of the chemicals, the microcosms with clay sediment always were observed to exhibit lower net production and higher variability.

Thomas, C.L.

1985-01-01

174

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

PubMed

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

2012-04-01

175

The Tumor-Selective Cytotoxic Agent ?-Lapachone is a Potent Inhibitor of IDO1  

PubMed Central

?-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate ?-lapachone. Enzyme kinetics-based analysis of ?-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that ?-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects. PMID:24023520

Flick, Hollie E.; LaLonde, Judith M.; Malachowski, William P.; Muller, Alexander J.

2013-01-01

176

3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives: synthesis and cytotoxicity against cancer cell lines.  

PubMed

Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimethoxy substituted naphthoquinones showed the best cytoxicity profile, while the ortho-nitro and the 2,4-dimethoxy substituted ones were more selective than doxorubicin and similar to the precursor lapachones, thus emerging as promising new lead compounds in anticancer drug development. PMID:19947600

da Silva, Eufrânio N; de Deus, Clara F; Cavalcanti, Bruno C; Pessoa, Cláudia; Costa-Lotufo, Letícia V; Montenegro, Raquel C; de Moraes, Manoel O; Pinto, Maria do Carmo F R; de Simone, Carlos A; Ferreira, Vitor F; Goulart, Marilia O F; Andrade, Carlos Kleber Z; Pinto, Antônio V

2010-01-14

177

Comparison of cation binding affinities of quinones  

NASA Astrophysics Data System (ADS)

The relative gas-phase basicity scale and the relative dimethoxy borinium ion affinity scale of various quinones were determined by the ligand exchange method to investigate the structural factors which influence the binding properties of the quinones. The relative gas-phase basicity scale and dimethoxy borinium ion affinity scale were similar, and were proved to correlate with the extent of favorable functional group interactions and counteractive electron-withdrawing effects of certain substituents. For 1,2-naphthoquinone and lawsone the order of affinities was reversed, presumably because of a secondary hydrogen-bonding interaction active for lawsone that particularly enhanced the stability of its borinium adduct.

Hall, Brad J.; Brodbelt, Jennifer S.

1996-11-01

178

Hydroxynaphthoquinone Metal Complexes as Antitumor Agents X: Synthesis, Structure, Spectroscopy and In Vitro Antitumor Activity of 3-Methyl-Phenylazo Lawsone Derivatives and Their Metal Complexes Against Human Breast Cancer Cell Line MCF-7  

PubMed Central

The C-3 substituted phenylazo derivatives of lawsone (2-hydroxy-l,4 p-naphthoquinone, III) were synthesized and characterized. The X-ray crystal structure was determined for the ligand 3-(3?-methyl phenylazo) lawsone. The copper complexes of these derivatives were found to possess 1:2 metal stoichiometry and square planar geometries with intermolecular stackings, resulting in antiferromagnetic exchange interactions. The in vitro activity of all the synthesized compounds was examined against human breast cancer cell-line, MCF-7, which revealed enhanced activities for the metal complexes, the highest activity being observed for the copper compound of 3-(3?-methyl phenylazo) lawsone. PMID:18475934

Gokhale, Nikhil; Newton, Chris; Pritchard, Robin

2000-01-01

179

Synthesis and antiproliferative evaluation of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones.  

PubMed

A simple synthesis of novel 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-dione derivatives was accomplished in excellent yields via the reaction of 2-aminobenzothiazole, aromatic aldehydes and 2-hydroxy-1,4-naphthoquinone in the presence of amberlyst-15. The antiproliferative activities of all the synthesized compounds were assessed on two different human cancer cell lines (HepG2 and Hela), and the results showed that most of the new compounds showed good to potent cytotoxic activities. PMID:24582982

Wu, Liqiang; Zhang, Chong; Li, Weilin

2014-03-15

180

Two approaches to the aromatic core of the aminonaphthoquinone antibiotics.  

PubMed

Two complementary approaches are presented for the synthesis of the quinone chromophores of the naphthoquinone ansamycins and related natural products. The first involves the use of an improved protocol for the manganese(III) acetate mediated cyclization of 5-aryl-1,3-dicarbonyl compounds to ?-naphthols, leading to the simple, scalable preparation of building blocks suitable for the synthesis of naturally occurring aminonaphthoquinones. The second approach involves the Diels-Alder reaction of a series of new, ester-containing Danishefsky-type dienes with N-protected aminobenzoquinones to allow more expeditious access to similar intermediates. PMID:23659591

Nawrat, Christopher C; Palmer, Leoni I; Blake, Alexander J; Moody, Christopher J

2013-06-01

181

Quinone-annulated N-heterocyclic carbene-transition-metal complexes: observation of pi-backbonding using FT-IR spectroscopy and cyclic voltammetry.  

PubMed

A new N-heterocyclic carbene architecture comprising a 1,4-naphthoquinone annulated to 1,3-dimesitylimidazolylidene (NpQ-NHC) was synthesized in two high yielding steps from commercially available starting materials. The free NpQ-NHC was characterized (solution and solid-state) and was used to synthesize various Rh and Ag complexes that ranged in pi-electron density. Enabled by the quinone moiety, the pi-systems of these complexes were analyzed using infrared spectroscopy and cyclic voltammetry. In contrast to previous reports, pi-backbonding was found to be non-negligible and was directly influenced by the metal's electronic character. PMID:17177396

Sanderson, Matthew D; Kamplain, Justin W; Bielawski, Christopher W

2006-12-27

182

Selective growth-inhibiting effects of compounds identified in Tabebuia impetiginosa inner bark on human intestinal bacteria.  

PubMed

The growth-inhibiting activity of anthraquinone-2-carboxylic acid and lapachol identified in the inner bark of taheebo, Tabebuia impetiginosa, toward 10 human intestinal bacteria was evaluated by using a paper disk diffusion bioassay and compared to those of seven lapachol congeners (1,4-naphthoquinone, naphthazarin, menadione, lawsone, plumbagin, juglone, and dichlone) as well as two commercially available antibiotics, chloramphenicol and tetracycline. Anthraquinone-2-carboxylic acid exhibited very strong growth inhibition of Clostridium paraputrificum at 1 microg/disk while 100 microg/disk of lapachol was needed for moderate growth inhibition of the same organism. These two isolates exhibited weak inhibition of Clostridium perfringens and Escherichia coli at 100 microg/disk while no adverse effects were observed on the growth of Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium infantis, Lactobacillus acidophilus, and Lactobacillus casei at 1000 microg/disk. Structure-activity relationships indicate that a methyl group in the C-2 position of 1,4-naphthoquinone derivatives might play an important role in antibacterial activity. PMID:15713033

Park, Byeoung-Soo; Kim, Jun-Ran; Lee, Sung-Eun; Kim, Kyoung Soon; Takeoka, Gary R; Ahn, Young-Joon; Kim, Jeong-Han

2005-02-23

183

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

PubMed

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

2013-01-01

184

Effects of rhinacanthin-C on function and expression of drug efflux transporters in Caco-2 cells.  

PubMed

Rhinacanthin-C is a bioactive naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae). This compound has potential therapeutic value as an anticancer and antiviral agent. The purposes of this study were to determine the effects of this compound on the function and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2), using the in vitro model of Caco-2 cells. The activities of P-gp and MRP2 were determined by following the intracellular accumulation of calcein and 5(6)-carboxy-2',7'-dichlorofluorescein in the uptake assays with fluorescence spectroscopy. The expression of P-gp after prolonged exposure was evaluated by flow cytometry with the use of a fluorescein isothiocyanate-conjugated anti-human P-gp antibody. Our results showed that the inhibitory effect of rhinacanthin-C was more potent toward P-gp than MRP2, and was reversible. Short-term exposure of Caco-2 cells with rhinacanthin-C (100 ?M) resulted in increase in P-gp expression without any significant change in its function. Extended exposure of Caco-2 cells to the naphthoquinone at the highest non-cytotoxic concentration (0.625 ?M) for 7 days had no effect on the expression and the function of P-gp. These findings suggested that rhinacanthin-C might raise the problem of herb-drug interaction when co-administered with other P-gp substrates. PMID:23742857

Wongwanakul, Ratjika; Vardhanabhuti, Nontima; Siripong, Pongpun; Jianmongkol, Suree

2013-09-01

185

SOM assembly of hydroxynaphthoquinone and its oxime: Polymorphic X-ray structures and EPR studies  

NASA Astrophysics Data System (ADS)

Investigation on solvent-induced polymorphism in X-ray structures of 2-hydroxy-1,4-naphthoquinone (Lawsone) 1, is carried out. In protic methanol, 1 crystallizes in monoclinic space group P2 1/ c ( 1a) comprising of 2D hydrogen bonded network via cyclic dimers. In aprotic solvent such as acetone on the other hand, 1 exhibits orthorhombic space group Pna 2 1 ( 1b) and emerges with 1D catemeric chain. Solvent-induced topological isomerism of cyclic dimers and helical catemeric chains arising from (i) bifurcated intra- and inter molecular hydrogen bondings viz. O sbnd H ⋯O dbnd C interactions between C(2) hydroxyl and C(1), C(4) carbonyls, (ii) C sbnd H ⋯O interactions viz. C(3) sbnd H ⋯O(1)C(1) have been discussed. A signal for radical in 1 at g = 2.0058 is signatured by EPR spectrum and it's oxime derivative viz. 2-hydroxy-4-naphthoquinone-1-oxime 2, in solid state shows biradical and monoradical formation with aggregation of dimer and monomer due to non-covalent hydrogen bonds. Zero field split parameters for 2 are estimated to be D = 215 G, Ex = 13 G, Ey = 47 G at 298 K. A half field signal at 77 K indicates triplet ground state. Frozen glass EPR of 2 resolves as regioregular dimeric-monomeric species showing hyperfine interactions with 1-oximino nitrogen in dimer A¯(N) = 15.5 G].

Todkary, Ashwini V.; Dalvi, Rupali; Salunke-Gawali, Sunita; Linares, Jorge; Varret, François; Marrot, Jérôme; Yakhmi, Jatinder V.; Bhadbhade, Mohan; Srinivas, D.; Gejji, Shridhar P.; Rane, Sandhya Y.

2006-01-01

186

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

PubMed

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

2010-11-01

187

Identification of Quinoide Redox Mediators That Are Formed during the Degradation of Naphthalene-2-Sulfonate by Sphingomonas xenophaga BN6  

PubMed Central

During aerobic degradation of naphthalene-2-sulfonate (2NS), Sphingomonas xenophaga strain BN6 produces redox mediators which significantly increase the ability of the strain to reduce azo dyes under anaerobic conditions. It was previously suggested that 1,2-dihydroxynaphthalene (1,2-DHN), which is an intermediate in the degradative pathway of 2NS, is the precursor of these redox mediators. In order to analyze the importance of the formation of 1,2-DHN, the dihydroxynaphthalene dioxygenase gene (nsaC) was disrupted by gene replacement. The resulting strain, strain AKE1, did not degrade 2NS to salicylate. After aerobic preincubation with 2NS, strain AKE1 exhibited much higher reduction capacities for azo dyes under anaerobic conditions than the wild-type strain exhibited. Several compounds were present in the culture supernatants which enhanced the ability of S. xenophaga BN6 to reduce azo dyes under anaerobic conditions. Two major redox mediators were purified from the culture supernatants, and they were identified by high-performance liquid chromatography-mass spectrometry and comparison with chemically synthesized standards as 4-amino-1,2-naphthoquinone and 4-ethanolamino-1,2-naphthoquinone. PMID:12200285

Keck, Andreas; Rau, Jörg; Reemtsma, Thorsten; Mattes, Ralf; Stolz, Andreas; Klein, Joachim

2002-01-01

188

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 Csbnd H⋯O, Nsbnd H⋯O and Osbnd H⋯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-rad ) 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

2012-02-01

189

Metal-Independent Reduction of Hydrogen Peroxide by Semiquinones.  

PubMed

The quinones 1,4-naphthoquinone (NQ), tetramethyl-1,4-benzoquinone (DQ), 2-methyl-1,4-naphthoquinone (MNQ), 2,3-dimethoxy-5-methyl-1,4-benzoquinone (UBQ-0), 2,6-dimethylbenzoquinone (DMBQ), 2,6-dimethoxybenzoquinone (DMOBQ), and 9,10-phenanthraquinone (PHQ) enhance the rate of H2O2 reduction by ascorbate, under anaerobic conditions, as detected from the amount of methane produced after hydroxyl radical reaction with dimethyl sulfoxide. The amount of methane produced increases with an increase in the quinone one-electron reduction potential. The most active quinone in this series, PHQ, is only 14% less active than the classic Fenton reagent cation, Fe(2+), at the same concentration. Since PHQ is a common toxin present in diesel combustion smoke, the possibility that PHQ-mediated catalysis of hydroxyl radical formation is similar to that of Fe(2+) adds another important pathway to the modes in which PHQ can execute its toxicity. Because quinones are known to enhance the antitumor activity of ascorbate and because ascorbate enhances the formation of H2O2 in tissues, the quinone-mediated reduction of H2O2 should be relevant to this type of antitumor activity, especially under hypoxic conditions. PMID:25046766

Sanchez-Cruz, Pedro; Santos, Areli; Diaz, Stephany; Alegría, Antonio E

2014-07-29

190

Pigment Cell Differentiation in Sea Urchin Blastula-Derived Primary Cell Cultures  

PubMed Central

The quinone pigments of sea urchins, specifically echinochrome and spinochromes, are known for their effective antioxidant, antibacterial, antifungal, and antitumor activities. We developed in vitro technology for inducing pigment differentiation in cell culture. The intensification of the pigment differentiation was accompanied by a simultaneous decrease in cell proliferation. The number of pigment cells was two-fold higher in the cells cultivated in the coelomic fluids of injured sea urchins than in those intact. The possible roles of the specific components of the coelomic fluids in the pigment differentiation process and the quantitative measurement of the production of naphthoquinone pigments during cultivation were examined by MALDI and electrospray ionization mass spectrometry. Echinochrome A and spinochrome E were produced by the cultivated cells of the sand dollar Scaphechinus mirabilis in all tested media, while only spinochromes were found in the cultivated cells of another sea urchin, Strongylocentrotus intermedius. The expression of genes associated with the induction of pigment differentiation was increased in cells cultivated in the presence of shikimic acid, a precursor of naphthoquinone pigments. Our results should contribute to the development of new techniques in marine biotechnology, including the generation of cell cultures producing complex bioactive compounds with therapeutic potential. PMID:24979272

Ageenko, Natalya V.; Kiselev, Konstantin V.; Dmitrenok, Pavel S.; Odintsova, Nelly A.

2014-01-01

191

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

PubMed

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

1991-03-01

192

Isolation and purification of acetylshikonin and beta-acetoxyisovalerylshikonin from cell suspension cultures of Arnebia euchroma (Royle) Johnston using rapid preparative HPLC.  

PubMed

Shikonin and its derivatives are important red colored naphthoquinone pigments found in a large number of Arnebia species, including A. euchroma, that are responsible for the various pharmacological activities exhibited by the plant. The precise separation of each naphthoquinone is essential for total quality evaluation and bioactivity analysis of herbal formulations of A. euchroma. Furthermore, the overexploitation of this useful plant has resulted in species becoming endangered. With this in mind, a simple and rapid preparative scale HPLC method with single compound recovery for the isolation and purification of two shikonin derivatives (i. e. acetylshikonin, beta-acetoxyisovalerylshikonin) from cell suspension cultures of A. euchroma is presented. The compounds were separated on a C(18) column within 10 min using acetonitrile/methanol (95:5) as mobile phase in isocratic mode. The isolated compounds were found to be more than 98% pure. The LOD for acetylshikonin and beta-acetoxyisovalerylshikonin was estimated at 0.063 and 0.146 mug/mL, respectively, while the LOQ was found to be 0.209 and 0.487 mug/mL, respectively. The recoveries accomplished for both the shikonin derivatives were in the range of 94.7-96.8%. The repeatability, expressed as %RSD, of acetylshikonin and beta-acetoxyisovalerylshikonin was found to be 1.74 and 1.27, respectively. PMID:18264989

Sharma, Nandini; Sharma, Upendra Kumar; Malik, Sonia; Bhushan, Shashi; Kumar, Vinod; Verma, Subash Chandra; Sharma, Naina; Sharma, Madhu; Sinha, Arun Kumar

2008-03-01

193

Anticancer Compound Plumbagin and Its Molecular Targets: A Structural Insight into the Inhibitory Mechanisms Using Computational Approaches  

PubMed Central

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3K?, AKT1/PKB?, Bcl-2, NF-?B, and Stat3 using molecular docking and (un)binding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease. PMID:24586269

Beg, Mohd A.; Suhail, Mohd; Chaudhary, Adeel G. A.; Damanhouri, Ghazi A.; Abuzenadah, Adel M.; Rehan, Mohd

2014-01-01

194

Pigment cell differentiation in sea urchin blastula-derived primary cell cultures.  

PubMed

The quinone pigments of sea urchins, specifically echinochrome and spinochromes, are known for their effective antioxidant, antibacterial, antifungal, and antitumor activities. We developed in vitro technology for inducing pigment differentiation in cell culture. The intensification of the pigment differentiation was accompanied by a simultaneous decrease in cell proliferation. The number of pigment cells was two-fold higher in the cells cultivated in the coelomic fluids of injured sea urchins than in those intact. The possible roles of the specific components of the coelomic fluids in the pigment differentiation process and the quantitative measurement of the production of naphthoquinone pigments during cultivation were examined by MALDI and electrospray ionization mass spectrometry. Echinochrome A and spinochrome E were produced by the cultivated cells of the sand dollar Scaphechinus mirabilis in all tested media, while only spinochromes were found in the cultivated cells of another sea urchin, Strongylocentrotus intermedius. The expression of genes associated with the induction of pigment differentiation was increased in cells cultivated in the presence of shikimic acid, a precursor of naphthoquinone pigments. Our results should contribute to the development of new techniques in marine biotechnology, including the generation of cell cultures producing complex bioactive compounds with therapeutic potential. PMID:24979272

Ageenko, Natalya V; Kiselev, Konstantin V; Dmitrenok, Pavel S; Odintsova, Nelly A

2014-07-01

195

2-Phenyl-beta-lapachone can affect mitochondrial function by redox cycling mediated oxidation.  

PubMed

2-Phenyl-beta-lapachone (3,4-dihydro-2-methyl-2-phenyl-2H-naphtho[1,2b]pyran-5,6-dione) (2PBL) is a o-naphthoquinone synthesized as a possible antitumoral agent. The addition of micromolar concentrations of 2PBL to rat liver mitochondria (in the presence of malate-glutamate or succinate, as respiratory substrates): (1) stimulated O(2) consumption in state 4 and inhibited O(2) consumption in state 3, thus decreasing respiratory control index (RCI); and (2) collapsed the mitochondrial membrane potential. The addition of 2PBL to rat liver submitochondrial particles: (1) stimulated NADH oxidation in the presence of rotenone, antimycin, myxothiazol or cyanide; (2) stimulated (.-)O(2)(-) production in the presence of NADH and antimycin; and (3) led to 2PBL semiquinone radical production. Control studies carried out with two p-naphthoquinones, menadione and atovaquone, did not produced equivalent effects. These findings support the hypothesis that 2PBL, undergoes redox cycling and affects mitochondrial function. The 2PBL effect is complex, involving inhibition of electron transfer, uncoupling of oxidative phosphorylation, collapse of mitochondrial membrane potential and (.-)O(2)(-) production by redox cycling. The mitochondrion could be a target organelle for 2PBL cytotoxicity. PMID:15542051

de Witte, Natacha V; Stoppani, Andrés O M; Dubin, Marta

2004-12-15

196

Anticancer compound plumbagin and its molecular targets: a structural insight into the inhibitory mechanisms using computational approaches.  

PubMed

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3K?, AKT1/PKB?, Bcl-2, NF-?B, and Stat3 using molecular docking and (un)binding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease. PMID:24586269

Jamal, Mohammad S; Parveen, Shadma; Beg, Mohd A; Suhail, Mohd; Chaudhary, Adeel G A; Damanhouri, Ghazi A; Abuzenadah, Adel M; Rehan, Mohd

2014-01-01

197

Inhibition of in vitro leukotriene B4 biosynthesis in human neutrophil granulocytes and docking studies of natural quinones.  

PubMed

Quinones are compounds frequently contained in medicinal plants used for the treatment of inflammatory diseases. Therefore, the impact of plant-derived quinones on the arachidonic acid metabolic pathway is worthy of investigation. In this study, twenty-three quinone compounds of plant origin were tested in vitro for their potential to inhibit leukotriene B4 (LTB4) biosynthesis in activated human neutrophil granulocytes with 5-lipoxygenase (5-LOX) activity. The benzoquinones primin (3) and thymohydroquinone (4) (IC50 = 4.0 and 4.1 microM, respectively) showed activity comparable with the reference inhibitor zileuton (1C50 = 4.1 microM). Moderate activity was observed for the benzoquinone thymoquinone (2) (1C50 = 18.2 microM) and the naphthoquinone shikonin (1) (IC50 = 24.3 microM). The anthraquinone emodin and the naphthoquinone plumbagin (5) displayed only weak activities (IC50 > 50 microM). The binding modes of the active compounds were further evaluated in silico by molecular docking to the human 5-LOX crystal structure. This process supports the biological data and suggested that, although the redox potential is responsible for the quinone's activity on multiple targets, in the case of 5-LOX the molecular structure plays a vital role in the inhibition. The obtained results suggest primin as a promising compound for the development of dual COX-2/5-LOX inhibitors. PMID:23472470

Landa, Premysl; Kutil, Zsofia; Temml, Veronika; Malik, Jan; Kokoska, Ladislav; Widowitz, Ute; Pribylova, Marie; Dvorakova, Marcela; Marsik, Petr; Schuster, Daniela; Bauer, Rudolf; Vanek, Tomas

2013-01-01

198

A mechanistic examination of redox cycling activity in carbonaceous particulate matter  

NASA Astrophysics Data System (ADS)

Mechanistic aspects of carbonaceous aerosol toxicity were examined with respect to the ability of particles to catalyse reactive oxygen species-generating redox cycling reactions. To investigate the role of secondary organic material, we examined two systems. In the first, two-stroke engine exhaust particles were found to increase their ability to catalyse redox cycling in the presence of a reducing agent, dithiothreitol (DTT), when the exhaust was exposed to ozone. This occurred through deposition of redox-active secondary organic aerosol (SOA) onto the particle that was ten times more redox active per microgram than the primary engine particle. In the second system, naphthalene SOA formed highly redox active particles. Activity was strongly correlated to the amount of the 1,4- and 1,2-naphthoquinone measured in the particle phase. However, these species and the newly quantified naphthalene oxidation product 5-hydroxy-1,4-naphthoquinone accounted for only 30% of the observed DTT decay from the particles. Gas-particle partitioning coefficients suggest 1,4- and 1,2- naphthoquinone are not strong contributors to ambient particle redox activity at 25 °C. However, a large number of redox active species are unidentified. Some of these may be highly oxidised products of sufficiently low vapour pressure to be atmospherically relevant. DTT activity of diesel particles was found to be high per unit mass. The activity was found to be associated with the insoluble fraction as filtration of the particles nearly eliminated DTT decay. Neither methanol nor dichloromethane extracts of diesel particles exhibited redox activity, indicating that the redox active species are associated with the black carbon portion of the particles. Examination of particle concentration techniques found that use of water condensation to grow and concentrate particles introduced a large organic artefact to the particles. Experiments with concentrated inorganic particles suggest that the source of this artefact is from irreversible uptake of water-soluble volatile organic compounds. Overall, carbonaceous redox active species can be thought of as a continuum from small, water-soluble species to redox active functionalities on elemental carbon backbones. In addition to clearly defined, quantifiable species, future research may need to consider examining broader chemical classes or redox-active chemical functionalities to overcome the inherent complexity of these constituents.

McWhinney, Robert David

199

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

PubMed

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

2007-07-01

200

Lapachol induces clastogenic effects in rats.  

PubMed

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

2010-06-01

201

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

2008-04-01

202

Novel zinc(II) and copper(II) complexes of a Mannich base derived from lawsone: Synthesis, single crystal X-ray analysis, ab initio density functional theory calculations and vibrational analysis  

NASA Astrophysics Data System (ADS)

Zinc(II) and copper(II) complexes of a tridentate Mannich base L1 derived from 2-hydroxy-1,4-naphthoquinone, pyridinecarboxyaldehyde and 2-aminomethylpyridine, [ZnL1Cl2]·H2O 1 and [CuL1Cl2]·2H2O 2, have been synthesized and fully characterized. The structure of complex 1 has been elucidated by a single crystal X-ray diffraction study: the zinc atom is pentacoordinate and the coordination geometry is a distorted square base pyramid, with a geometric structural parameter ? equal to 0.149. Vibrational spectroscopy and ab initio DFT calculations of both compounds have confirmed that the two complexes exhibit similar structures. Full assignment of the vibrational spectra was also supported by careful analysis of the distorted geometries generated by the normal modes

Neves, Amanda P.; Vargas, Maria D.; Soto, Claudio A. Téllez; Ramos, Joanna M.; Visentin, Lorenzo do C.; Pinheiro, Carlos B.; Mangrich, Antônio S.; de Rezende, Edivaltrys I. P.

203

Novel zinc(II) and copper(II) complexes of a Mannich base derived from lawsone: Synthesis, single crystal X-ray analysis, ab initio density functional theory calculations and vibrational analysis.  

PubMed

Zinc(II) and copper(II) complexes of a tridentate Mannich base L1 derived from 2-hydroxy-1,4-naphthoquinone, pyridinecarboxyaldehyde and 2-aminomethylpyridine, [ZnL1Cl(2)]·H(2)O 1 and [CuL1Cl(2)]·2H(2)O 2, have been synthesized and fully characterized. The structure of complex 1 has been elucidated by a single crystal X-ray diffraction study: the zinc atom is pentacoordinate and the coordination geometry is a distorted square base pyramid, with a geometric structural parameter ? equal to 0.149. Vibrational spectroscopy and ab initio DFT calculations of both compounds have confirmed that the two complexes exhibit similar structures. Full assignment of the vibrational spectra was also supported by careful analysis of the distorted geometries generated by the normal modes. PMID:22513170

Neves, Amanda P; Vargas, Maria D; Téllez Soto, Claudio A; Ramos, Joanna M; Visentin, Lorenzo do C; Pinheiro, Carlos B; Mangrich, Antônio S; de Rezende, Edivaltrys I P

2012-08-01

204

Lawsone dimerization in cobalt(III) complexes toward the design of new prototypes of bioreductive prodrugs.  

PubMed

Dimerization of lawsone occurs upon reaction with Co(BF(4))(2)·6H(2)O and N,N'-bis(pyridin-2-ylmethyl)ethylenediamine (py(2)en) to produce the mononuclear complex [Co(III)(bhnq)(py(2)en)]BF(4)·H(2)O (1). This complex has been investigated as a prototype of a bioreductive prodrug, where the bhnq(2-) ligand acts as a model for cytotoxic naphthoquinones. Cyclic voltammetry data in aqueous solution have shown a quasi-reversible Co(III)/Co(II) process at E(1/2) = -0.26 V vs Fc/Fc(+). Reactivity studies revealed the dissociation of bhnq(2-) from the complex upon reduction of 1 with ascorbic acid, and a dependence of the reaction rate on the oxygen concentration suggests the occurrence of redox cycling. PMID:23343393

Bustamante, Francisco L S; Metello, Julia M; de Castro, Frederico A V; Pinheiro, Carlos B; Pereira, Marcos D; Lanznaster, Mauricio

2013-02-01

205

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

PubMed

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

1990-04-01

206

The effect of halofuginone, Wellcome 993 C, oxytetracycline, and diminazene diaceturate on Babesia equi-infected lymphoblastoid cell cultures.  

PubMed

The efficacy of halofuginone (DL-trans-7-bromo-6-chloro-3,3-(3-hydroxy-2-piperidyl) acetonyl-4-(3H) quinazolinone), Wellcome 993 C (2-hydroxy-3-cyclohexyl-1,4-naphthoquinone), and oxytetracycline, all of which have been shown to have a schizonticidal effect in the treatment of bovine theileriosis, and the babesicidal drug diminazene diaceturate, were tested against the schizont stages of Babesia equi in cell culture. The in vitro test system measured DNA synthesis in treated and untreated cell lines. Halofuginone (0.02 microgram/ml) and Wellcome 993 C (5 micrograms/ml) suppressed the incorporation of tritiated thymidine by more than 80%. Oxytetracycline was less effective, while diminazene diaceturate showed no notable effect. The insufficient schizonticidal activity may explain the failure of diminazene diaceturate to cure B. equi infections. Schizonticidal drugs either alone, or in combination with known babesicidal drugs, should be tested in the chemotherapy of B. equi infections. PMID:6502356

Zweygarth, E; Ahmed, J S; Rehbein, G

1984-08-01

207

Photogenerated radical intermediates of vitamin K 1: a time-resolved resonance Raman study  

NASA Astrophysics Data System (ADS)

Quinones play a vital role in the process of electron transfer in bacterial photosynthetic reaction centers. It is of interest to investigate the photochemical reactions involving quinones with a view to elucidating the structure-function relationships in the biological processes. Resonance Raman spectra of radical anions and the time-resolved resonance Raman spectra of vitamin K 1 (model compound for Q A in Rhodopseudomonas viridis, a bacterial photosynthetic reception center) are presented. The photochemical intermediates of vitamin K 1, viz. radical anion, ketyl radical and o-quinone methide have been identified. The vibrational assignments of all these intermediates are made on the basis of comparison with our earlier TR3 studies on radical anions of naphthoquinone and menaquinone.

Balakrishnan, G.; Umapathy, S.

1999-01-01

208

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

SciTech Connect

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 not stimulated by an imposed K{sup +}-diffusion membrane potential of a physiological sign (positive inside the vesicles). Nor does the imposed membrane potential increase the reduction level of the haems in R. marinus SQR poised with the succinate/fumarate redox couple. The data do not support a widely discussed hypothesis on the electrogenic transmembrane electron transfer from succinate to menaquinone catalysed by di-haem SQRs. The role of the membrane potential in regulation of the SQR activity is discussed.

Fernandes, Andreia S. [Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Av. da Republica, Apartado 127, 2784-505 Oeiras (Portugal); Konstantinov, Alexander A. [Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Av. da Republica, Apartado 127, 2784-505 Oeiras (Portugal); A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow (Russian Federation); Teixeira, Miguel [Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Av. da Republica, Apartado 127, 2784-505 Oeiras (Portugal); Pereira, Manuela M. [Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Av. da Republica, Apartado 127, 2784-505 Oeiras (Portugal)]. E-mail: mpereira@itqb.unl.pt

2005-05-06

209

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

PubMed

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

2012-11-01

210

Chemical Constituents from Sinningia canescens and S. warmingii.  

PubMed

A new naphthoquinone, 6-methoxy-7-hydroxy-a-dunnione (1), along with four known compounds (2, 4, 10, and 11) were isolated from Sinningia canescens (Mart.) Wiehler tubers, while S. warmingii (Hiern.) Chautems furnished eight known compounds (3-10). The known compounds were identified as 7-hydroxy- ?-dunnione (2), lapachenole (3), tectoquinone (4), 7-methoxytectoquinone (5), 1-hydroxytectoquinone (6), 7-hydroxytectoquinone (7), aggregatin C (8), aggregatin D (9), halleridone (10), and cedrol (11). In addition, S. canescens yielded a volatile fraction, which was analyzed by GC/FID and GC/MS. This fraction was constituted mainly by sesquiterpene hydrocarbons (82.6%). The major components were ?-santalene (14.6%), ?-cedrene (10.4%), and trans-cadina-1(6)-4-diene (10.0%). PMID:25522555

Verdan, Maria Helena; Ehrenfried, Carlos Augusto; Scharf, Dilamara Riva; Cervi, Armando Carlos; Salvadore, Marcos José; Barison, Andersson; Stefanello, Elida A

2014-10-01

211

Isolation of an antimicrobial compound from Impatiens balsamina L. using bioassay-guided fractionation.  

PubMed

By using brine shrimp (Artemia salina) lethality test-guided fractionation, a single bioactive compound (LC(50)=26 ppm) was isolated from the 95% ethanol extract of the dried aerial parts of Impatiens balsamina L. and subsequently identified as 2-methoxy-1,4-naphthoquinone (MNQ). The structure of MNQ was confirmed by UV, FT-IR, MS, and 1-and 2-D NMR spectroscopy. The antimicrobial activity of MNQ was evaluated using 12 bacterial and eight fungal strains. Five gram-positive and two gram-negative bacteria as well as all eight fungi (including multi-drug resistant strains) tested were highly sensitive to MNQ. A tea prepared according to traditional methods was found to contain sufficient MNQ to account for its antimicrobial properties. PMID:11746859

Yang, X; Summerhurst, D K; Koval, S F; Ficker, C; Smith, M L; Bernards, M A

2001-12-01

212

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

PubMed

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

2007-03-16

213

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

PubMed

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

2013-03-18

214

Lithospermum erythrorhizon suppresses high-fat diet-induced obesity, and acetylshikonin, a main compound of Lithospermum erythrorhizon, inhibits adipocyte differentiation.  

PubMed

Lithospermum erythrorhizon, which has traditionally been used as a vegetable and to make the liquor Jindo Hongju, contains several naphthoquinone pigments, including shikonin. This study aimed to evaluate the antiobesity effects of Lithospermum erythrorhizon ethanol extract (LE) and elucidate the underlying mechanism. C57BL/6J mice were fed a normal or high-fat diet with or without LE supplementation for 8 weeks. LE reduced high-fat diet-induced increases in body weight, white adipose tissue mass, serum triglyceride and total cholesterol levels, and hepatic lipid levels while decreasing lipogenic and adipogenic gene expression. Furthermore, acetylshikonin suppressed adipocyte differentiation in a dose-dependent manner and significantly attenuated adipogenic transcription factor expression in 3T3-L1 cells. These findings suggest that Lithospermum erythrorhizon prevents obesity by inhibiting adipogenesis through downregulation of genes involved in the adipogenesis pathway and may be a useful dietary supplement for the prevention of obesity. PMID:22900585

Gwon, So Young; Ahn, Ji Yun; Chung, Chang Hwa; Moon, BoKyung; Ha, Tae Youl

2012-09-12

215

Shikonin blocks migration and invasion of human breast cancer cells through inhibition of matrix metalloproteinase-9 activation.  

PubMed

Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicinal herb, has been reported to promote tumor cell death. However, there are few reports concerning its effect on metastasis-related cell invasion and migration behavior. In the present study, we investigated the effect of shikonin on human breast cancer invasion and migration. We found that shikonin inhibited phorbol 12-myristate 13-acetate (PMA)-induced cell migration and invasion in MCF-7 breast cancer cells, which was correlated with modulation of matrix metalloproteinase-9 (MMP-9) through suppression of both expression and proteolytic and promoter activity. We also found that shikonin inhibited both MMP-9 expression and promoter activity in MDA-MB?231 cells with high metastatic potential. These results indicated that shikonin induces the suppression of migration and invasion through modulation of MMP-9 in human breast cancer cells. Therefore, shikonin may be a potential anticancer drug for human breast cancer therapy. PMID:24789371

Jang, Soon Young; Lee, Jae Koan; Jang, Eun Hyang; Jeong, Seo Young; Kim, Jong-Ho

2014-06-01

216

Semi-synthesis and antitumor activity of 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives.  

PubMed

We recently discovered that 5, 8-O-dimethyl acylshikonin derivatives displayed the selectivity towards MCF-7 and no toxicity to normal cells. Herein, a series of the corresponding 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives were synthesized starting from shikonin. In vitro evidence of the cytotoxicities indicated that most of thecompounds were more active than or comparative to shikonin and retained the selectivity against MCF-7, MDA-MB-231 besides no toxicity in the normal cells. Also, in vivo anticancer activity of the positional isomers 5p, 6c further showed that 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives were more active than their corresponding 2-isomers. Thus, we may conclude that the position of the side chain of shikonin attached to 5,8-dimethoxy -1,4-naphthoquinone is associated with the antitumor activity. PMID:21620530

Zhou, Wen; Zhang, Xu; Xiao, Ling; Ding, Jing; Liu, Quan-Hua; Li, Shao-Shun

2011-08-01

217

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. PMID:21243402

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

2013-01-01

218

Antimalarial efficacy of dynamic compound of plumbagin chemical constituent from Plumbago zeylanica Linn (Plumbaginaceae) against the malarial vector Anopheles stephensi Liston (Diptera: Culicidae).  

PubMed

In the present investigation, the effective root compound of plumbagin of Plumbago zeylanica (Plumbaginaceae) was evaluated for chemical constituent and antimalarial effect against the fourth instar larvae of Anopheles stephensi Liston (Diptera). In the chromatographic analyses of root compound with Rf value of 0.788 and NMR analyses also revealed that the effective compound contain naphthoquinone plumbagin were identified as the major chemical constituent. Larval mortality was observed after 3 h of exposure period. The plumbagin compound showed remarkable larvicidal activity against A. stephensi (LC50 32.65 and LC9072.27 ppm). Histopathological effects of compound was observed in the treated larvae. Based on the results, the plumbagin compound of P. zeylanica can be considered as a new source of natural larvicide for the control of malarial vector. PMID:25028206

Pradeepa, Venkatraman; Sathish-Narayanan, Subbiah; Kirubakaran, Suyambulingam Arunachalam; Senthil-Nathan, Sengottayan

2014-08-01

219

Quinone-enhanced sonochemical production of nitric oxide from s-nitrosoglutathione  

PubMed Central

Sonolysis at 75 kHz of argon- and air-saturated aqueous solutions at pH 7.4 containing s-nitrosogluthathione (GSNO) enhances the production rate of nitric oxide (NO). The quinones, anthraquinone-2-sulfonate (AQ2S) and anthraquinone-2,7-disulfonate (AQ27S) further enhance the NO production over that produced in quinone-depleted sonicated solutions. In contrast, the hydrophobic quinones juglone (JQ) and 1,4-naphthoquinone (NQ) inhibit ultrasound-induced NO detection as compared to quinone-depleted solutions. Larger sonolytical decomposition of the hydrophobic quinones NQ and JQ, as compared to AQ2S and AQ27S, is detected which correlates with a larger production of pyrolysis-derived carbon-centered radicals. Reaction of those radicals with NO could explain NQ and JQ inhibition. This work suggests that sulfonated quinones could be used to enhance NO release from GSNO in tissues undergoing ultrasound irradiation. PMID:18595761

Alegría, Antonio E.; Dejesús-Andino, Francisco J.; Sanchez-Cruz, Pedro

2008-01-01

220

REGIOSELECTIVE MULTICOMPONENT DOMINO REACTIONS PROVIDING RAPID AND EFFICIENT ROUTES TO FUSED ACRIDINES  

PubMed Central

Regioselective three-component reactions of aromatic aldehydes with indazol-5-amine and 2-hydroxy-1,4-naphthoquinone in HOAc under microwave irradiation have been developed. In this one-pot reaction, a series of new pyrazole-fused benzo[h]acridine derivatives with 1,2-diketone unit were synthesized with high chemical yields. The resulting pyrazole-fused acridines were employed to further react with aldehydes and ammonium acetate to give polycyclic oxazole-fused pyrazolo[3,4-j]acridines. The present green synthesis shows several advantages including operational simplicity and fast reaction rates, which makes it a useful and attractive process of library generation for drug discovery. PMID:25364095

Zhang, Jin-Peng; Fan, Wei; Ding, Jie; Jiang, Bo; Tu, Shu-Jiang; Li, Guigen

2014-01-01

221

Naphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2/ARE pathway  

SciTech Connect

Highlights: •Naphthazarin activates the Nrf2/ARE pathway. •Naphthazarin induces Nrf2-driven genes in neurons and astrocytes. •Naphthazarin protects neurons against excitotoxicity. -- Abstract: Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. We previously screened several natural phytochemicals and identified plumbagin as a novel activator of the Nrf2/ARE pathway that can protect neurons against ischemic injury. Here we extended our studies to natural and synthetic derivatives of plumbagin. We found that 5,8-dimethoxy-1,4-naphthoquinone (naphthazarin) is a potent activator of the Nrf2/ARE pathway, up-regulates the expression of Nrf2-driven genes in primary neuronal and glial cultures, and protects neurons against glutamate-induced excitotoxicity.

Son, Tae Gen; Kawamoto, Elisa M.; Yu, Qian-Sheng; Greig, Nigel H. [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States)] [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States); Mattson, Mark P. [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States) [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States); Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD (United States); Camandola, Simonetta, E-mail: camandolasi@mail.nih.gov [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States)] [Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd., Baltimore, MD 21224 (United States)

2013-04-19

222

Onosma L.: A review of phytochemistry and ethnopharmacology  

PubMed Central

The genus Onosma L. (Boraginaceae) includes about 150 species distributed world-wide in which only about 75 plants has been described for its morphology and less than 10 plants for their chemical constituents and clinical potential. The phytochemical reports of this genus revels that it comprise mainly aliphatic ketones, lipids, naphthazarins, alkaloids, phenolic compounds, naphthoquinones, flavones while most important are shikonins and onosmins. The plants are traditionally used as laxative, anthelmintic and for alexipharmic effects. The plants are also equally use in eye, blood diseases, bronchitis, abdominal pain, stangury, thirst, itch, lecoderma, fever, wounds, burns, piles and urinary calculi. The flowers of various plants are prescribed as stimulants, cardiotonic, in body swelling while leaves are used as purgative and in cutaneous eruptions. The roots are used for coloring food stuffs, oils and dying wool and in medicinal preparations. This review emphasizes the distribution, morphology, phytochemical constituents, ethnopharmacology, which may help in future research. PMID:24347922

Kumar, Neeraj; Kumar, Rajnish; Kishore, Kamal

2013-01-01

223

Plumbagin inhibits prostate cancer development in TRAMP mice via targeting PKC?, Stat3 and neuroendocrine markers.  

PubMed

Plumbagin (PL), 5-hydroxy-2-methyl-1,4-naphthoquinone, is a quinoid constituent isolated from the roots of the medicinal plant Plumbago zeylanica L. (also known as chitrak). PL has also been found in Juglans regia (English Walnut), Juglans cinerea (whitenut) and Juglans nigra (blacknut). The roots of P. zeylanica have been used in Indian and Chinese systems of medicine for more than 2500 years for the treatment of various types of ailments. We were the first to report that PL inhibits the growth and invasion of hormone refractory prostate cancer (PCa) cells [Aziz,M.H. et al. (2008) Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res., 68, 9024-9032.]. Now, we present that PL inhibits in vivo PCa development in the transgenic adenocarcinoma of mouse prostate (TRAMP). PL treatment (2 mg/kg body weight i.p. in 0.2 ml phosphate-buffered saline, 5 days a week) to FVB-TRAMP resulted in a significant (P < 0.01) decrease in prostate tumor size and urogenital apparatus weights at 13 and 20 weeks. Histopathological analysis revealed that PL treatment inhibited progression of prostatic intraepithelial neoplasia (PIN) to poorly differentiated carcinoma (PDC). No animal exhibited diffuse tumor formation in PL-treated group at 13 weeks, whereas 75% of the vehicle-treated mice elicited diffuse PIN and large PDC at this stage. At 20 weeks, 25% of the PL-treated animals demonstrated diffuse PIN and 75% developed small PDC, whereas 100% of the vehicle-treated mice showed large PDC. PL treatment inhibited expression of protein kinase C epsilon (PKC?), signal transducers and activators of transcription 3 phosphorylation, proliferating cell nuclear antigen and neuroendocrine markers (synaptophysin and chromogranin-A) in excised prostate tumor tissues. Taken together, these results further suggest PL could be a novel chemopreventive agent against PCa. PMID:22976928

Hafeez, Bilal Bin; Zhong, Weixiong; Mustafa, Ala; Fischer, Joseph W; Witkowsky, Olya; Verma, Ajit K

2012-12-01

224

MOF with hydroxynaphthoquinone as organic linker: Molecular structure of [Zn(Chlorolawsone)2(H2O)2] and thermogravimetric studies  

NASA Astrophysics Data System (ADS)

Zinc complexes as MOF with hydroxynaphthoquinone as organic linkers are synthesized and characterized. The complexes Zn-1; [Zn(lawsone)2(H2O)2]?3H2O and Zn-2; [Zn(chlorolawsone)2(H2O)2]?H2O, where lawsone is 2-hydroxy-1,4-naphthoquinone and chlorolawsone is 3-chloro-2-hydroxy-1,4-naphthoquinone, serve as hosts for adsorbed water molecules. ?Cdbnd O shows shift towards lower frequencies ˜25 cm-1 in Zn-1 and ˜35 cm-1 in Zn-2 in FTIR spectra. 1H NMR shows upfield shift in Zn-1 and downfield shift in Zn-2 to the benzenoid ring protons. Bathochromic shift has been observed to the charge transfer band in UV-visible spectra of both complexes. The mass loss of adsorbed water molecules have been observed <100 °C in thermogravimetric (TG) studies. Three adsorbed water molecules are present in Zn-1, while one in Zn-2. X-ray diffraction studies of Zn-2 show, distorted octahedral geometry around Zn(II). The two chlorolawsone ligands are in plane with the metal, while water molecules are trans to this plane. Formation of MOF has been observed in the synthesis of Zn-2 with chlorolawsone as organic linkers. The structure is stabilized by Osbnd H⋯O, Csbnd H⋯O hydrogen bonding H-bonding along with Cl⋯? interactions to form a beautiful MOF architecture. Zn(II) atoms along with organic ligand form a tetramer via Osbnd H?O interactions. The shortest Zn⋯Zn distance is 5.04 Å.

Salunke-Gawali, Sunita; Kathawate, Laxmi; Puranik, Vedavati G.

2012-08-01

225

Modeling Binding Kinetics at the QA Site in Bacterial Reaction Centers†  

PubMed Central

Bacterial reaction centers (RCs) catalyze a series of electron-transfer reactions reducing a neutral quinone to a bound, anionic semiquinone. The dissociation constants and association rates of 13 tailless neutral and anionic benzo- and naphthoquinones for the QA site were measured and compared. The Kd values for these quinones range from 0.08 to 90 ?M. For the eight neutral quinones, including duroquinone (DQ) and 2,3-dimethoxy-5-methyl-1,4-benzoquinone (UQ0), the quinone concentration and solvent viscosity dependence of the association rate indicate a second-order rate-determining step. The association rate constants (kon) range from 105 to 107 M?1 s?1. Association and dissociation rate constants were determined at pH values above the hydroxyl pKa for five hydroxyl naphthoquinones. These negatively charged compounds are competitive inhibitors for the QA site. While the neutral quinones reach equilibrium in milliseconds, anionic hydroxyl quinones with similar Kd values take minutes to bind or dissociate. These slow rates are independent of ionic strength, solvent viscosity, and quinone concentration, indicating a first-order rate-limiting step. The anionic semiquinone, formed by forward electron transfer at the QA site, also dissociates slowly. It is not possible to measure the association rate of the unstable semiquinone. However, as the protein creates kinetic barriers for binding and releasing anionic hydroxyl quinones without greatly increasing the affinity relative to neutral quinones, it is suggested that the QA site may do the same for anionic semiquinone. Thus, the slow semiquinone dissociation may not indicate significant thermodynamic stabilization of the reduced species in the QA site. PMID:16101283

Madeo, Jennifer; Gunner, M. R.

2009-01-01

226

Carbonyl reductase provides the enzymatic basis of quinone detoxication in man.  

PubMed

Enzymes catalyzing the two-electron reduction of quinones to hydroquinones are thought to protect the cell against quinone-induced oxidative stress. Using menadione as a substrate, carbonyl reductase, a cytosolic, monomeric oxidoreductase of broad specificity for carbonyl compounds, was found to be the main NADPH-dependent quinone reductase in human liver, whereas DT-diaphorase, the principal two-electron transferring quinone reductase in rat liver, contributed a very minor part to the quinone reductase activity of human liver. Carbonyl reductase from liver was indistinguishable from carbonyl reductase previously isolated from brain (B. Wermuth, J. biol. Chem. 256, 1206 (1981] on the basis of molecular weight, isoelectric point, immunogenicity, substrate specificity and inhibitor sensitivity. The purified enzyme from liver catalyzed the reduction of a great variety of quinones. The best substrates were benzo- and naphthoquinones with short substituents, and the K-region orthoquinones of phenanthrene, benz(a)anthracene, pyrene and benzo(a)pyrene. A long hydrophobic side chain in the 3-position of the benzo- and naphthoquinones and the vicinity of a bay area or aliphatic substituent (pseudo bay area) to the oxo groups of the polycyclic compounds decreased or abolished the ability of the quinone to serve as a substrate. Non-k-region orthoquinones of polycyclic aromatic hydrocarbons were more slowly reduced than the corresponding K-region derivatives. The broad specificity of carbonyl reductase for quinones is in keeping with a role of the enzyme as a general quinone reductase in the catabolism of these compounds. PMID:3083821

Wermuth, B; Platts, K L; Seidel, A; Oesch, F

1986-04-15

227

Comparison of the cytotoxic activities of naturally occurring hydroxyanthraquinones and hydroxynaphthoquinones.  

PubMed

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) Pauls. (Boraginaceae). The cytotoxicity of the anthraquinone and naphthoquinone derivatives on P-gp-underexpressing HCT 116 cells and P-gp-overexpressing Hep G2 cells was examined by MTT assay. Among the anthraquinone derivatives, compounds 3-5 which had OH, CH(2)OH and COOH substituent groups on the anthraquinone skeletons, respectively, showed potent growth inhibitory activities against both types of cancer cells (IC(50) values: 5.7+/-0.9 to 13.0+/-0.7 microM in the case of HCT 116 cells and 5.2+/-0.7 to 12.3+/-0.9 microM in the case of Hep G2 cells). All hydroxynaphthoquinone derivatives isolated in this study exhibited extremely potent growth inhibitory activities against both types of cancer cells (IC(50) values: 0.3+/-0.09 to 0.46+/-1.0 microM in the case of HCT 116 cells and 0.22+/-0.03 to 0.59+/-0.06 microM in the case of Hep G2 cells) as well as shikonin 10 (IC(50) values: 0.32+/-0.02 microM in the case of HCT 116 cells and 0.24+/-0.03 microM in the case of Hep G2 cells). PMID:17949858

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

2008-06-01

228

Polycyclic aromatic hydrocarbons and their quinones modulate the metabolic profile and induce DNA damage in human alveolar and bronchiolar cells.  

PubMed

The release of particulate pollutants into the air through burning of coal, crude oil, diesel, coal tar, etc. raises concerns of potential health hazards to the exposed human population. Polycyclic aromatic hydrocarbons (PAHs) are major toxic constituents of particulate matter (PM), which upon ingestion get metabolized to even more toxic metabolites such as quinones. The PAHs levels were assessed in both respirable particulate matter (RSPM, <10?M size) and suspended particulate matter (SPM, >10?M size) of urban ambient air (UAA) and that of major contributors viz. diesel exhaust particles (DEPs) and coal tar combustions emissions (CTCE). Seven US Environmental Protection Agency (USEPA) prioritized PAHs in RSPM and 10 in SPM were detected in UAA. Ten and 15 prioritized PAHs, respectively, were also detected in diesel exhaust particles (DEP) and coal tar combustion emission (CTCE) evidencing their release in the air. These PM associated PAHs for UAA, DEP and CTCE showed significant increase (p<0.05) in mutagenicity and mammalian genotoxicity in the order CTCE>DEP>UAA. Human lung alveolar (A549) and bronchiolar (BEAS-2B) cells when treated with PAH-metabolites viz. 1,4-benzoquinone (1,4-BQ), hydroquinone (HQ), 1,2-naphthoquinone (1,2-NQ), 1,4-naphthoquinone (1,4-NQ) and 9,10-phenanthroquinone (9,10-PQ) showed metabolic modulation in these cell lines with significant depletion of principal cellular metabolites viz. NADP, uracil, asparagines, glutamine, and histidine and accumulation of di-methyl amine and beta-hydroxybutyrate, identified using (1)H NMR spectroscopy. These results suggest that PAH-quinones induce genotoxic effects by modulating the metabolic machinery inside the cells by a combined effect of oxidative stress and energy depletion. Our data for metabolic profiling of human lung cells could also help in understanding the mechanism of toxicity of other xenobiotics. PMID:23735462

Gurbani, Deepak; Bharti, Santosh Kumar; Kumar, Ashutosh; Pandey, Alok K; Ana, Godson R E E; Verma, Ambrish; Khan, Altaf Husain; Patel, Devendra K; Mudiam, M K R; Jain, Swatantra K; Roy, Raja; Dhawan, Alok

2013-08-01

229

Plumbagin inhibits prostate cancer development in TRAMP mice via targeting PKC?, Stat3 and neuroendocrine markers  

PubMed Central

Plumbagin (PL), 5-hydroxy-2-methyl-1,4-naphthoquinone, is a quinoid constituent isolated from the roots of the medicinal plant Plumbago zeylanica L. (also known as chitrak). PL has also been found in Juglans regia (English Walnut), Juglans cinerea (whitenut) and Juglans nigra (blacknut). The roots of P. zeylanica have been used in Indian and Chinese systems of medicine for more than 2500 years for the treatment of various types of ailments. We were the first to report that PL inhibits the growth and invasion of hormone refractory prostate cancer (PCa) cells [Aziz,M.H. et al. (2008) Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res., 68, 9024–9032.]. Now, we present that PL inhibits in vivo PCa development in the transgenic adenocarcinoma of mouse prostate (TRAMP). PL treatment (2mg/kg body weight i.p. in 0.2ml phosphate-buffered saline, 5 days a week) to FVB–TRAMP resulted in a significant (P < 0.01) decrease in prostate tumor size and urogenital apparatus weights at 13 and 20 weeks. Histopathological analysis revealed that PL treatment inhibited progression of prostatic intraepithelial neoplasia (PIN) to poorly differentiated carcinoma (PDC). No animal exhibited diffuse tumor formation in PL-treated group at 13 weeks, whereas 75% of the vehicle-treated mice elicited diffuse PIN and large PDC at this stage. At 20 weeks, 25% of the PL-treated animals demonstrated diffuse PIN and 75% developed small PDC, whereas 100% of the vehicle-treated mice showed large PDC. PL treatment inhibited expression of protein kinase C epsilon (PKC?), signal transducers and activators of transcription 3 phosphorylation, proliferating cell nuclear antigen and neuroendocrine markers (synaptophysin and chromogranin-A) in excised prostate tumor tissues. Taken together, these results further suggest PL could be a novel chemopreventive agent against PCa. PMID:22976928

Hafeez, Bilal Bin

2012-01-01

230

Time-resolved visible and infrared difference spectroscopy for the study of photosystem I with different quinones incorporated into the A1 binding site.  

PubMed

Room (298K) and low (77K) temperature time-resolved visible and infrared difference spectroscopy has been used to study photosystem I particles with phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone), menadione (2-methyl-1,4-naphthoquinone) and plastoquinone 9 (2,3-dimethyl-5-prenyl-l,4-benzoquinone), incorporated into the A1 binding site. Concentrated samples in short path-length (~5?m) sample cells are typically used in FTIR experiments. Measurements were undertaken using standard "dilute" samples at 298K, and concentrated (~5×) samples at both 298 and 77K. No concentration induced alterations in the flash-induced absorption changes were observed. Concentrated samples in short path-length cells form a transparent film at 77K, and could therefore be studied spectroscopically at 77K without addition of a cryoprotectant. At 298K, for photosystem I with plastoquinone 9/menadione/phylloquinone incorporated, P700(+)FA/B(-) radical pair recombination is characterized by a time constant of 3/14/80ms, and forward electron transfer from A1A(-) to Fx by a time constant of 211/3.1/0.309?s, respectively. At 77K, for concentrated photosystem I with menadione/phylloquinone incorporated, P700(+)A1(-) radical pair recombination is characterized by a time constant of 240/340?s, with this process occurring in 58/39% of the PSI particles, respectively. The origin of these differences is discussed. Marcus electron transfer theory in combination with kinetic modeling is used to simulate the observed electron transfer time constants at 298K. This simulation allows an estimate of the redox potential for the different quinones in the A1 binding site. PMID:25534606

Makita, Hiroki; Zhao, Nan; Hastings, Gary

2015-03-01

231

Anti-Tumor Effects of Novel 5-O-Acyl Plumbagins Based on the Inhibition of Mammalian DNA Replicative Polymerase Activity  

PubMed Central

We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase ? (pol ?). In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol ? and human pol ?. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol ?, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50?=?2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol ? inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin. PMID:24520419

Kawamura, Moe; Kuriyama, Isoko; Maruo, Sayako; Kuramochi, Kouji; Tsubaki, Kazunori; Yoshida, Hiromi; Mizushina, Yoshiyuki

2014-01-01

232

Synthesis, characterization and molecular structures of homologated analogs of 2-bromo-3-(n-alkylamino)-1,4-napthoquinone  

NASA Astrophysics Data System (ADS)

Four analogues of 2-bromo-3-(n-alkylamino)-1,4-napthoquinone (where n-alkyl is methyl in L-1Br, ethyl in L-2Br, propyl in L-3Br and butyl in L-4Br) are synthesized and characterized. A reaction mechanism is proposed for the formation of L-1Br to L-4Br from the starting material 2,3-dibromo-1,4-naphthoquinone. The ?NH frequency in the FT-IR spectra is affected by the intramolecular hydrogen bonding in L-1Br to L-4Br and is observed ˜3267 cm-1 in L-2Br. A shift of ˜25 cm-1 is observed in the ?CBr frequency in all the compounds as compared to 2,3-dibromo-1,4-naphthoquinone (627 cm-1). A broad charge transfer band is observed between 400 and 600 nm in the UV-Vis spectra, which imparts red colour to all the compounds. Molecular structures of L-2Br and L-3Br were studied by single crystal X-ray diffraction studies. Molecules of L-2Br crystallize in Pca21, whereas the molecule L-3Br crystallizes in the P-1 space group. Molecules of L-2Br forms a polymeric chain through NH⋯O interaction and forms beautiful butterfly like arrangement of molecules when viewed down the 'a' axis. Ladder like polymeric chain of molecules is observed in L-3Br via CH⋯O and NH⋯O interactions. Every alternating neighbouring chains of L-3Br, show ?-? stacking interactions between the quinonoid rings of the molecules, however this interaction is not observed in L-2Br.

Salunke-Gawali, Sunita; Pawar, Omkar; Nikalje, Milind; Patil, Rishikesh; Weyhermüller, Thomas; Puranik, Vedavati G.; Badireenath Konkimalla, V.

2014-01-01

233

Chemoprevention of skin cancer: effect of Lawsonia inermis L. (Henna) leaf powder and its pigment artifact, lawsone in the Epstein- Barr virus early antigen activation assay and in two-stage mouse skin carcinogenesis models.  

PubMed

In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy- 1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis. PMID:23848207

Kapadia, Govind J; Rao, G Subba; Sridhar, Rajagopalan; Ichiishi, Eiichiro; Takasaki, Midori; Suzuki, Nobutaka; Konoshima, Takao; Iida, Akira; Tokuda, Harukuni

2013-12-01

234

Vibrational spectroscopy of photosystem I.  

PubMed

Fourier transform infrared difference spectroscopy (FTIR DS) has been widely used to study the structural details of electron transfer cofactors (and their binding sites) in many types of photosynthetic protein complexes. This review focuses in particular on work that has been done to investigate the A?cofactor in photosystem I photosynthetic reaction centers. A review of this subject area last appeared in 2006 [1], so only work undertaken since then will be covered here. Following light excitation of intact photosystem I particles the P700?A?(1) secondary radical pair state is formed within 100ps. This state decays within 300ns at room temperature, or 300?s at 77K. Given the short-lived nature of this state, it is not easily studied using "static" photo-accumulation FTIR difference techniques at either temperature. Time-resolved techniques are required. This article focuses on the use of time-resolved step-scan FTIR DS for the study of the P700?A?(1) state in intact photosystem I. Up until now, only our group has undertaken studies in this area. So, in this article, recent work undertaken in our lab is described, where we have used low-temperature (77K), microsecond time-resolved step-scan FTIR DS to study the P700?A?(1) state in photosystem I. In photosystem I a phylloquinone molecule occupies the A?binding site. However, different quinones can be incorporated into the A1 binding site, and here work is described for photosystem I particles with plastoquinone-9, 2-phytyl naphthoquinone and 2-methyl naphthoquinone incorporated into the A?binding site. Studies in which ¹?O isotope labeled phylloquinone has been incorporated into the A1 binding site are also discussed. To fully characterize PSI particles with different quinones incorporated into the A1 binding site nanosecond to millisecond visible absorption spectroscopy has been shown to be of considerable value, especially so when undertaken using identical samples under identical conditions to that used in time-resolved step-scan FTIR measurements. In this article the latest work that has been undertaken using both visible and infrared time resolved spectroscopies on the same sample will be described. Finally, vibrational spectroscopic data that has been obtained for phylloquinone in the A1 binding site in photosystem I is compared to corresponding data for ubiquinone in the QA binding site in purple bacterial reaction centers. This article is part of a Special Issue entitled: Vibrational spectroscopies and bioenergetic systems. PMID:25086273

Hastings, Gary

2015-01-01

235

Kinetic studies of electron transfer from Q(A) to Q(B) in the photosynthetic reaction center protein  

NASA Astrophysics Data System (ADS)

Reaction center (RC) function and electron transfer kinetics were measured following changes in the protein environment at the QB site by mutation and changes in the QA- energy level by quinone exchange. A mutant with M220-M261 from the QA site substituted for L193-1,227 in the QB site in Rb. capsulatus RCs were studied. Despite the huge change in the QB pocket, secondary quinone function still can be reconstituted. The UQ4 dissociation constant for the QB site in the mutant is only 2 times larger than in the wild type RCs. The electron transfer rate of the mutant from QA- to QB is 14/s, 3 orders of magnitude slower than the wild type RCs. The equilibrium constant between QA-Q B and QAQB- is bigger than 200 in the mutant compared to 10 in the wild type, showing a large stabilization of QB-. Electron transfer from P+QA-QB to P+QAQB- was measured in R-26 Rb. sphaeroides RCs where QA was substituted with different naphthoquinones (NQA), QB was ubiquinone (UQB) in all cases. These substitutions change the redox midpoint potential of Q A and therefore change the driving force (?GAB) for electron transfer. The absorption change provides a direct monitor of the electron transfer from NQA- to UQB. The electron transfer rate is heterogeneous. In RCs with 2-methyl-3-phytyl-1,4-naphthoquinone (MQ) substituted at QA, three rates are observed: ?1 ~ 3?s +/- 0.9?s, ?2 = 80 +/- 20?s, and ? 3 = 0.4 +/- 0.2ms at pH=8 and 22°C. Analysis of the time correlated spectra shows that the changes at ?l are mostly due to electron transfer, electron transfer and charge compensation are mixed in ? 2, while little or no electron transfer occurs at ?3 in MQAUQB RCs. The activation energy for electron transfer is AG=3.5 kcal/Mol for both ?l and ?2. With different NQs at QA, ?l is found to be free energy dependent with a reaction reorganization energy of 850 +/- 100 meV. The slower phase ?2 is free energy independent.

Li, Jiali

1999-11-01

236

(+/-)-catechin: chemical weapon, antioxidant, or stress regulator?  

PubMed

(+/-)-Catechin is a flavan-3-ol that occurs in the organs of many plant species, especially fruits. Health-beneficial effects have been studied extensively, and notable toxic effects have not been found. In contrast, (+/-)-catechin has been implicated as a 'chemical weapon' that is exuded by the roots of Centaurea stoebe, an invasive knapweed of northern America. Recently, this hypothesis has been rejected based on (+/-)-catechin's low phytotoxicity, instability at pH levels higher than 5, and poor recovery from soil. In the current study, (+/-)-catechin did not inhibit the development of white and black mustard to an extent that was comparable to the highly phytotoxic juglone, a naphthoquinone that is allegedly responsible for the allelopathy of the walnut tree. At high stress levels, caused by sub-lethal methanol concentrations in the medium, and a 12 h photoperiod, (+/-)-catechin even attenuated growth retardation. A similar effect was observed when (+/-)-catechin was assayed for brine shrimp mortality. Higher concentrations reduced the mortality caused by toxic concentrations of methanol. Further, when (+/-)-catechin was tested in variants of the deoxyribose degradation assay, it was an efficient scavenger of reactive oxygen species (ROS) when they were present in higher concentrations. This antioxidant effect was enhanced when iron was chelated directly by (+/-)-catechin. Conversely, if iron was chelated to EDTA, pro-oxidative effects were demonstrated at higher concentrations; in this case (+/-)-catechin reduced molecular oxygen and iron to reagents required by the Fenton reaction to produce hydroxyl radicals. A comparison of cyclic voltammograms of (+/-)-catechin with the phytotoxic naphthoquinone juglone indicated similar redox-cycling properties for both compounds although juglone required lower electrochemical potentials to enter redox reactions. In buffer solutions, (+/-)-catechin remained stable at pH 3.6 (vacuole) and decomposed at pH 7.4 (cytoplasm) after 24 h. The results support the recent rejection of the hypothesis that (+/-)-catechin may serve as a 'chemical weapon' for invasive plants. Instead, accumulation and exudation of (+/-)-catechin may help plants survive periods of stress. PMID:19701725

Chobot, Vladimir; Huber, Christoph; Trettenhahn, Guenter; Hadacek, Franz

2009-08-01

237

A quantitative high-throughput in vitro splicing assay identifies inhibitors of spliceosome catalysis.  

PubMed

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. PMID:22252314

Berg, Michael G; Wan, Lili; Younis, Ihab; Diem, Michael D; Soo, Michael; Wang, Congli; Dreyfuss, Gideon

2012-04-01

238

2-Phenylaminonaphthoquinones and related compounds: synthesis, trypanocidal and cytotoxic activities.  

PubMed

A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds. PMID:25127463

Sieveking, Ivan; Thomas, Pablo; Estévez, Juan C; Quiñones, Natalia; Cuéllar, Mauricio A; Villena, Juan; Espinosa-Bustos, Christian; Fierro, Angélica; Tapia, Ricardo A; Maya, Juan D; López-Muñoz, Rodrigo; Cassels, Bruce K; Estévez, Ramon J; Salas, Cristian O

2014-09-01

239

?-Lapachone activity in synergy with conventional antimicrobials against methicillin resistant Staphylococcus aureus strains.  

PubMed

The aim of this study was to evaluate the antimicrobial activity of lapachol, ?-lapachone, ?-lapachone and six antimicrobials (ampicillin, amoxicillin/clavulanic acid, cefoxitin, gentamicin, ciprofloxacin and meropenem) against twelve strains of Staphylococcus aureus from which resistance phenotypes were previously determined by the disk diffusion method. Five S. aureus strains (LFBM 01, LFBM 26, LFBM 28, LFBM 31 and LFBM 33) showed resistance to all antimicrobial agents tested and were selected for the study of the interaction between ?-lapachone and antimicrobial agents, busing checkerboard method. The criteria used to evaluate the synergistic activity were defined by the Fractional Inhibitory Concentration Index (FICI). Among the naphthoquinones, ?-lapachone was the most effective against S. aureus strains. FICI values ranged from 0.07 to 0.5, suggesting a synergistic interaction against multidrug resistant S. aureus (MRSA) strains. An additive effect was observed with the combination ?-lapachone/ciprofloxacin against the LFBM 33 strain. The combination of ?-lapachone with cefoxitin showed no added benefit against LFBM 31 and LFBM 33 strains. This study demonstrated that, in general, ?-lapachone combined with beta lactams antimicrobials, fluoroquinolones and carbapenems acts synergistically inhibiting MRSA strains. PMID:24035227

Macedo, L; Fernandes, T; Silveira, L; Mesquita, A; Franchitti, A A; Ximenes, E A

2013-12-15

240

Modulatory effects of Tabebuia impetiginosa (Lamiales, Bignoniaceae) on doxorubicin-induced somatic mutation and recombination in Drosophila melanogaster.  

PubMed

The wing Somatic Mutation and Recombination Test (SMART) in D. melanogaster was used to study genotoxicity of the medicinal plant Tabebuia impetiginosa. Lapachol (naphthoquinone) and ?-lapachone (quinone) are the two main chemical constituents of T. impetiginosa. These compounds have several biological properties. They induce apoptosis by generating oxygen-reactive species, thereby inhibiting topoisomerases (I and II) or inducing other enzymes dependent on NAD(P)H:quinone oxidoreductase 1, thus affecting cell cycle checkpoints. The SMART was used in the standard (ST) version, which has normal levels of cytochrome P450 (CYP) enzymes, to check the direct action of this compound, and in the high bioactivation (HB) version, which has a high constitutive level of CYP enzymes, to check for indirect action in three different T. impetiginosa concentrations (10%, 20% or 40% w/w). It was observed that T. impetiginosa alone did not modify the spontaneous frequencies of mutant spots in either cross. The negative results observed prompted us to study this phytotherapeuticum in association with the reference mutagen doxorubicin (DXR). In co-treated series, T. impetiginosa was toxic in both crosses at higher concentration, whereas in the HB cross, it induced a considerable potentiating effect (from ~24.0 to ~95.0%) on DXR genotoxity. Therefore, further research is needed to determine the possible risks associated with the exposure of living organisms to this complex mixture. PMID:21637695

de Sousa, Neila C; de Rezende, Alexandre A A; da Silva, Regildo M G; Guterres, Zaira R; Graf, Ulrich; Kerr, Warwick E; Spanó, Mário A

2009-04-01

241

Structural elucidation of the metabolites of lapachol in rats by liquid chromatography-tandem mass spectrometry.  

PubMed

Lapachol is a natural naphthoquinone compound derived from Bignoniaceae (Tabebuia sp.) that possesses a range of significant biological activities. Nine phase I and four phase II metabolites of lapachol in rat bile were firstly elucidated and identified using a sensitive LC-ESI-MS(n) method. The molecular structures of the metabolites have been presented on the basis of the characteristics of their precursor and product ions, as well as their fragmentation mechanisms and chromatographic retention times. The results indicated that the phase I metabolites were predominantly biotransformed by the hydroxylation, semiquinone hydrogenation at the oxygen position or a side chain rearrangement. The phase II metabolites were identified as the glucuronidated conjugates which showed a characteristic neutral loss of 176Da. Based on the results of this research, we have proposed the metabolic pathways for lapachol in rats. This work has provided novel information for the in vivo lapachol metabolism which could be used to develop a novel drug candidate, as well as a better understanding of the safety and efficacy of the drug. PMID:24316523

Bai, Lu; Han, Ying; Yao, Jinfeng; Li, Xiaorong; Li, Yuhang; Xu, Pinxiang; Xue, Ming

2014-01-01

242

Dissimilar effects of ?-lapachone- and hydroxyurea-induced DNA replication stress in root meristem cells of Allium cepa.  

PubMed

Two anticancer drugs, ?-lapachone (?-lap, a naphthoquinone) and hydroxyurea (HU, an inhibitor of ribonucleotide reductase), differently affect nuclear morphology and cell cycle control mechanisms in root meristem cells of Allium cepa. The 18 h treatment with 100 ?M ?-lap results in a lowered number of M-phase cells, increased occurrence of mitotic abnormalities, including over-condensation of chromosomes, their enhanced stickiness, formation of anaphase bridges, micronucleation and reduced mitotic spindles. Following prolonged incubations using high doses of ?-lap, cell nuclei reveal dark-red fluorescence evenly distributed in chromatin surrounding the unstained regions of nucleoli. Both drugs generate H2O2 and induce DNA double strand breaks, which is correlated with ?-phoshorylation of H2AX histones. However, the extent of H2AX phosphorylation (including the frequency of ?-H2AX foci and the relative number cells creating phospho-H2AX domains) is considerably reduced in root meristem cells treated jointly with the ?-lap/HU mixture. Furthermore, various effects of caffeine (an inhibitor of ATM/ATR cell cycle checkpoint kinases) on ?-lap- and HU-induced ?-phoshorylation of H2AX histones and the protective activity of HU against ?-lap suggest that their genotoxic activities are largely dissimilar. ?-Lap treatment results in the induction of apoptosis-like programmed cell death, while HU treatment leads to cell adaptation to replication stress and promotion of abnormal nuclear divisions with biphasic interphase/mitotic states of chromatin condensation. PMID:24184448

Zabka, Aneta; Trzaskoma, Pawe?; Maszewski, Janusz

2013-12-01

243

Chemical constituents from Aphanamixis grandifolia.  

PubMed

(23E)-25-Methylcycloart-23-en-3?-ol (1), a cycloartane-type triterpenoid featuring an unusual skeleton of 31 carbon atoms, (17E)-cycloart-17,26-dien-3?-ol (2), a new cycloartane-type triterpenoid, and the other two new compounds 4R-hydroxy-4-(9S-hydroxy-12-methylhexan-6-yl)-3-methylcyclopent-2-enone (6) and 7-hydroxy-5-(2'-hydroxy-4',5'-dimethoxyphenyl)-2-methoxy-6-methyl-1,4-naphthoquinone (7), together with three known cycloart-3?-ol triterpenoids (3-5) were isolated from aerial parts of Aphanamixis grandifolia. Their structures were elucidated by spectroscopic analysis, and that of 1 was confirmed by single-crystal X-ray diffraction. The absolute configuration of two carbon stereocenters of compound 6 was determined to be 4R,9S by means of circular dichroism (CD) and auxiliary chiral ?-methoxy-?-(trifluoromethyl)phenylacetic acid (MTPA) derivatives, respectively. The compound 3 exhibited significant cytotoxicities against HL-60, Hep G2 and HeLa, and compounds 1, 2, 5, 6 and 7 exhibited modest cytotoxicities. No activity of compound 4 could be due to the absence of the hydroxyl group at C-24. PMID:21048332

Liu, Quan; Chen, Chao-Jun; Shi, Xiang; Zhang, Li; Chen, Hui-Juan; Gao, Kun

2010-11-01

244

Spectrophotometric and spectrofluorimetric determination of atomoxetine in pharmaceutical preparations.  

PubMed

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

2011-11-01

245

Microbial fuel cell using anaerobic respiration as an anodic reaction and biomineralized manganese as a cathodic reactant.  

PubMed

We have operated a microbial fuel cell in which glucose was oxidized by Klebsiella pneumoniae in the anodic compartment, and biomineralized manganese oxides, deposited by Leptothrix discophora, were electrochemically reduced in the cathodic compartment. In the anodic compartment, to facilitate the electron transfer from glucose to the graphite electrode, we added a redox mediator, 2-hydroxy-1,4-naphthoquinone. We did not add any redox mediator to the cathodic compartment because the biomineralized manganese oxides were deposited on the surface of a graphite electrode and were reduced directly by electrons from the electrode. We have demonstrated that biomineralized manganese oxides are superiorto oxygen when used as cathodic reactants in microbial fuel cells. The current density delivered by using biomineralized manganese oxides as the cathodic reactant was almost 2 orders of magnitude higher than that delivered using oxygen. Several fuel cells were operated for 500 h, reaching anodic potentials of -441.5 +/- 31 mVscE and cathodic potentials of +384.5 +/- 64 mVscE. When the electrodes were connected by a 50 Ohms resistor, the fuel cell delivered the peak power density of 126.7 +/- 31.5 mW/m2. PMID:16047807

Rhoads, Allison; Beyenal, Haluk; Lewandowski, Zbigniew

2005-06-15

246

Removal of water-insoluble Sudan dyes by Shewanella oneidensis MR-1.  

PubMed

Decolorization of water-insoluble Sudan dyes was studied with Shewanella oneidensis MR-1, which removed 66.8%, 43.4%, 56.0% and 33.7% Sudan I-IV in 104 h, respectively and reduced Sudan I to aniline and 1-amino-2-naphthol. Lactate was identified as the most efficient electron donor for Sudan I reduction. Improved reduction performance was obtained in the presence of higher lactate or biomass concentration. The correlation between specific reduction rate and initial Sudan I concentration could be described with Michaelis-Menten kinetics (V(max)=1.8 mg Sudan I mg cell(-1) h(-1) and K(m)=5.3 mg l(-1)). The addition of anthraquinone-2-sulfonate stimulated the reduction significantly whereas the presence of 2-hydroxy-1,4-naphthoquinone had little enhancing effect. The main azoreductase activity was found with membrane-bound proteins of MR-1 and no reduction occurred when Sudan I was incubated with cell extracts. These data indicated for the first time that Shewanella could reduce solid-phase Sudan dye particles. PMID:22456237

Ji, Qiuyan; Liu, Guangfei; Zhou, Jiti; Wang, Jing; Jin, Ruofei; Lv, Hong

2012-06-01

247

Effects of several quinones on insulin aggregation  

PubMed Central

Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants or food. In this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones and four natural anthraquinone derivatives from rhubarb, a traditional herbal medicine used for treating Alzheimer's disease. Our results demonstrated that all eight quinones show inhibitory effects to different extent on insulin oligomerization, especially for 1,4-benzoquinone and 1,4-naphthoquinone. Significantly attenuated oligomerization, reduced amount of amyloid fibrils and reduced hemolysis levels were found after quinones treatments, indicating quinones may inhibit insulin from forming toxic oligomeric species. The results suggest a potential action of native anthraquinone derivatives in preventing protein misfolding diseases, the quinone skeleton may thus be further explored for designing effective anti-amyloidosis compounds. PMID:25008537

Gong, Hao; He, Zihao; Peng, Anlin; Zhang, Xin; Cheng, Biao; Sun, Yue; Zheng, Ling; Huang, Kun

2014-01-01

248

Cloning and expression of the gene encoding flavodoxin from Desulfovibrio vulgaris (Miyazaki F).  

PubMed

The gene encoding a flavodoxin of Desulfovibrio vulgaris (Miyazaki F) was cloned, and overexpressed in Escherichia coli. A 1.6-kbp DNA fragment, isolated from D. vulgaris (Miyazaki F) by double digestion with SalI and EcoRI, contained the flavodoxin gene and its regulatory region. An expression system for the flavodoxin gene under control of the T7 promoter was constructed in E. coli. The purified protein was soluble and exhibited a characteristic visible absorption spectrum. HPLC analysis of the recombinant flavodoxin revealed the presence of an identical FMN to that found in the native D. vulgaris flavodoxin, and its dissociation constant with FMN was determined to be 0.38 nM. In vitro H2 reduction analysis indicated that the recombinant flavodoxin is active, and its redox potential was determined to be E1 = -434 and E2 = -151 mV using methyl viologen and 2-hydroxy-1,4-naphthoquinone, respectively. Its redox behavior was also examined with the recombinant flavodoxin adsorbed onto a graphite electrode. The mutant, A16E, was also produced, which revealed the feature of a conserved Glu residue at the surface of the molecule. PMID:9562622

Kitamura, M; Sagara, T; Taniguchi, M; Ashida, M; Ezoe, K; Kohno, K; Kojima, S; Ozawa, K; Akutsu, H; Kumagai, I; Nakaya, T

1998-05-01

249

AhR sensing of bacterial pigments regulates antibacterial defence.  

PubMed

The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns. PMID:25119038

Moura-Alves, Pedro; Faé, Kellen; Houthuys, Erica; Dorhoi, Anca; Kreuchwig, Annika; Furkert, Jens; Barison, Nicola; Diehl, Anne; Munder, Antje; Constant, Patricia; Skrahina, Tatsiana; Guhlich-Bornhof, Ute; Klemm, Marion; Koehler, Anne-Britta; Bandermann, Silke; Goosmann, Christian; Mollenkopf, Hans-Joachim; Hurwitz, Robert; Brinkmann, Volker; Fillatreau, Simon; Daffe, Mamadou; Tümmler, Burkhard; Kolbe, Michael; Oschkinat, Hartmut; Krause, Gerd; Kaufmann, Stefan H E

2014-08-28

250

Phytochemistry of the carnivorous sundew genus Drosera (Droseraceae) - future perspectives and ethnopharmacological relevance.  

PubMed

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

2013-10-01

251

Absorption spectrometric and thermodynamic study of charge transfer complexes of menadione (Vitamin K 3) with a series of phenols  

NASA Astrophysics Data System (ADS)

The electron donor-acceptor (EDA) interactions between menadione (i.e., 2-methyl-1,4-naphthoquinone, which is also called 'Vitamin K 3') and a series of phenols (viz., phenol, resorcinol and p-quinol) have been studied in CCl 4 medium. In all the cases, charge transfer (CT) bands have been located. The CT transition energies ( h?CT) of the complexes are found to change systematically with change in the number and position of the -OH groups in the aromatic ring of the phenol moiety. From the trends in the h?CT values, the Hückel parameters ( hÖ and kC-Ö) for the -OH group have been obtained. The CT transition energies are well correlated with the ionisation potentials of the phenols. From an analysis of this variation the electron affinity of Vitamin K 3 has been found to be 2.28 eV. The stoichiometry of the complexes in each case has been found to be 1(menadione):2 (phenol). Formation constants of the complexes have been determined at four different temperatures from which the enthalpies and entropies of formation of the complexes have been estimated.

Pal, Purnendu; Bhattacharya, Sumanta; Mukherjee, Asok K.; Mukherjee, Dulal C.

2005-03-01

252

Vitamin K 3 family members - Part II: Single crystal X-ray structures, temperature-induced packing polymorphism, magneto-structural correlations and probable anti-oncogenic candidature  

NASA Astrophysics Data System (ADS)

Temperature-induced packing polymorphism is observed for vitamin K 3 (menadione, 3-methyl-1,4-naphthoquinone, 1). Form 1a crystallizes at 300 K and 1b at 277 K both in the same space group P2 1/ c. Form 1b contains one molecule per asymmetric unit, performing anisotropy in g-factor viz. g z = 2.0082, g y = 2.0055 and g x = 2.0025, whereas form 1a contains two molecules in its asymmetric unit. Vitamin K 3 family members 2, [2-hydroxy vitamin K 3] and 3, [2-hydroxy-1-oximino vitamin K 3] also perform intrinsic neutral active naphthosemiquinone valence tautomers even in dark having spin concentrations due to hydrogen bonding and aromatic stacking interactions which are compared to vitamin K 3. The significant lateral C-H⋯O and O-H⋯? bifurcated or ?-? ? interactions are discussed for molecular associations and radical formations. X-ray structure of 3 revealed ?-? ? stack dimers as radicals signatured in EPR as triplet with five hyperfine splits [ ?( 14N) = 11.9 G]. The centrosymmetric biradicals in 3 show diamagnetism at high temperature but below 10 K it shows paramagnetism with ?eff as 0.19 B.M. Vitamin K 3 and its family members inhibit biological activities of acid phosphatase ( APase), which are proportional to their spin concentrations. This may relate to their probable anti-oncogenic candidature in future.

Rane, Sandhya; Ahmed, Khursheed; Salunke-Gawali, Sunita; Zaware, Santosh B.; Srinivas, D.; Gonnade, Rajesh; Bhadbhade, Mohan

2008-12-01

253

Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-? aggregation and to exert anticholinesterase and antioxidant effects.  

PubMed

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-? (A?) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by A?. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit. PMID:25259726

Nepovimova, Eugenie; Uliassi, Elisa; Korabecny, Jan; Peña-Altamira, Luis Emiliano; Samez, Sarah; Pesaresi, Alessandro; Garcia, Gregory E; Bartolini, Manuela; Andrisano, Vincenza; Bergamini, Christian; Fato, Romana; Lamba, Doriano; Roberti, Marinella; Kuca, Kamil; Monti, Barbara; Bolognesi, Maria Laura

2014-10-23

254

Simultaneous derivative spectrophotometric determination of thorium and uranium in a micellar medium.  

PubMed

Derivative photometric methods for trace analysis of Th(IV) and UO(2)(II), and their simultaneous determination in mixtures using 5,8-dihydroxy-1,4-naphthoquinone in a micellar medium are reported. Molar absorptivity and Sandell's sensitivity of 1:2 Th(IV) and 1:1 UO(2)(II) complexes at their lambda(max), 614.5 nm and 637.0 nm are, 1.19 x 10(4) 1/mol/cm and 1.12 x 10(4) 1/mol/cm and 1.95 x 10(-2) mug/cm(2) and 2.13 x 10(-2) mug/cm(2) mug/cm(2), respectively. Calibration graph is linear over the range 9.28 x 10(-2)-18.56 mug/ml of Th(IV) and 9.52 x 10(-2)-19.04 mug/ml of UO(2)(II). Though presence of Th(IV) and UO(2)(II) causes interference in each others determination, 9.28 x 10(-1)-9.28 mug/ml Th(IV) and 9.52 x 10(-1)-9.52 mug/ml UO(2)(II) when present together, can be simultaneously determined using derivative spectra. PMID:18965862

Agnihotri, N K; Singh, V K; Singh, H B

1993-12-01

255

The in vitro effects of superoxide, some commercially available antioxidants and red palm oil on sperm motility  

PubMed Central

In this study, two commercially available superoxide scavengers, tetrakis (1-methyl-4-pyridyl) porphyrin (Mn[III]TMPyP) and superoxide dismutase (SOD), as well as red palm oil (RPO), a natural vegetable oil, had been used to investigate their possible in vitro effects against the toxic effects of superoxide (O2·) on human sperm motility. Semen samples were obtained from 12 normozoospermic healthy volunteer donors aged between 19 and 23 years. The O2· donor 2,3-dimetoxyl-1,4-naphthoquinone (DMNQ) (2.5 ?mol L?1–100 ?mol L?1) was added to normozoospermic post-swim-up sperm in the presence or absence of Mn(III)TMPyP (50 ?mol L?1), SOD (50 IU) or RPO (0.1% or 0.5%). Computer-assisted semen analysis was used to analyze various motility parameters. The parameters of interest were percentage of motile cells, progressive motility, rapid cells and static cells. Concentrations of higher than 25 ?mol L?1 DMNQ were detrimental to sperm motility. Mn(III)TMPyP was able to attenuate the effect of O2· on the motility parameters. In vitro addition of SOD and RPO showed harmful effects on sperm motility. PMID:19802000

Aboua, Yapo Guillaume; Plessis, Stefan Stephanus du; Reichgelt, Patricia; Brooks, Nicole

2009-01-01

256

Carvacrol and rosemary essential oil manifest cytotoxic, DNA-protective and pro-apoptotic effect having no effect on DNA repair.  

PubMed

For several thousand years natural products were successfully used to treat a?variety of diseases and to maintain health in humans, but until now it is not fully known what causes these medicinal effects. In our study we assessed the cytotoxic, DNA-protective and pro-apoptotic effect of two frequently occurring natural compounds, carvacrol and rosemary essential oil, on human hepatoma HepG2 cells. In addition we examined the in vitro incision repair activity of liver cell extracts prepared from hepatocytes isolated from Sprague-Dawley (SD) rats fed with water containing carvacrol or rosemary oil. Using conventional and modified single cell gel electrophoresis we proved that incubation of HepG2 cells with selected concentrations of carvacrol and rosemary oil significantly protected cellular DNA against two dangerous oxidative agents, hydrogen peroxide (H2O2) and 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). It is interesting that despite this DNA protection, the addition of both volatiles to the drinking water of SD rats had no effect on incision repair capacity of hepatocyte extracts. In this paper we also showed that carvacrol and rosemary oil can trigger apoptotic cell death pathways in HepG2 cells, which is probably connected with their cytotoxicity. Keywords: carvacrol, rosemary oil, cytotoxicity, comet assay, in vitro BER assay, apoptosis. PMID:25150314

Melusova, M; Slamenova, D; Kozics, K; Jantova, S; Horvathova, E

2014-08-23

257

Interventional Effects of Plumbagin on Experimental Ulcerative Colitis in Mice  

PubMed Central

Plumbagin (1) is a naphthoquinone constituent of plants that have been used in traditional systems of medicine since ancient times. In the present study, the role of 1 was examined on the amelioration of ulcerative colitis, an inflammatory bowel disease that is not curable currently. Plumbagin was tested at a dose of 6-10 mg/kg body weight in acute and chronic disease models. Diseased mice receiving 1 at 8-10 mg/kg demonstrated a significant suppression of disease symptoms in both models. However, body weight loss was not restored in either of the models. Levels of proinflammatory cytokines (TNF-?, IFN-?, and IL-17) were reduced significantly by 1 in mice suffering from chronic disease, while cytokine levels remained unaffected in mice with acute disease. However, the percentage of inflammatory (CD14+/CD16+) monocytes present in peripheral blood was significantly reduced (>three-fold) (p <0.05) in treatment groups relative to controls in the acute model. Histological evaluations exhibited the restoration of goblet cells, crypts, and the submucosa along with a significant reduction in monocyte aggregation in colon sections from mice receiving treatment with 1. Restoration in colon size was also observed in the treatment groups. PMID:23742275

Pile, Justin E.; Navalta, James W.; Davis, Cheryl D.; Sharma, Nilesh C.

2013-01-01

258

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. PMID:12788749

Rau, Jörg; Stolz, Andreas

2003-01-01

259

Effect of quinoid redox mediators on the aerobic decolorization of azo dyes by cells and cell extracts from Escherichia coli.  

PubMed

It is widely accepted that the addition of redox mediators increases the decolorization rates of azo dyes by bacterial strains under anaerobic conditions. However, little information exists about whether quinoid redox mediators can enhance the performance of aerobic azo dye decolorization. In the present study, quinone-mediated decolorization of different azo dyes by whole cells and cell extracts from the Escherichia coli strain CD-2 under aerobic conditions were investigated. The results demonstrated that reduction rates of different azo dyes were greatly increased when quinone compounds were used as redox mediators. Compared with menadione, 2-hydroxy-1,4-naphthoquinone (lawsone) was more effective at aiding azo dye degradation and the optimum concentration for lawsone is 0.1 mM. Strain CD-2 and the anthraquinone were co-immobilized by entrapment in different polymeric matrices. The co-immobilized beads exhibited good catalytic activity for azo dye degradation and kept stable during successive repeated experiments. The mechanism of the quinone-mediated reduction showed that although whole cells incubated with quinones could significantly increase the rate of decolorization of azo dyes, the quinone compounds did not directly promote azoreductase activity. According to the survey, this is the first report to confirm that the addition of quinoid redox mediators to bacteria increased decolorization under aerobic conditions. PMID:25323408

Cui, Daizong; Li, Guofang; Zhao, Dan; Zhao, Min

2014-10-18

260

Cobalt lawsone complexes: searching for new valence tautomers.  

PubMed

Bi-stable molecular systems presenting valence tautomerism are associated with the development of new functional materials, which can be used for applications in organic electric conductors, optoelectronic and molecular magnetic devices. The properties of these materials can be adjusted with slight chemical changes and can be induced by external stimuli. Typical examples of valence tautomer compounds are coordination complexes of Co and o-dioxolene ligands, notably quinone like ones. In the search for a new class of cobalt complexes presenting valence tautomerism we report herein the synthesis and characterization of five new coordination compounds of cobalt and 2-hydroxy-1,4-naphthoquinone (lawsone or shortly Law). Complexes [Co(Law)2(im)2]·C6H5CH3 (1), [Co(Law)2(py)2]·CH3OH (2), [Co(Law)2(phen)]·(C4H8O)2 (3), [Co(Law)2(2,2-bpy)]·C6H5CH3 (4) and [Co(Law)2(2,2-bpy)] (5) were synthesized and fully characterized by X-ray diffraction and EPR techniques in a wide range of temperatures and under illumination. Despite presenting similar molecular and geometry packing of the valence tautomer complexes of cobalt and o-dioxolenes, neither structural nor electronic evidence of valence tautomerism could be found in the Co and lawsone complexes. PMID:23423385

Ribeiro, Marcos A; Lanznaster, Maurício; Silva, Marcos M P; Resende, Jackson A L C; Pinheiro, Maurício V B; Krambrock, Klaus; Stumpf, Humberto O; Pinheiro, Carlos B

2013-04-21

261

Enhanced dechlorination of carbon tetrachloride by Geobacter sulfurreducens in the presence of naturally occurring quinones and ferrihydrite.  

PubMed

The effect of naturally occurring quinones including lawsone (LQ), ubiquinone (UQ), juglone (JQ), and 1,4-naphthoquinone (NQ) on the biotransformation of carbon tetrachloride (CT) in the presence of Geobacter sulfurreducens and ferrihydrite was investigated. AQDS was used as the model compound for comparison. The reductive dissolution of ferrihydrite by G. sulfurreducens was enhanced by AQDS, NQ, and LQ. However, addition of UQ and JQ had little enhancement effect on Fe(II) production. The bioreduction efficiency and rate of ferrihydrite was highly dependent on the natural property and concentration of quinone compounds and the addition of low concentrations of LQ and NQ significantly accelerated the biotransformation rate of CT. The pseudo-first-order rate constants for CT dechlorination (kobsCT) in AQDS-, LQ- and NQ-amended batches were 5.4-5.8, 4.6-7.4 and 2.4-5.8 times, respectively, higher than those in the absence of quinone. A good relationship between kobsCT for CT dechlorination and bioreduction ratio of ferrihydrite was observed, indicating the important role of biogenic Fe(II) in dechlorination of CT under iron-reducing conditions. Spectroscopic analysis showed that AQDS and NQ could be reduced to semiquinones and hydroquinones, while only hydroquinones were generated in LQ-amended batches. PMID:24290294

Doong, Ruey-an; Lee, Chun-chi; Lien, Chia-min

2014-02-01

262

Possible mechanism of superoxide formation through redox cycling of plumbagin in pig heart.  

PubMed

The purpose of this study is to elucidate the possible mechanism of superoxide formation through redox cycling of plumbagin (PLG) in pig heart. Of four 1,4-naphthoquinones tested in this study, PLG was most efficiently reduced in the cytosolic fraction of pig heart. On the other hand, lawsone (LAS) was little reduced. Thus, whether or not PLG and LAS induce the formation of superoxide anion radical in pig heart cytosol was examined, by using the methods of cytochrome c reduction and chemiluminescence. PLG significantly induced the formation of superoxide anion radical, even though LAS had no ability to mediate superoxide formation. PLG was a significant inhibitor for the stereoselective reduction of 4-benzoylpyridine (4-BP) catalyzed by tetrameric carbonyl reductase (TCBR) in pig heart cytosol. Furthermore, PLG was confirmed to competitively inhibit the 4-BP reduction, and the optimal pH for the PLG reduction was around 6.0 similar to that for the 4-BP reduction. These results suggest that PLG mediates superoxide formation through its redox cycling involved in the two-electron reduction catalyzed by TCBR, and induces oxidative stress in pig heart. PMID:22198053

Shimada, Hideaki; Yamaoka, Yusuke; Morita, Reiko; Mizuno, Takayuki; Gotoh, Kousei; Higuchi, Toshiyuki; Shiraishi, Takayuki; Imamura, Yorishige

2012-03-01

263

Synthesis and cytotoxic activity of metallic complexes of lawsone.  

PubMed

In the present study, a series of metallic complexes of the 1,4-naphthoquinone lawsone (2-6) were synthesized and evaluated for potential cytotoxicity in a mouse leukemic macrophagic RAW 264.7 cell line. Cell viability was determined by the MTT assay. Significant growth inhibition was observed for the copper complex (4) with an IC(50) value of 2.5 ?M. This compound was selected for further evaluation of cytotoxic activity on several human cancer cells including HT-29 (human colorectal adenocarcinoma), HepG2 (human hepatocellular carcinoma) and HeLa, (human cervical adenocarcinoma cells). Significant cell viability decrease was also observed in HepG2 cells. The apoptotic potential of this complex was evaluated in these cells. Compound 4 induced apoptosis by a mechanism that involves the activation of caspases 3, 8 and 9 and modulation of apoptotic-related proteins such as Bax, Bad, and p53. These results indicate that metal complexes of lawsone derivatives, in particular compound 4, might be used for the design of new antitumoral agents. PMID:23545136

Oramas-Royo, Sandra; Torrejón, Concepción; Cuadrado, Irene; Hernández-Molina, Rita; Hortelano, Sonsoles; Estévez-Braun, Ana; de Las Heras, Beatriz

2013-05-01

264

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. PMID:21629508

Soeiro, Maria de Nazaré C; de Castro, Solange Lisboa

2011-01-01

265

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. PMID:20187635

Lee, Kuo-Hsiung

2010-01-01

266

5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-Dione Inhibits Vascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor ?  

PubMed Central

As the abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis and vascular restenosis, a candidate drug with antiproliferative properties is needed. We investigated the antiproliferative action and underlying mechanism of a newly synthesized naphthoquinone derivative, 5,8-dimethoxy-2-nonylamino-naphthalene-1,4-dione (2-nonylamino-DMNQ), using VSMCs treated with platelet-derived growth factor (PDGF). 2-Nonylamino-DMNQ inhibited proliferation and cell number of VSMCs induced by PDGF, but not epidermal growth factor (EGF), in a concentration-dependent manner without any cytotoxicity. This derivative suppressed PDGF-induced [3H]-thymidine incorporation, cell cycle progression from G0/G1 to S phase, and the phosphorylation of phosphor-retinoblastoma protein (pRb) as well as the expression of cyclin E/D, cyclin-dependent kinase (CDK) 2/4, and proliferating cell nuclear antigen (PCNA). Importantly, 2-nonylamino-DMNQ inhibited the phosphorylation of PDGF receptor?(PDGF-R?) enhanced by PDGF at Tyr579, Tyr716, Tyr751, and Tyr1021 residues. Subsequently, 2-nonylamino-DMNQ inhibited PDGF-induced phosphorylation of STAT3, ERK1/2, Akt, and PLC?1. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-R? autophosphorylation, and subsequently PDGF-R?-mediated downstream signaling pathways. PMID:23776396

Kim, Yohan; Lee, Jung-Jin; Lee, Sang-Gil; Jung, Sang-Hyuk; Han, Joo-Hui; Yang, So Young; Yun, Eunju; Song, Gyu-Yong

2013-01-01

267

Menaquinone Analogs Inhibit Growth of Bacterial Pathogens  

PubMed Central

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

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.

2013-01-01

268

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. 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

2013-01-01

269

A novel lung slice system with compromised antioxidant defenses  

SciTech Connect

In order to facilitate the study of oxidative stress in lung tissue, rat lung slices with impaired antioxidant defenses were prepared and used. Incubation of lung slices with the antineoplastic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (100 {mu}M) in an amino acid-rich medium for 45 min produced a near-maximal (approximately 85%), irreversible inhibition of glutathione reductase, accompanied by only a modest (approximately 15%) decrease in pulmonary nonprotein sulfhydryls (NPSH) and no alteration in intracellular ATP, NADP{sup +}, and NADPH levels. The amounts of NADP(H), ATP, and NPSH were stable over a 4-hr incubation period following the removal from BCNU. The viability of the system was further evaluated by measuring the rate of evolution of {sup 14}CO{sub 2} from D-({sup 14}C(U))-glucose. The rates of evolution were almost identical in the compromised system when compared with control slices over a 4-hr time period. By using slices with compromised oxidative defenses, preliminary results have been obtained with paraquat, nitrofurantoin, and 2,3-dimethoxy-1,4-naphthoquinone.

Hardwick, S.J.; Adam, A.; Cohen, G.M. (Univ. of London (England)); Smith, L.L. (Imperial Chemical Industries PLC, Cheshire (England))

1990-04-01

270

Involvement of the cell-specific pigment genes pks and sult in bacterial defense response of sea urchins Strongylocentrotus intermedius.  

PubMed

Bacterial infections are one of the most important problems in mass aquaculture, causing the loss of millions of juvenile organisms. We isolated 22 bacterial strains from the cavity fluid of the sea urchin Strongylocentrotus pallidus and used phylogenetic analysis based on 16S rRNA gene sequences to separate the bacterial strains into 9 genera (Aliivibrio, Bizionia, Colwellia, Olleya, Paenibacillus, Photobacterium, Pseudoalteromonas, Shewanella, and Vibrio). Incubating Strongylocentrotus intermedius larvae with a strain from each of the 9 bacterial genera, we investigated the viability of the larvae, the amount of pigment cells, and the level of polyketide synthase (pks) and sulfotransferase (sult) gene expression. Results of the assay on sea urchin development showed that all bacterial strains, except Pseudoalteromonas and Bizionia, suppressed sea urchin development (resulting in retardation of the embryos' development with cellular disorders) and reduced cell viability. We found that pks expression in the sea urchin larvae after incubation with the bacteria of 9 tested genera was significantly increased, while the sult expression was increased only after the treatment with Pseudoalteromonas and Shewanella. Shikimic acid, which is known to activate the biosynthesis of naphthoquinone pigments, increased the tolerance of the sea urchin embryos to the bacteria. In conclusion, we show that the cell-specific pigment genes pks and sult are involved in the bacterial defense response of sea urchins. PMID:23548362

Kiselev, Konstantin V; Ageenko, Natalya V; Kurilenko, Valeria V

2013-03-26

271

Structural studies of the Trypanosoma cruzi Old Yellow Enzyme: insights into enzyme dynamics and specificity.  

PubMed

The flavoprotein old yellow enzyme of Trypanosoma cruzi (TcOYE) is an oxidoreductase that uses NAD(P)H as cofactor. This enzyme is clinically relevant due to its role in the action mechanism of some trypanocidal drugs used in the treatment of Chagas' disease by producing reactive oxygen species. In this work, the recombinant enzyme TcOYE was produced and collectively, X-ray crystallography, small angle X-ray scattering, analytical ultracentrifugation and molecular dynamics provided a detailed description of its structure, specificity and hydrodynamic behavior. The crystallographic structure at 1.27Å showed a classical (?/?)8 fold with the FMN prosthetic group buried at the positively-charged active-site cleft. In solution, TcOYE behaved as a globular monomer, but it exhibited a molecular envelope larger than that observed in the crystal structure, suggesting intrinsic protein flexibility. Moreover, the binding mode of ?-lapachone, a trypanocidal agent, and other naphthoquinones was investigated by molecular docking and dynamics suggesting that their binding to TcOYE are stabilized mainly by interactions with the isoalloxazine ring from FMN and residues from the active-site pocket. PMID:24056191

Murakami, Mário T; Rodrigues, Nathalia C; Gava, Lisandra M; Honorato, Rodrigo V; Canduri, Fernanda; Barbosa, Leandro R S; Oliva, Glaucius; Borges, Júlio C

2013-12-31

272

Physicochemical characteristics, oxidative capacities and cytotoxicities of sulfate-coated, 1,4-NQ-coated and ozone-aged black carbon particles  

NASA Astrophysics Data System (ADS)

Black carbon (BC) particles play important roles in climate change, visibility impairment, atmospheric reaction process, and health effect. The aging processes of BC alter not only atmospheric composition, but also the physicochemical characteristics of BC itself, thus impacting the environment and health effects. Here, three types of BC including sulfate-coated, 1,4-naphthoquinone (1,4-NQ)-coated, and O3-aged BC are presented. The morphologies, structures, extraction components, the amount of water-soluble organic carbon (WSOC) and free radical intensities of the three types of BC particles are examined by transmission electron microscopy, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), ultraviolet-visible spectrophotometry, total organic carbon detector and electron paramagnetic resonance, respectively. Dithiothreitol (DTT) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assays are utilized to assess the changes in oxidative capacity and cytotoxicity towards murine alveolar macrophage cells. The orders of DTT activities and cytotoxicities of the particles are both arranged as follows: BC/1,4-NQ > BC/O3 > BC > BC/sulfate, mainly because 1,4-NQ owned high oxidative potential and cytotoxicity, while sulfate did not exhibit oxidative capacity and cytotoxicity. The insoluble components of particles contribute most of the total DTT activity, whereas either water or methanol extract is minor contributor. DTT activity was positively correlated with both WSOC content and free radical intensity, with the correlation between DTT activity and WSOC content was stronger than that between DTT activity and free radical intensity.

Li, Qian; Shang, Jing; Liu, Jia; Xu, Weiwei; Feng, Xiang; Li, Rui; Zhu, Tong

2015-02-01

273

CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis and enables heterologous production of ferruginol in yeasts  

PubMed Central

Cytochrome P450 enzymes (CYPs) play major roles in generating highly functionalized terpenoids, but identifying the exact biotransformation step(s) catalyzed by plant CYP in terpenoid biosynthesis is extremely challenging. Tanshinones are abietane-type norditerpenoid naphthoquinones that are the main lipophilic bioactive components of the Chinese medicinal herb danshen (Salvia miltiorrhiza). Whereas the diterpene synthases responsible for the conversion of (E,E,E)-geranylgeranyl diphosphate into the abietane miltiradiene, a potential precursor to tanshinones, have been recently described, molecular characterization of further transformation of miltiradiene remains unavailable. Here we report stable-isotope labeling results that demonstrate the intermediacy of miltiradiene in tanshinone biosynthesis. We further use a next-generation sequencing approach to identify six candidate CYP genes being coregulated with the diterpene synthase genes in both the rhizome and danshen hairy roots, and demonstrate that one of these, CYP76AH1, catalyzes a unique four-electron oxidation cascade on miltiradiene to produce ferruginol both in vitro and in vivo. We then build upon the previous establishment of miltiradiene production in Saccharomyces cerevisiae, with incorporation of CYP76AH1 and phyto-CYP reductase genes leading to heterologous production of ferruginol at 10.5 mg/L. As ferruginol has been found in many plants including danshen, the results and the approaches that were described here provide a solid foundation to further elucidate the biosynthesis of tanshinones and related diterpenoids. Moreover, these results should facilitate the construction of microbial cell factories for the production of phytoterpenoids. PMID:23812755

Guo, Juan; Zhou, Yongjin J.; Hillwig, Matthew L.; Shen, Ye; Yang, Lei; Wang, Yajun; Zhang, Xianan; Liu, Wujun; Peters, Reuben J.; Chen, Xiaoya; Zhao, Zongbao K.; Huang, Luqi

2013-01-01

274

Activation of c-Jun N-terminal kinase and apoptosis in endothelial cells mediated by endogenous generation of hydrogen peroxide  

NASA Technical Reports Server (NTRS)

Reactive oxygen species have been implicated in the activation of signal transduction pathways. However, extracellular addition of oxidants such as hydrogen peroxide (H2O2) often requires concentrations that cannot be readily achieved under physiological conditions to activate biological responses such as apoptosis. Explanations for this discrepancy have included increased metabolism of H2O2 in the extracellular environment and compartmentalization within the cell. We have addressed this issue experimentally by examining the induction of apoptosis of endothelial cells induced by exogenous addition of H2O2 and by a redox cycling agent, 2,3-dimethoxy-1,4-naphthoquinone, that generates H2O2 in cells. Here we show that low nanomolar steady-state concentrations (0.1-0.5 nmol x min(-1) x 10(6) cells) of H2O2 generated intracellularly activate c-Jun N terminal kinase and initiate apoptosis in endothelial cells. A comparison with bolus hydrogen peroxide suggests that the low rate of intracellular formation of this reactive oxygen species results in a similar profile of activation for both c-Jun N terminal kinase and the initiation of apoptosis. However, a detailed analysis reveals important differences in both the duration and profile for activation of these signaling pathways.

Ramachandran, Anup; Moellering, Douglas; Go, Young-Mi; Shiva, Sruti; Levonen, Anna-Liisa; Jo, Hanjoong; Patel, Rakesh P.; Parthasarathy, Sampath; Darley-Usmar, Victor M.

2002-01-01

275

Expression Patterns of Glutathione Transferase Gene (GstI) in Maize Seedlings Under Juglone-Induced Oxidative Stress  

PubMed Central

Juglone (5-hydroxy-1,4-naphthoquinone) has been identified in organs of many plant species within Juglandaceae family. This secondary metabolite is considered as a highly bioactive substance that functions as direct oxidant stimulating the production of reactive oxygen species (ROS) in acceptor plants. Glutathione transferases (GSTs, E.C.2.5.1.18) represent an important group of cytoprotective enzymes participating in detoxification of xenobiotics and limiting oxidative damages of cellular macromolecules. The purpose of this study was to investigate the impact of tested allelochemical on growth and development of maize (Zea mays L.) seedlings. Furthermore, the effect of juglone-induced oxidative stress on glutathione transferase (GstI) gene expression patterns in maize seedlings was recorded. It was revealed that 4-day juglone treatment significantly stimulated the transcriptional activity of GstI in maize seedlings compared to control plants. By contrast, at the 6th and 8th day of experiments the expression gene responses were slightly lower as compared with non-stressed seedlings. Additionally, the specific gene expression profiles, as well as the inhibition of primary roots and coleoptile elongation were proportional to juglone concentrations. In conclusion, the results provide strong molecular evidence that allelopathic influence of juglone on growth and development of maize seedlings may be relevant with an induction of oxidative stress in acceptor plants. PMID:22174645

Sytykiewicz, Hubert

2011-01-01

276

Manganese, superoxide dismutase, and oxygen tolerance in some lactic acid bacteria.  

PubMed Central

A previous study of the aerotolerant bacterium Lactobacillus plantarum, which lacks superoxide dismutase (SOD), demonstrated that it possesses a novel substitute for this defensive enzyme. Thus, L. plantarum contains 20 to 25 mM Mn(II),m in a dialyzable form, which is able to scavenge O2- apparently as effectively as do the micromolar levels of SOD present in most other organisms. This report describes a survey of the lactic acid bacteria. The substitution of millimolar levels of Mn(II) for micromolar levels of SOD is a common occurrence in this group of microorganisms, which contained either SOD or high levels of Mn(II), but not both. Two strains were found which had neither high levels of Mn(II) nor SOD, and they were, as was expected, very oxygen intolerant. Lactic acid bacteria containing SOD grew better aerobically than anaerobically, whereas the organisms containing Mn(II) in place of SOD showed aerobic growth which was best, at best, equal to anaerobic growth. Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) increases the rate of O2- production in these organisms. Lactobacillus strains containing high intracellular Mn(II) were more resistant to the oxygen-dependent toxicity of plumbagin than were strains containing lower levels of Mn(II). The results support the conclusion that a high internal level of Mn(II) provides these organisms with an important defence against endogenous O2-. PMID:6263860

Archibald, F S; Fridovich, I

1981-01-01

277

Mediators-assisted reductive biotransformation of tetrabromobisphenol-A by Shewanella sp. XB.  

PubMed

The anaerobic biotransformation of tetrabromobisphenol A (TBBPA) was mainly observed in the consortia so far. The role of redox mediators in anaerobic TBBPA biotransformation by Shewanella sp. distributed widely in environments was investigated for the first time. The results showed the flavins secretion of Shewanella sp. XB was highly dependent on initial TBBPA concentration. The corresponding first-order rate constants (k) of TBBPA transformation decreased to 0.007 d(-1) when TBBPA concentration increased up to 80 mg/L. Moreover, the removal rate of TBBPA (80 mg/L) was significantly enhanced in treatments amended with cyanocobalamin, riboflavin, 2-hydroxy-1,4-naphthoquinone and Aldrich humic acid with k values of 0.42, 0.19, 0.16, and 0.07 d(-1), respectively. In addition, some redox proteins were secreted and played a role in flavins-mediated extracellular biotransformation of TBBPA by Shewanella sp. XB. These findings are beneficial to better understand TBBPA fate in natural environments and to develop efficient biotreatment strategies of TBBPA pollutions. PMID:23735802

Wang, Jing; Fu, Zhenzhen; Liu, Guangfei; Guo, Ning; Lu, Hong; Zhan, Yaoyao

2013-08-01

278

Reduction of chalcogen oxyanions and generation of nanoprecipitates by the photosynthetic bacterium Rhodobacter capsulatus.  

PubMed

The facultative photosynthetic bacterium Rhodobacter capsulatus is characterized in its interaction with the toxic oxyanions tellurite (Te(IV)) and selenite (Se(IV)) by a highly variable level of resistance that is dependent on the growth mode making this bacterium an ideal organism for the study of the microbial interaction with chalcogens. As we have reported in the past, while the oxyanion tellurite is taken up by R. capsulatus cells via acetate permease and it is reduced to Te(0) in the cytoplasm in the form of splinter-like black intracellular deposits no clear mechanism was described for Se(0) precipitation. Here, we present the first report on the biotransformation of tellurium and selenium oxyanions into extracellular Te(0) and Se(0)nanoprecipitates (NPs) by anaerobic photosynthetically growing cultures of R. capsulatus as a function of exogenously added redox-mediator lawsone, i.e. 2-hydroxy-1,4-naphthoquinone. The NPs formation was dependent on the carbon source used for the bacterial growth and the rate of chalcogen reduction was constant at different lawsone concentrations, in line with a catalytic role for the redox mediator. X-ray diffraction (XRD) analysis demonstrated the Te(0) and Se(0) nature of the nanoparticles. PMID:24462199

Borghese, Roberto; Baccolini, Chiara; Francia, Francesco; Sabatino, Piera; Turner, Raymond J; Zannoni, Davide

2014-03-30

279

Experimental therapy of theileriosis.  

PubMed

A tissue culture method was used to screen compounds for activity against Theileria parva, and demonstrated that the hydroxy-alkylated naphthoquinones, 'menoctone' and 993C were highly active, with ED50 values around 0,005 mg/l. When injected into cattle artificially infected the T. parva, menoctone cured all of 7 cattle at a total dosage of 10 mg/kg injected intravenously (i.v.). A further trial showed that injection of menoctone, 10 mg/kg, as a single dose gby the intramuscular (i.m.) route was more effective than when a similar dose was given by the i.v. route. Titration of serum from these cattle in the in vitro system showed that inhibitory levels of drug persisted for three days after i.v. injection and six days when menoctone was injected i.m. The minimum effective dose level of 993C was 20 mg/kg i.m. either as a single dose, or as two doses of 10 mg/kg with an interval of 48 hours. PMID:553970

McHardy, N

1979-12-01

280

Enhanced Ca2+ entry, ceramide formation, and apoptotic death of erythrocytes triggered by plumbagin.  

PubMed

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone, 1), a natural product from plants with potential anticancer potency, induces apoptosis. Mechanisms involved in 1-induced apoptosis include mitochondrial depolarization, inactivation of NF-?B, and altered expression of anti- and proapoptotic Bcl proteins. Similar to nucleated cells, erythrocytes may undergo suicidal death or eryptosis, which, like apoptosis, results in cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increase of cytosolic Ca(2+) activity ([Ca(2+)]i) and ceramide formation. The present study explored whether 1 stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin-V-binding, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo-3 fluorescence, and ceramide abundance utilizing antibodies. A 48 h exposure to 1 (2 ?M) decreased forward scatter and increased annexin-V-binding significantly, events paralleled by increased [Ca(2+)]i and ceramide formation. Exposure to 1 was followed by a slight but significant increase of hemolysis. Removal of extracellular Ca(2+) slightly, but significantly blunted the effect of 1 (2 ?M) on annexin-V-binding. The present observations demonstrate that 1 may trigger suicidal death of erythrocytes, cells devoid of mitochondria and nuclei. PMID:23110447

Lupescu, Adrian; Jilani, Kashif; Zbidah, Mohanad; Lang, Elisabeth; Lang, Florian

2012-11-26

281

Comparative study on enantiomeric excess of main akannin/shikonin derivatives isolated from the roots of three endemic Boraginaceae plants in China.  

PubMed

This work systematically investigated the enantiomeric excess (e.e.) of main components isolated from the roots of three endemic Boraginaceae plants distributed extensively in China, named Arnebia euchroma (Royle) Johnst (A.e.), Lithospermum erythrorhizon Sieb. et Zucc. (L.e.) and Onosma confertum W. W. Smith (O.c.), and the optical purity of their hydrolysis products separately, by means of three different approaches. The influence of HCl on the e.e. values of the major constituents was also studied. Analysis of the absolute configurations and e.e. values of all the derivatives acquired was performed by CD and chiral-HPLC respectively. The results of the main constituents demonstrated that A.e. mainly yields S-form naphthoquinone derivatives, while the R-form is predominant in the derivatives of L.e. and O.c. The optical purity of alkannin and shikonin and their derivatives was not influenced by acid treatment in the course of separation and hydrolysis. Additionally, it was found that 100% e.e. of shikinon could be acquired from a specific shikinon ester derivative, ?,?-dimethylacrylshikonin occurring in the roots of O.c., as did 100% e.e. of alkannin from ?,?-dimethylacrylalkannin contained in the roots of A.e. PMID:21308700

Zhou, Wen; Jiang, Hu Da Gu La; Peng, Ying; Li, Shao Shun

2011-10-01

282

Impairment of vascular function of rat thoracic aorta in an endothelium-dependent manner by shikonin/alkannin and derivatives isolated from roots of Macrotomia euchroma.  

PubMed

The effects of a naphthoquinone analogue, shikonin/alkannin (SA) and derivatives (acetylshikonin and beta,beta-dimethylacrylshikonin), on vascular reactivity were studied with isolated rat aortic rings. At lower concentrations, SA and its derivatives concentration-dependently inhibit the agonist-induced (acetylcholine and histamine) relaxation in PE precontracted aorta in an endothelium-dependent manner with IC (50) values ranging from 0.2 to 1.5 microM. In addition to the effect on agonist-induced vasorelaxation, the Ca (2+) ionophore A23187-induced vasorelaxation was also inhibited or reversed by SA. However, SA had no effect on sodium nitroprusside-induced (guanylate cyclase activator) vasorelaxation. These data suggested that SA and its derivatives might be acting as inhibitors of nitric oxide synthesis in endothelium. At a concentration greater than 10 microM, SA induced contraction of intact but not denuded aorta which could be inhibited by prior treatment with indomethacin, a cyclooxygenase inhibitor. In summary, the results from this study showed that SA and its derivatives inhibited agonist-induced relaxation at lower concentrations and induced vasocontraction at higher concentrations. All the effects seen with SA were endothelium-dependent, however, through different mechanisms. Abbreviations. SA:shikonin/alkannin PE:phenylephrine Ach:acetylcholine SNP:sodium nitroprusside eNOS:endothelial nitric oxide synthase L-NAME: Nw-nitro- L-arginine methyl ester PMID:14765288

Hu, Chien-Ming; Cheng, Yu-Wen; Cheng, Hui-Wen; Kang, Jaw-Jou

2004-01-01

283

Simultaneous densitometric determination of shikonin, acetylshikonin, and beta-acetoxyisovaleryl-shikonin in ultrasonic-assisted extracts of four Arnebia species using reversed-phase thin layer chromatography.  

PubMed

A simple, precise, and rapid high-performance thin-layer chromatographic (HPTLC) method for the simultaneous quantification of pharmacologically important naphthoquinone shikonin (1) together with its derivatives acetylshikonin (2), and beta-acetoxyisovalerylshikonin (3) in four species of genus Arnebia (A. euchroma, A. guttata, A. benthamii, and A. hispidissima) from the Indian subcontinent has been developed. In addition, the effect of solvents with varying polarity (hexane, chloroform, ethyl acetate, and methanol) for the extraction of these compounds was studied. HPTLC was performed on precoated RP-18 F(254S )TLC plates. For achieving good separation, mobile phase consisting of ACN/methanol/5% formic acid in water (40:02:08 v/v/v) was used. The densitometric determination of shikonin derivatives was carried out at 520 nm in reflection/absorption mode. The method was validated in terms of linearity, accuracy, precision, robustness, and specificity. The calibration curves were linear in the range of 100-600 ng for shikonin and acetylshikonin, and 100-1800 ng for beta-acetoxyisovalerylshikonin. Lower LOD obtained for compounds 1-3 were 18, 15, and 12 ng, respectively, while the LOQ obtained were 60, 45, and 40 ng, respectively. PMID:19697311

Sharma, Nandini; Sharma, Upendra K; Gupta, Ajai P; Sinha, Arun K; Lal, Brij; Ahuja, Paramvir S

2009-09-01

284

Bioactive compounds from Stuhlmannia moavi from the Madagascar dry forest?  

PubMed Central

Bioassay-directed fractionation of the leaf and root extracts of the antiproliferative Madagascar plant Stuhlmannia moavi afforded 6-acetyl-5,8-dihydroxy-2-methoxy-7-methyl-1,4-naphthoquinone (stuhlmoavin, 1) as the most active compound, with an IC50 value of 8.1 µM against the A2780 human ovarian cancer cell line, as well as the known homoisoflavonoid bonducellin (2) and the stilbenoids 3,4,5'-trihydroxy-3'-methoxy-trans-stilbene (3), piceatannol (4), resveratrol (5), rhapontigenin (6), and isorhapontigenin (7). The structure elucidation of all compounds was based on NMR and mass spectroscopic data, and the structure of 1 was confirmed by a single crystal X-ray analysis. Compounds 2–5 showed weak A2780 activities, with IC50 values of 10.6, 54.0, 41.0, and 74.0 µM, respectively. Compounds 1–3 also showed weak antimalarial activity against Plasmodium falciparum with IC50 values of 23, 26, and 27 µM, respectively. PMID:24239390

Liu, Yixi; Harinantenaina, Liva; Brodie, Peggy J.; Bowman, Jessica D.; Cassera, Maria B.; Slebodnick, Carla; Callmander, Martin W.; Randrianaivo, Richard; Rakotobe, Etienne; Rasamison, Vincent E.; Applequist, Wendy; Birkinshaw, Chris; Lewis, Gwilym P.; Kingston, David G. I.

2013-01-01

285

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. PMID:22252314

Berg, Michael G.; Wan, Lili; Younis, Ihab; Diem, Michael D.; Soo, Michael; Wang, Congli

2012-01-01

286

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

PubMed

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

2011-12-16

287

The Pin 1 inhibitor juglone attenuates kidney fibrogenesis via Pin 1-independent mechanisms in the unilateral ureteral occlusion model  

PubMed Central

Background Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E). Results After 2 weeks of UUO, immunoblot analyses demonstrated that juglone (0.25 and 1 mg/kg/24 h) inhibited the deposition of matrix (?-smooth muscle actin (SMA), collagen type III and vimentin) and the activation of signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27). Juglone also reduced EMT (?-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney. There was no difference in Pin 1 levels between treatment and control groups. Pin 1 activity was significantly decreased in obstructed kidneys regardless of treatment status. In vitro, juglone (1 ?M) significantly decreased ?-SMA and p-smad levels compared to vehicle. Conclusions Juglone attenuates fibrogenesis via Pin 1-independent mechanisms in the UUO model. The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress. PMID:20047646

2010-01-01

288

Resistance of Rhizobium strains to phygon, spergon, and thiram.  

PubMed Central

Strains of Rhizobium meliloti, Rhizobium sp. nodulating cowpeas, and R. phaseoli derived from cultures susceptible to tetramethylthiuram disulfide (thiram), 2,3-dichloro-1,4-naphthoquinone (phygon), and 2,3,5,6-tetrachloro-p-benzoquinone (spergon), respectively, grew in the presence of high concentrations of the fungicides and converted them to products not toxic to the sensitive rhizobia. The results of chemical assays demonstrated that the pesticides were destroyed by the resistant bacteria but not by the susceptible parent rhizobia. Resting cells of thiram-metabolizing R. meliloti formed large quantities of dimethyldithiocarbamate, dimethylamine, and CS2 from the pesticide. The products were characterized by gas and thin-layer chromatography, colorimetric reactions, and ultraviolet spectrometry. Dimethylamine and CS2 were formed spontaneously from dimethyldithiocarbamate, but the yield was higher in the presence of R. meliloti. The phygon-resistant bacterium converted the fungicide to five metabolites and thereby rendered the chemical nontoxic to a test fungus. The resistant strain of R. phaseoli generated at least one organic product and released about one-third of the chlorine during its detoxication of spergon. PMID:869529

Odeyemi, O; Alexander, M

1977-01-01

289

Evaluation of the effectiveness of an ointment based on Alkannins/Shikonins on second intention wound healing in the dog  

PubMed Central

The enantiomeric naphthoquinones alkannins and shikonins (A/S) have been established as potent wound healing agents. The purpose of this study was to evaluate the effectiveness of an A/S based ointment for humans on second intention wound healing in the dog, as compared to wound flushing with Lactated Ringer’s solution (LRS). Ten mixed breed dogs, aged 2 to 5 y, were used. One 2.5 × 2.5 cm full-thickness skin defect was created on the lateral aspect of each arm for subjective evaluation, laser-Doppler flowmetry (LDF), and planimetry. Additionally, 3 matching 2 × 2 cm wounds were created on opposite sides of the dorsal midline for histologic evaluation. Wounds were treated once daily with the A/S based ointment on the right side and by flushing with LRS on the left until healed (about 20 d). During the healing process, tissue perfusion (mean LDF value) was found to be significantly higher on the side treated with the A/S based ointment compared with the LRS-treated side. Histologically, angiogenesis (on days 4 and 11), collagen production score (on days 4, 11, and 20), and epithelial thickness score (on day 11) were significantly higher in the wounds treated with the A/S based ointment. Wound size, as evaluated by planimetry, decreased significantly from day 0 to day 20 on both sides, but no significant differences were found between the A/S based ointment and LRS-treated wounds. PMID:21461194

Karayannopoulou, Maria; Tsioli, Vassiliki; Loukopoulos, Panayiotis; Anagnostou, Tilemahos L.; Giannakas, Nikolaos; Savvas, Ioannis; Papazoglou, Lysimachos G.; Kaldrymidou, Eleni

2011-01-01

290

Chimaphilin induces apoptosis in human breast cancer MCF-7 cells through a ROS-mediated mitochondrial pathway.  

PubMed

Chimaphilin, 2,7-dimethyl-1,4-naphthoquinone, is extracted from pyrola [Passiflora incarnata Fisch.]. In this study, the anticancer activity and underlying mechanisms of chimaphilin toward human breast cancer MCF-7 cells are firstly investigated. Chimaphilin could inhibit the viability of MCF-7 cells in a concentration-dependent manner, and the IC50 value was 43.30?M for 24h. Chimaphilin markedly induced apoptosis through the investigation of characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining. Flow cytometry assay revealed that chimaphilin triggered a significant generation of ROS and disruption of mitochondrial membrane potential. Additionally, western blotting assay showed that chimaphilin suppressed Bcl-2 level and enhanced Bad level, then activated caspase-9 and caspase-3, and further activated the poly ADP-ribose polymerase (PARP), finally induced cell apoptosis involving the mitochondrial pathway. Furthermore, free radical scavengers N-acetyl-L-cysteine (NAC) pretreatment test testified that chimaphilin could increase the generation of ROS, then induce cell apoptosis. In general, the present results demonstrated that chimaphilin induced apoptosis in human breast cancer MCF-7 cells via a ROS-mediated mitochondrial pathway. PMID:24793375

Ma, Wei-Dong; Zou, Yong-Peng; Wang, Peng; Yao, Xiao-Hui; Sun, Yao; Duan, Ming-Hui; Fu, Yu-Jie; Yu, Bo

2014-08-01

291

Catalytic reaction of cytokinin dehydrogenase: preference for quinones as electron acceptors.  

PubMed Central

The catalytic reaction of cytokinin oxidase/dehydrogenase (EC 1.5.99.12) was studied in detail using the recombinant flavoenzyme from maize. Determination of the redox potential of the covalently linked flavin cofactor revealed a relatively high potential dictating the type of electron acceptor that can be used by the enzyme. Using 2,6-dichlorophenol indophenol, 2,3-dimethoxy-5-methyl-1,4-benzoquinone or 1,4-naphthoquinone as electron acceptor, turnover rates with N6-(2-isopentenyl)adenine of approx. 150 s(-1) could be obtained. This suggests that the natural electron acceptor of the enzyme is quite probably a p-quinone or similar compound. By using the stopped-flow technique, it was found that the enzyme is rapidly reduced by N6-(2-isopentenyl)adenine (k(red)=950 s(-1)). Re-oxidation of the reduced enzyme by molecular oxygen is too slow to be of physiological relevance, confirming its classification as a dehydrogenase. Furthermore, it was established for the first time that the enzyme is capable of degrading aromatic cytokinins, although at low reaction rates. As a result, the enzyme displays a dual catalytic mode for oxidative degradation of cytokinins: a low-rate and low-substrate specificity reaction with oxygen as the electron acceptor, and high activity and strict specificity for isopentenyladenine and analogous cytokinins with some specific electron acceptors. PMID:14965342

Frébortová, Jitka; Fraaije, Marco W; Galuszka, Petr; Sebela, Marek; Pec, Pavel; Hrbác, Jan; Novák, Ondrej; Bilyeu, Kristin D; English, James T; Frébort, Ivo

2004-01-01

292

Un nouveau film conducteur poly(aminoquinone) pour le stockage de l'énergie  

NASA Astrophysics Data System (ADS)

The electrooxidation of 5-amino-1,4-naphthoquinone (ANQ) in acetonitrile leads to conducting (10-1 S.cm-1) functionalized polymer films of polyaniline- type bearing one quinone group per ANQ moiety, electroactive in organic or aqueous solvents. The polymer exchanges cations during the redox process of quinones and is therefore interesting for lithium ions batteries devices. The measured specific charge is particularly hight with about 290 Ah/kg. L'oxydation électrochimique du 5-amino-1,4-naphtoquinone (ANQ) dans l'acétonitrile conduit à la formation de films conducteurs (10-1 S.cm-1) fonctionnalisés de structure type polyaniline portant une fonction quinone par motif ANQ, qui sont électroactifs en milieu aqueux comme en milieu organique. Le polymère échange des cations au cours du processus rédox des quinones et est ainsi intéressant pour les applications dans les accumulateurs au lithium. La charge spécifique mesurée de ce polymère est particulièrement élevée avec environ 290 Ah/kg.

Piro, B.; Pham, M. C.; Bazzaoui, E. A.; Lacroix, J.-C.; Lacaze, P.-C.; Novak, P.; Hass, O.

1998-06-01

293

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.

1986-01-01

294

Antiallergic effects of pigments isolated from green sea urchin (Strongylocentrotus droebachiensis) shells.  

PubMed

This study was undertaken to evaluate possible antiallergic effects of an extract of pigments from green sea urchin (Strongylocentrotus droebachiensis) shells. Effects were studied on animal models - guinea pig ileum contraction, rabbit eyes allergic conjunctivitis, and rabbit local skin irritation. The extract significantly reduced, in a dose-dependent manner, the histamine-induced contractions of the isolated guinea pig ileum with ID50 =1.2 µg/mL (in equivalents of spinochrome B), had an inhibitory effect on the model of ocular allergic inflammation surpassing the reference drug olopatadine, and did not show any irritating effect in rabbits. The extract predominantly contained polyhydroxy-1,4-naphthoquinone which would be responsible for the pharmacological activity. The active compounds of the extract were evaluated in silico with molecular docking. Molecular docking into H1R receptor structures obtained from molecular dynamic simulations showed that all spinochrome derivatives bind to the receptor active site, but spinochrome monomers fit better to it. The results of the present study suggest possibilities for the development of new agents for treating allergic diseases on the base of pigments from sea urchins shells. PMID:24288292

Pozharitskaya, Olga N; Shikov, Alexander N; Makarova, Marina N; Ivanova, Svetlana A; Kosman, Vera M; Makarov, Valery G; Bazgier, Václav; Berka, Karel; Otyepka, Michal; Ulrichová, Jitka

2013-12-01

295

A fluorescence-based rapid screening assay for cytotoxic compounds.  

PubMed

A simple fluorescence-based assay was developed for the rapid screening of potential cytotoxic compounds generated by combinatorial chemistry. The assay is based on detection of nuclear green fluorescent protein (GFP) staining of a human cervical cancer cell line (HeLa) carrying an integrated histone H2B-GFP fusion gene. Addition of a cytotoxic compound to the HeLa-GFP cells results in the eventual degradation of DNA and loss of the GFP nuclear fluorescence. Using this assay, we screened 11 distinct quinone derivatives and found that several of these compounds were cytotoxic. These compounds are structurally related to plumbagin an apoptosis-inducing naphthoquinone isolated from Black Walnut. In order to determine the mechanism by which cell death was induced, we performed additional experiments with the most cytotoxic quinones. These compounds were found to induce morphological changes (blebbing and nuclear condensation) consistent with induction of apoptosis. Additional tests revealed that the cytotoxic compounds induce both necrotic and apoptotic modes of death. PMID:15555600

Montoya, Jessica; Varela-Ramirez, Armando; Estrada, Abril; Martinez, Luis E; Garza, Kristine; Aguilera, Renato J

2004-12-24

296

Conjugated polymer and drug co-encapsulated nanoparticles for Chemo- and Photo-thermal Combination Therapy with two-photon regulated fast drug release.  

PubMed

The spatial-temporal synchronization of photothermal therapy and chemotherapy is highly desirable for an efficient cancer treatment with synergistic effect. Herein, we developed a chemotherapeutic drug doxorubicin (DOX) and photothermal conjugated polymer (CP) co-loaded nanoplatform using a near-infrared (NIR) laser responsive amphiphilic brush copolymer as the encapsulation matrix. The obtained nanoparticles (NPs) exhibit good monodispersity and excellent stability, which can efficiently convert laser energy into thermal energy for photothermal therapy. Moreover, the hydrophobic polymer matrix bearing a number of 2-diazo-1,2-naphthoquinones (DNQ) moieties could be transformed to a hydrophilic one upon NIR two-photon laser irradiation, which leads to fast drug release. Furthermore, the surface modification of the NPs with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide significantly enhances the accumulation of the NPs within integrin ?v?3 overexpressed cancer cells. The half-maximal inhibitory concentration (IC50) of the combination therapy is 13.7 ?g mL(-1), while the IC50 for chemotherapy and photothermal therapy alone is 147.8 ?g mL(-1) and 36.2 ?g mL(-1), respectively. The combination index (C.I.) is 0.48 (<1), which indicates the synergistic effect for chemotherapy and PTT. These findings provide an excellent NIR laser regulated nanoplatform for combined cancer treatment with synergistic effect due to the synchronous chemo- and photo-thermal therapy. PMID:25608113

Yuan, Youyong; Wang, Zuyong; Cai, Pingqiang; Liu, Jie; Liao, Lun-De; Hong, Minghui; Chen, Xiaodong; Thakor, Nitish; Liu, Bin

2015-02-01

297

Shikonin inhibits the growth of human prostate cancer cells via modulation of the androgen receptor.  

PubMed

Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been shown to possess tumor cell killing activity. The human androgen receptor (AR) is a nuclear transcription factor that serves as a major therapeutic target for prostate cancer. However, AR regulation by shikonin has not been reported. We investigated the effects of shikonin on the growth of prostate cancer cells. We observed that shikonin decreased the expression of AR at both the mRNA and the protein levels in LNCaP and 22RV1 human prostate cancer cells. The results from a luciferase assay showed that shikonin decreased the transcriptional activity of AR. Moreover, shikonin treatment inhibited AR target gene expression, PSA and growth inhibition of prostate cancer cells. In conclusion, the present study shows for the first time that shikonin treatment causes transcriptional repression of AR and inhibition of its nuclear localization in human prostate cancer cells. We propose that shikonin, an anticancer drug extracted from natural sources, induces inhibition of cell growth through modulation of AR in androgen-responsive prostate cancer cells and is a candidate for use in cancer chemotherapy for human prostate cancer. PMID:24573652

Jang, Soon Young; Jang, Eun Hyang; Jeong, Seo Young; Kim, Jong-Ho

2014-05-01

298

Shikonin induces apoptosis and inhibits migration of ovarian carcinoma cells by inhibiting the phosphorylation of Src and FAK  

PubMed Central

The present study identified that shikonin, a naphthoquinone extracted from the roots of Lithospermum erythrorhizon, inhibits the migration of ovarian cancer cells and induces their apoptosis by impairing the phosphorylation of two kinases, proto-oncogene tyrosine protein kinase Src (Src) and focal adhesion kinase (FAK). Ovarian carcinoma SKOV-3 cells were treated with various concentrations of shikonin and analyzed for the effects on cell migration, invasion and apoptosis via Transwell assays and flow cytometry. In addition, the effects of shikonin administration on the expression and phosphorylation of Src and FAK in the SKOV-3 cells were analyzed by western blotting. Shikonin appeared to induce apoptosis and decrease cell migration in the SKOV-3 ovarian cells. Furthermore, the present study provides evidence that shikonin may exert these effects on human ovarian carcinoma cells via the inhibition of the protein tyrosine kinases, Src and FAK. Thus, shikonin should be considered for additional investigation as a candidate agent for the prevention and treatment of human ovarian cancer. PMID:25621031

HAO, ZHENFENG; QIAN, JING; YANG, JISHI

2015-01-01

299

?,?-Dimethylacrylshikonin sensitizes human colon cancer cells to ionizing radiation through the upregulation of reactive oxygen species  

PubMed Central

Shikonin, a naphthoquinone derivative, has been shown to possess antitumor activity. In the present study, the effects of shikonin and its analog, ?,?-dimethylacrylshikonin, were investigated as radiosensitizers on the human colon cancer cell line, HCT-116. Shikonin and, to a greater extent, its analog-induced apoptosis of HCT-116 cells further synergistically potentiated the induction of apoptosis when combined with ionizing radiation (IR) treatment. Shikonins also stimulated an increase in reactive oxygen species (ROS) production and IR-induced DNA damage. Pre-treatment with the ROS scavenger, N-acetylcysteine, suppressed the enhancement of IR-induced DNA damage and apoptosis stimulated by shikonins, indicating that shikonins exert their radiosensitizing effects through ROS upregulation. The radiosensitizing effect of shikonins was also examined in vivo using the xenograft mouse model. Consistent with the in vitro results, injection of ?,?-dimethylacrylshikonin combined with IR treatment significantly suppressed tumor growth of the HCT-116 xenograft. Taken together, the results show that ?,?-dimethylacrylshikonin is a promising agent for developing an improved strategy for radiotherapy against tumors. PMID:24932238

KWAK, SEO-YOUNG; JEONG, YOUN KYOUNG; KIM, BU-YEON; LEE, JI YOUNG; AHN, HYUN-JOO; JEONG, JAE-HOON; KIM, MI-SOOK; KIM, JOON; HAN, YOUNG-HOON

2014-01-01

300

Shikonin inhibits the growth of human prostate cancer cells via modulation of the androgen receptor  

PubMed Central

Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been shown to possess tumor cell killing activity. The human androgen receptor (AR) is a nuclear transcription factor that serves as a major therapeutic target for prostate cancer. However, AR regulation by shikonin has not been reported. We investigated the effects of shikonin on the growth of prostate cancer cells. We observed that shikonin decreased the expression of AR at both the mRNA and the protein levels in LNCaP and 22RV1 human prostate cancer cells. The results from a luciferase assay showed that shikonin decreased the transcriptional activity of AR. Moreover, shikonin treatment inhibited AR target gene expression, PSA and growth inhibition of prostate cancer cells. In conclusion, the present study shows for the first time that shikonin treatment causes transcriptional repression of AR and inhibition of its nuclear localization in human prostate cancer cells. We propose that shikonin, an anticancer drug extracted from natural sources, induces inhibition of cell growth through modulation of AR in androgen-responsive prostate cancer cells and is a candidate for use in cancer chemotherapy for human prostate cancer. PMID:24573652

JANG, SOON YOUNG; JANG, EUN HYANG; JEONG, SEO YOUNG; KIM, JONG-HO

2014-01-01

301

The molecular mechanisms and gene expression profiling for shikonin-induced apoptotic and necroptotic cell death in U937 cells.  

PubMed

Shikonin (SHK), a natural naphthoquinone derived from the Chinese medical herb Lithospermum erythrorhizon, induces both apoptosis and necroptosis in several cancer cell lines. However, the detailed molecular mechanisms involved in the initiation of cell death are still unclear. In the present study, caspase-dependent apoptosis was induced by SHK treatment at 1?M after 6h in U937 cells, with increase in DNA fragmentation, generation of intracellular reactive oxygen species (ROS), fraction of cells with low mitochondrial membrane potential (MMP), and in the expression of BH3 only proteins Noxa and tBid. Interestingly, caspase-independent cell death was also detected with SHK treatment at 10?M, observed as increase in SYTOX® Green staining and release of lactate dehydrogenase (LDH). Necrostatin-1 (Nec-1) completely inhibited the SHK-induced leakage of LDH and SYTOX® Green staining. Cell permeable exogenous glutathione (GSH) completely inhibited 1?M SHK-induced apoptosis and converted 10?M SHK-induced necroptosis to apoptosis. Gene expression profiling revealed that 353 genes were found to be significantly regulated by 1?M and 85 genes by 10?M of SHK treatment, respectively. Among these genes, the transcription factor 3 (ATF3) and DNA-damage-inducible transcript 3 (DDIT3) were highly expressed at 1?M of SHK treatment, while tumor necrosis factor (TNF) expression mainly increased at 10?M treatment. These findings provide novel information for the molecular mechanism of SHK-induced apoptosis and necroptosis. PMID:23811387

Piao, Jin-Lan; Cui, Zheng-Guo; Furusawa, Yukihiro; Ahmed, Kanwal; Rehman, Mati Ur; Tabuchi, Yoshiaki; Kadowaki, Makoto; Kondo, Takashi

2013-09-25

302

Extracellular signal-regulated kinase, receptor interacting protein, and reactive oxygen species regulate shikonin-induced autophagy in human hepatocellular carcinoma.  

PubMed

Shikonin, a naphthoquinone derived from the Chinese medicinal plant Lithospermum erythrorhizon, shows potential to be a cancer chemotherapeutic agent. Our previous data demonstrate that high doses (about 6 ?M) of shikonin induce apoptosis in human hepatocellular carcinoma (HCC) cells. Here, we discovered that a low dose of shikonin (2.5 ?M) and a short treatment time (12h) induced autophagy, as evidenced by the upregulation of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, the formation of acidic autophagic vacuoles (AVOs), and the punctate fluorescence pattern of GFP-LC3 protein. Next, we investigated the mechanism and found reactive oxygen species accumulation after shikonin treatment. The reactive oxygen species scavengers NAC and Tiron completely blocked autophagy. We further found activation of ERK by generation of reactive oxygen species and inhibition of RIP pathway, which are at least partially connected to shikonin-induced autophagy. Moreover, experiments in vivo revealed similar results: shikonin caused the accumulation of reactive oxygen species and phospho-ERK and thus induced autophagy in a tumor xenograft model. These findings suggest that shikonin is an inducer of autophagy and may be a promising clinical antitumor drug. PMID:24886888

Gong, Ke; Zhang, Zhenxing; Chen, Yicheng; Shu, Hong-Bing; Li, Wenhua

2014-09-01

303

Evaluation of radical scavenging properties of shikonin.  

PubMed

With the aim of developing effective anti-inflammatory drugs, we have been investigating the biochemical effects of shikonin of "Shikon" roots, which is a naphthoquinone with anti-inflammatory and antioxidative properties. Shikonin scavenged reactive oxygen species like hydroxyl radical, superoxide anion (O2 (•-)) and singlet oxygen in previous studies, but its reactivity with reactive oxygen species is not completely understood, and comparison with standard antioxidants is lacking. This study aimed elucidation of the reactivity of shikonin with nitric oxide radical and reactive oxygen species such as alkyl-oxy radical and O2 (•-). By using electron paramagnetic resonance spectrometry, shikonin was found unable of reacting with nitric oxide radical in a competition assay with oxyhemoglobin. However, shikonin scavenged alkyl-oxy radical from 2,2'-azobis(2-aminopropane) dihydrochloride with oxygen radical absorbance capacity, ORAC of 0.25 relative to Trolox, and showed a strong O2 (•-)-scavenging ability (42-fold of Trolox; estimated reaction rate constant: 1.7 × 10(5) M(-1)s(-1)) in electron paramagnetic resonance assays with CYPMPO as spin trap. Concerning another source of O2 (•-), the phagocyte NADPH oxidase (Nox2), shikonin inhibited the Nox2 activity by impairing catalysis when added before enzyme activation (IC50: 1.1 µM; NADPH oxidation assay). However, shikonin did not affect the preactivated Nox2 activity, although having potential to scavenge produced O2 (•-). In conclusion, shikonin scavenged O2 (•-) and alkyl-oxy radical, but not nitric oxide radical. PMID:25320455

Yoshida, Lucia S; Kohri, Shunji; Tsunawaki, Shohko; Kakegawa, Tomohito; Taniguchi, Taizo; Takano-Ohmuro, Hiromi; Fujii, Hirotada

2014-09-01

304

Integration of Different "-omics" Technologies Identifies Inhibition of the IGF1R-Akt-mTOR Signaling Cascade Involved in the Cytotoxic Effect of Shikonin against Leukemia Cells.  

PubMed

Hematological malignancies frequently have a poor prognosis and often remain incurable. Drug resistance, severe side effects, and relapse are major problems of currently used drugs, and new candidate compounds are required for improvement of therapy success. The naphthoquinone shikonin derived from the Chinese medicinal herb, Lithospermum erythrorhizon, is a promising candidate for the next generation of chemotherapy. The basal cellular mechanism of shikonin is the direct targeting of mitochondria. Cytotoxicity screenings showed that the compound is particularly effective against leukemia cells suggesting an additional cellular mechanism. mRNA and miRNA microarrays were used to analyze changes in gene expression in leukemia cells after shikonin treatment and combined with stable-isotope dimethyl labeling for quantitative proteomics. The integration of bioinformatics and the three "-omics" assays showed that the PI3K-Akt-mTOR pathway was affected by shikonin. Deregulations of this pathway are frequently associated with cancerogenesis, especially in a wide range of hematological malignancies. The effect on the PI3K-Akt-mTOR axis was validated by demonstrating a decreased phosphorylation of Akt and a direct inhibition of the IGF1R kinase activity after shikonin treatment. Our results indicate that inhibiting the IGF1R-Akt-mTOR signaling cascade is a new cellular mechanism of shikonin strengthening its potential for the treatment of hematological malignancies. PMID:23861714

Wiench, Benjamin; Chen, Yet-Ran; Paulsen, Malte; Hamm, Rebecca; Schröder, Sven; Yang, Ning-Sun; Efferth, Thomas

2013-01-01

305

?,?-Dimethylacrylshikonin sensitizes human colon cancer cells to ionizing radiation through the upregulation of reactive oxygen species.  

PubMed

Shikonin, a naphthoquinone derivative, has been shown to possess antitumor activity. In the present study, the effects of shikonin and its analog, ?,?-dimethylacrylshikonin, were investigated as radiosensitizers on the human colon cancer cell line, HCT-116. Shikonin and, to a greater extent, its analog-induced apoptosis of HCT-116 cells further synergistically potentiated the induction of apoptosis when combined with ionizing radiation (IR) treatment. Shikonins also stimulated an increase in reactive oxygen species (ROS) production and IR-induced DNA damage. Pre-treatment with the ROS scavenger, N-acetylcysteine, suppressed the enhancement of IR-induced DNA damage and apoptosis stimulated by shikonins, indicating that shikonins exert their radiosensitizing effects through ROS upregulation. The radiosensitizing effect of shikonins was also examined in vivo using the xenograft mouse model. Consistent with the in vitro results, injection of ?,?-dimethylacrylshikonin combined with IR treatment significantly suppressed tumor growth of the HCT-116 xenograft. Taken together, the results show that ?,?-dimethylacrylshikonin is a promising agent for developing an improved strategy for radiotherapy against tumors. PMID:24932238

Kwak, Seo-Young; Jeong, Youn Kyoung; Kim, Bu-Yeon; Lee, Ji Young; Ahn, Hyun-Joo; Jeong, Jae-Hoon; Kim, Mi-Sook; Kim, Joon; Han, Young-Hoon

2014-06-01

306

Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-?B signaling pathway.  

PubMed

Although gemcitabine is currently the best chemotherapeutic agent available for the treatment of advanced pancreatic cancer, eventual failure of response is a significant clinical problem. Therefore, novel therapeutic approaches against this disease are highly needed. The aim of this study was to evaluate whether shikonin, a naphthoquinone derivative, has potential in the treatment of pancreatic cancer when used either alone or in combination with gemcitabine. Our in vitro results showed that shikonin inhibited the proliferation of three different human pancreatic cancer cell lines and potentiated the cytotoxic effect of gemcitabine, which correlated with the down-regulation of constitutive as well as gemcitabine-induced activation of NF-?B and NF-?B-regulated gene products. Most importantly, using a xenograft model of human pancreatic cancer, we found shikonin alone significantly suppressed tumor growth and argumented the antitumor activity of gemcitabine. These effects also correlated with the down-regulation of NF-?B activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that shikonin can suppress the growth of human pancreatic tumors and potentiate the antitumor effects of gemcitabine through the suppression of NF-?B and NF-?B-regulated gene products. PMID:24522113

Wang, Yongwei; Zhou, Yinan; Jia, Guang; Han, Bing; Liu, Ji; Teng, Yueqiu; Lv, Jiachen; Song, Zengfu; Li, Yilong; Ji, Liang; Pan, Shangha; Jiang, Hongchi; Sun, Bei

2014-04-01

307

Biotechnological approaches to the production of shikonins: a critical review with recent updates.  

PubMed

Abstract Shikonins are commercially important secondary compounds, known for array of biological activities such as antimicrobial, insecticidal, antitumor, antioxidants, etc. These compounds are usually colored and therefore have application in food, textiles and cosmetics. Shikonin and its derivatives, which are commercially most important of the naphthoquinone pigments, are distributed among members of the family Boraginaceae. These include different species of Lithospermum, Arnebia, Alkanna, Anchusa, Echium and Onosma. The growing demand for plant-based natural products has made this group of compounds one of the enthralling targets for their in vitro production. The aim of this review is to highlight the recent progress in production of shikonins by various biotechnological means. Different methods of increasing the levels of shikonins in plant cells such as selection of cell lines, optimization of culture conditions, elicitation, in situ product removal, genetic transformation and metabolic engineering are discussed. The experience of different researchers working worldwide on this aspect is also considered. Further, to meet market demand, the needs for continuous and reliable production systems, as well as future prospects, are included. PMID:25319455

Malik, Sonia; Bhushan, Shashi; Sharma, Madhu; Ahuja, Paramvir Singh

2014-10-16

308

Shikonin shortens the circadian period: possible involvement of Top2 inhibition.  

PubMed

The naphthoquinone pigment, shikonin, is a natural product derived from Lithospermum erythrorhizon and an active component of a Chinese traditional herbal therapeutic. We identified shikonin as a candidate for shortening the circadian period using real-time reporter gene assays based on NIH3T3-derived stable reporter cells. Period length that became shortened in cells incubated with shikonin or etoposide reverted to that of control cells after continued incubation without these compounds. These findings indicated that shikonin and etoposide shorten the circadian period reversibly and through similar mechanisms. Topoisomerase II (Top2)-specific decatenation assays confirmed that shikonin, liker etoposide, is a Top2 inhibitor. Shikonin was incorporated into the nucleus and Top2 was located in the Bmal1 promoter, suggesting the relationship between Bmal1 transcription and Top2 inhibition. Top2a siRNA also shortened period length, suggesting that Top2 is involved in this process. Promoter assays showed that Top2a siRNA, etoposide and shikonin reduce Bmal1 promoter activity. These findings indicated that Top2 is involved in Bmal1 transcription and influences the circadian period, and that shikonin is a novel contributor to the control of period length in mammalian cells. PMID:24321095

Ogawa, Yoshikatsu; Kawano, Yasuhiro; Yamazaki, Yoshimitsu; Onishi, Yoshiaki

2014-01-01

309

Mechanisms behind the inhibition of lung adenocarcinoma cell by shikonin.  

PubMed

Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicinal herb, can exert inhibitory effect on tumor cell growth. However, little has been known concerning the effect of shikonin on lung adenocarcinoma cell and underlying mechanisms. In the present study, we investigated the effect of shikonin on the proliferation, cell cycle arrest, and apoptosis in human lung adenocarcinoma cells. We found that shikonin significantly suppressed the proliferation of lung adenocarcinoma cells compared with control in dose- and time-dependent manner (P < 0.05). In the meantime, our results showed that shikonin markedly increased the proportion of A549 cells at stage G1 as well as induced apoptosis in A549 cells. Furthermore, suppressed CCND1 and elevated caspase3 and caspase7 expression levels at mRNA were found in this study, indicating that shikonin may inhibit the growth of lung adenocarcinoma cell by changing cell cycle and promoting cell apoptosis through the regulation of CCND1, caspase3, and caspase7. Although more studies are needed, this study suggests that shikonin has the potential to be used as an anti-cancer agent in the treatment of lung adenocarcinoma. PMID:24972691

Lan, Wenjing; Wan, Shengbang; Gu, Weiqing; Wang, Heyong; Zhou, Songwen

2014-11-01

310

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. PMID:23118796

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

2012-01-01

311

Modulatory effects of Tabebuia impetiginosa (Lamiales, Bignoniaceae) on doxorubicin-induced somatic mutation and recombination in Drosophila melanogaster  

PubMed Central

The wing Somatic Mutation and Recombination Test (SMART) in D. melanogaster was used to study genotoxicity of the medicinal plant Tabebuia impetiginosa. Lapachol (naphthoquinone) and ?-lapachone (quinone) are the two main chemical constituents of T. impetiginosa. These compounds have several biological properties. They induce apoptosis by generating oxygen-reactive species, thereby inhibiting topoisomerases (I and II) or inducing other enzymes dependent on NAD(P)H:quinone oxidoreductase 1, thus affecting cell cycle checkpoints. The SMART was used in the standard (ST) version, which has normal levels of cytochrome P450 (CYP) enzymes, to check the direct action of this compound, and in the high bioactivation (HB) version, which has a high constitutive level of CYP enzymes, to check for indirect action in three different T. impetiginosa concentrations (10%, 20% or 40% w/w). It was observed that T. impetiginosa alone did not modify the spontaneous frequencies of mutant spots in either cross. The negative results observed prompted us to study this phytotherapeuticum in association with the reference mutagen doxorubicin (DXR). In co-treated series, T. impetiginosa was toxic in both crosses at higher concentration, whereas in the HB cross, it induced a considerable potentiating effect (from ~24.0 to ~95.0%) on DXR genotoxity. Therefore, further research is needed to determine the possible risks associated with the exposure of living organisms to this complex mixture. PMID:21637695

2009-01-01

312

Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC-UV and HPTLC.  

PubMed

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

2013-07-01

313

CRM1 is a direct cellular target of the natural anti-cancer agent plumbagin.  

PubMed

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, has been shown to exert anti-cancer and anti-proliferative activities in vitro as well as in animal tumor models. However, the mechanism underlying its anti-tumor action still remains unclear. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors whose function is altered in cancer due to increased expression and overactive transport. We showed that CRM1 is a direct cellular target of plumbagin. The nuclei of cells incubated with plumbagin accumulated tumor-suppressor proteins and inhibited the interactions between CRM1 and these proteins. Particularly, we demonstrated that plumbagin could specifically react with the conserved Cys(528) of CRM1 but not with a Cys(528) mutant peptide through Mass spectrometric analysis. More importantly, cancer cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of plumbagin, demonstrating that the inhibition is through direct interaction with Cys(528) of CRM1. The inhibition of nuclear traffic by plumbagin may account for its therapeutic properties in cancer and inflammatory diseases. Our findings could contribute to the development of a new class of CRM1 inhibitors. PMID:24739265

Liu, Xuejiao; Niu, Mingshan; Xu, Xiaoyu; Cai, Wei; Zeng, Lingyu; Zhou, Xiuping; Yu, Rutong; Xu, Kailin

2014-01-01

314

Evaluation of radical scavenging properties of shikonin  

PubMed Central

With the aim of developing effective anti-inflammatory drugs, we have been investigating the biochemical effects of shikonin of “Shikon” roots, which is a naphthoquinone with anti-inflammatory and antioxidative properties. Shikonin scavenged reactive oxygen species like hydroxyl radical, superoxide anion (O2•?) and singlet oxygen in previous studies, but its reactivity with reactive oxygen species is not completely understood, and comparison with standard antioxidants is lacking. This study aimed elucidation of the reactivity of shikonin with nitric oxide radical and reactive oxygen species such as alkyl-oxy radical and O2•?. By using electron paramagnetic resonance spectrometry, shikonin was found unable of reacting with nitric oxide radical in a competition assay with oxyhemoglobin. However, shikonin scavenged alkyl-oxy radical from 2,2'-azobis(2-aminopropane) dihydrochloride with oxygen radical absorbance capacity, ORAC of 0.25 relative to Trolox, and showed a strong O2•?-scavenging ability (42-fold of Trolox; estimated reaction rate constant: 1.7 × 105 M?1s?1) in electron paramagnetic resonance assays with CYPMPO as spin trap. Concerning another source of O2•?, the phagocyte NADPH oxidase (Nox2), shikonin inhibited the Nox2 activity by impairing catalysis when added before enzyme activation (IC50: 1.1 µM; NADPH oxidation assay). However, shikonin did not affect the preactivated Nox2 activity, although having potential to scavenge produced O2•?. In conclusion, shikonin scavenged O2•? and alkyl-oxy radical, but not nitric oxide radical. PMID:25320455

Yoshida, Lucia S.; Kohri, Shunji; Tsunawaki, Shohko; Kakegawa, Tomohito; Taniguchi, Taizo; Takano-Ohmuro, Hiromi; Fujii, Hirotada

2014-01-01

315

Synthesis and molecular structure of a zinc complex of the vitamin K3 analogue phthiocol  

NASA Astrophysics Data System (ADS)

The complex [Zn(phthiocol)2(H2O)2]; 1, where phthiocol is 2-hydroxy-3-methyl-1,4-naphthoquinone, has been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-vis spectroscopy, thermogravimetric (TG) analysis, electrochemical and single crystal X-ray diffraction studies. The ?CO stretch shifts to lower frequencies upon complexation of phthiocol to Zn2+. 1H NMR spectra show an upfield shift of the benzenoid ring protons in 1. There is a bathochromic shift of the LMCT band in the UV-vis spectra of 1. Single crystal X-ray structure of 1 show distorted octahedral geometry around Zn2+. Two phthiocol ligands are in plane with the metal, while water molecules are trans to this plane. Coordination of deprotonated phthiocol ligands is 'trans, trans' to Zn2+. Intra as well as intermolecular interactions are observed in 1. Molecules of 1 show three dimensional network through CH⋯O and OH⋯O interactions. Additional anodic peaks are observed in cyclic voltammogram of phthiocol ligand due to oxidation of reduced species formed during reduction. One-electron reduction of 1 is shown to be reversible and DFT studies define this redox event as ligand-centered.

Kathawate, Laxmi; Sproules, Stephen; Pawar, Omkar; Markad, Ganesh; Haram, Santosh; Puranik, Vedavati; Salunke-Gawali, Sunita

2013-09-01

316

Biopesticides from plants: Calceolaria integrifolia s.l.  

PubMed

The effects of persistent organic pollutants (POPs) on humans and biodiversity are multiple and varied. Nowadays environmentally-friendly pesticides are strongly preferred to POPs. It is noteworthy that the crop protection role of pesticides and other techniques, i.e. biopesticides, plant extracts, prevention methods, organic methods, evaluation of plant resistance to certain pests under an integrated pest management (IPM), could improve the risks and benefits which must be assessed on a sound scientific basis. For this directive it is crucial to bring about a significant reduction in the use of chemical pesticides, not least through the promotion of sustainable alternative solutions such as organic farming and IPM. Biopesticides are derived from natural materials such as animals, plants, bacteria, and certain minerals. Most of them are biodegradable in relatively short periods of time. On this regard, substances from Calceolaria species emerge as a strong alternative to the use of POPs. The American genus Calceolaria species are regarded both as a notorious weeds and popular ornamental garden plants. Some have medicinal applications. Other taxa of Calceolaria are toxic to insects and resistant to microbial attack. These properties are probably associated with the presence of terpenes, iridoids, flavonoids, naphthoquinones and phenylpropanoids previously demonstrated to have interesting biological activities. In this article a comprehensive evaluation of the potential utilization of Calceolaria species as a source of biopesticides is made. The chemical profile of selected members of the Chilean Calceolaria integrifolia sensu lato complex represents a significant addition to previous studies. New secondary metabolites were isolated, identified and tested for their antifeedant, insect growth regulation and insecticidal activities against Spodoptera frugiperda and Drosophila melanogaster. These species serve as a model of insect pests using conventional procedures. Additionally, bactericidal and fungicidal activity were determined. Dunnione mixed with gallic acid was the most active fungistatic and fungicidal combination encountered. Several compounds as isorhamnetin, combined with ferulic and gallic acid quickly reduced cell viability, but cell viability was recovered quickly and did not differ from that of the control. The effect of these mixtures on cultures of Aspergillus niger, Fusarium moniliforme, Fusarium sporotrichum, Rhizoctonia solani, and Trichophyton mentagrophytes, was sublethal. However, when fungistatic isorhamnetin and dunnione were combined with sublethal amounts of both ferulic and gallic acid, respectively, strong fungicidal activity against theses strains was observed. Thus, dunnione combined with gallic acid completely restricted the recovery of cell viability. This apparent synergistic effect was probably due to the blockade of the recovery process from induced-stress. The same series of phenolics (iridoids, flavonoids, naphthoquinones and phenylpropanoids) were also tested against the Gram-negative bacteria Escherichia coli, Enterobacter agglomerans, and Salmonella typhi, and against the Gram-positive bacteria Bacillus subtilis, Sarcinia lutea, and Staphylococcus aureus and their effects compared with those that of kanamycin. Mixtures of isorhamnetin/dunnione/kaempferol/ferulic/gallic acid in various combinations were found to have the most potent bactericidal and fungicidal activity with MFC between 10 and 50 ?g/ml. Quercetin was found to be the most potent fungistatic single compound with an MIC of 15 µg/ml. A time-kill curve study showed that quercetin was fungicidal against fungi assayed at any growth stage. This antifungal activity was slightly enhanced by combination with gallic acid. The primary antifungal action of the mixtures assayed likely comes from their ability to act as nonionic surfactants that disrupt the function of native membrane-associated proteins. Hence, the antifungal activity of isorhamnetin and other O-methyl flavonols appears to be mediated by biophysical processes. Maxim

Céspedes, Carlos L; Salazar, Juan R; Ariza-Castolo, Armando; Yamaguchi, Lydia; Avila, José G; Aqueveque, Pedro; Kubo, Isao; Alarcón, Julio

2014-07-01

317

Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants.  

PubMed

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

2012-04-01

318

Isolation and characterization of photosynthetic reaction centers from Rhodopseudomonas capsulata and Rhodopseudomonas sphaeroides  

SciTech Connect

Reaction centers were isolated by affinity chromatography on equine cytochrome C. Peripheral proteins were removed with 0.05% LDAO. Absorption and EPR spectra and bleaching assays indicate that the reaction centers retained their electron donors and acceptors in the native environment. Three reaction center polypeptides were isolated and submitted for amino-terminal sequence determination. By comparing these sequences to those deduced from DNA, it was established that the M and L subunits are post-translationally modified to remove the aminoterminal Met, whereas the H subunit is not. Inhibition of O/sub 2/ evolution in photosystem II particles from spinach by naphthoquinone derivatives show O/sub 2/ inhibition by bromomethyl and acetoxymethyl derivatives but not with hydroxymethyl derivatives. Inhibition by acetoxymethyl derivatives in irreversible and dependent on illumination suggesting that reduction of the quinone is necessary. Therefore acetoxymethyl derivatives may be useful as suicide reagents for labelling quinone binding sites. Procedures were developed to extract one or both of the quinones present in reaction centers and preserve the integrity of the co-factor binding sites. The H and M subunits were cleaned using furmic acid. Both fragments were isolated from the H subunit, while the larger fragment was isolated from the M subunit. Electrophoretic mobilities of the isolated fragments agrees well with the expected molecular weights. The L subunit was digested with Staphylococcus areus vs protease. The pattern obtained was consistant with the potential sites of cleavage, but it was not possible to assign cleavage sites unambiguously. 112 references, 37 figures, 2 tables.

Worland, S.T.

1984-09-01

319

Reactive Oxygen Species Prevent Imiquimod-Induced Psoriatic Dermatitis through Enhancing Regulatory T Cell Function  

PubMed Central

Psoriasis is a chronic inflammatory skin disease resulting from immune dysregulation. Regulatory T cells (Tregs) are important in the prevention of psoriasis. Traditionally, reactive oxygen species (ROS) are known to be implicated in the progression of inflammatory diseases, including psoriasis, but many recent studies suggested the protective role of ROS in immune-mediated diseases. In particular, severe cases of psoriasis vulgaris have been reported to be successfully treated by hyperbaric oxygen therapy (HBOT), which raises tissue level of ROS. Also it was reported that Treg function was closely associated with ROS level. However, it has been only investigated in lowered levels of ROS so far. Thus, in this study, to clarify the relationship between ROS level and Treg function, as well as their role in the pathogenesis of psoriasis, we investigated imiquimod-induced psoriatic dermatitis (PD) in association with Treg function both in elevated and lowered levels of ROS by using knockout mice, such as glutathione peroxidase-1?/? and neutrophil cytosolic factor-1?/? mice, as well as by using HBOT or chemicals, such as 2,3-dimethoxy-1,4-naphthoquinone and N-acetylcysteine. The results consistently showed Tregs were hyperfunctional in elevated levels of ROS, whereas hypofunctional in lowered levels of ROS. In addition, imiquimod-induced PD was attenuated in elevated levels of ROS, whereas aggravated in lowered levels of ROS. For the molecular mechanism that may link ROS level and Treg function, we investigated the expression of an immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO) which is induced by ROS, in PD lesions. Taken together, it was implied that appropriately elevated levels of ROS might prevent psoriasis through enhancing IDO expression and Treg function. PMID:24608112

Choi, Eun-Jeong; Hong, Min-Pyo; Kie, Jeong-Hae; Lim, Woosung; Lee, Hyeon Kook; Moon, Byung-In; Seoh, Ju-Young

2014-01-01

320

Utility of certain nucleophilic aromatic substitution reactions for the assay of pregabalin in capsules  

PubMed Central

Background Pregabalin (PG) is an anticonvulsant, analgesic and anxiolytic drug. A survey of the literature reveals that all the reported spectrophotometric methods are either don't offer high sensitivity, need tedious extraction procedures, recommend the measurement of absorbance in the near UV region where interference most probably occurs and/or use non specific reagent that don't offer suitable linearity range. Results Two new sensitive and simple spectrophotometric methods were developed for determination of pregabalin (PG) in capsules. Method (I) is based on the reaction of PG with 1,2-naphthoquinone-4-sulphonate sodium (NQS), yielding an orange colored product that was measured at 473 nm. Method (II) is based on the reaction of the drug with 2,4-dinitrofluorobenzene (DNFB) producing a yellow product measured at 373 nm. The different experimental parameters affecting the development and stability of the reaction product in methods (I) and (II) were carefully studied and optimized. The absorbance-concentration plots were rectilinear over the concentration ranges of 2-25 and 0.5-8 ?g mL-1 for methods (I) and (II) respectively. The lower detection limits (LOD) were 0.15 and 0.13 ?g mL-1 and the lower quantitation limits (LOQ) were 0.46 and 0.4 ?g mL-1 for methods (I) and (II) respectively. Conclusion The developed methods were successfully applied to the analysis of the drug in its commercial capsules. The mean percentage recoveries of PG in its capsule were 99.11 ± 0.98 and 100.11 ± 1.2 (n = 3). Statistical analysis of the results revealed good agreement with those given by the comparison method. Proposals of the reaction pathways were postulated. PMID:21711563

2011-01-01

321

Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents.  

PubMed

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

2012-01-01

322

Accelerated removal of Sudan dye by Shewanella oneidensis MR-1 in the presence of quinones and humic acids.  

PubMed

Although there have been many studies on bacterial removal of soluble azo dyes, much less information is available for biological treatment of water-insoluble azo dyes. The few bacterial species capable of removing Sudan dye generally require a long time to remove low concentrations of insoluble dye particles. The present work examined the efficient removal of Sudan I by Shewanella oneidensis MR-1 in the presence of redox mediator. It was found that the microbially reduced anthraquinone-2,6-disulfonate (AQDS) could abiotically reduce Sudan I, indicating the feasibility of microbially-mediated reduction. The addition of 100 ?M AQDS and other different quinone compounds led to 4.3-54.7 % increase in removal efficiencies in 22 h. However, adding 5-hydroxy-1,4-naphthoquinone into the system inhibited Sudan I removal. The presence of 10, 50 and 100 ?M AQDS stimulated the removal efficiency in 10 h from 26.4 to 42.8, 54.9 and 64.0 %, respectively. The presence of 300 ?M AQDS resulted in an eightfold increase in initial removal rate from 0.19 to 1.52 mg h?¹ g?¹ cell biomass. A linear relationship was observed between the initial removal rates and AQDS concentrations (0-100 ?M). Comparison of Michaelis-Menten kinetic constants revealed the advantage of AQDS-mediated removal over direct reduction. Different species of humic acid could also stimulate the removal of Sudan I. Scanning electronic microscopy analysis confirmed the accelerated removal performance in the presence of AQDS. These results provide a potential method for the efficient removal of insoluble Sudan dye. PMID:23539152

Liu, Guangfei; Zhou, Jiti; Ji, Qiuyan; Wang, Jing; Jin, Ruofei; Lv, Hong

2013-09-01

323

Mechanism-based inactivation of cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus constituents.  

PubMed

  Human cytochrome P450 CYP2A6 and CYP2A13 catalyze nicotine metabolisms and mediate activation of tobacco-specific carcinogens including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we found rhinacanthins A, B, and C isolated from Rhinacanthus nasutus potentially inhibited coumarin 7-hydroxylation mediated by reconstituted purified recombinant CYP2A6 and CYP2A13. Rhinacanthins A-C are mechanism-based inactivators of CYP2A6 and CYP2A13 as they cause concentration, time and NADPH-dependent inhibition. Among the three rhinacanthins, rhinacanthin-B possessed highest inhibitory potency against CYP2A13 with apparent KI and kinact of 0.16 µM and 0.1 min(-1), respectively, while values of 0.44 µM and 0.12 min(-1) were found against CYP2A6. Rhinacanthin-C had least inhibition potency, with apparent KI and kinact of 0.97 µM and 0.07 min(-1) for CYP2A6, respectively, and values of 1.68 µM and 0.05 min(-1) for CYP2A13. Rhinacanthin-A inhibited CYP2A6 and CYP2A13 with apparent KI values of 0.69 and 0.42 µM, respectively and apparent kinact of 0.18 and 0.06 min(-1), respectively. The inhibition of both enzymes by rhinacanthins A-C could not be prevented by addition of trapping agents or reversed by dialysis or potassium ferricyanide. These findings demonstrated that rhinacanthins A-C, which are 1,4-naphthoquinone derivatives, irreversibly inhibited CYP2A6 and CYP2A13 in a mechanism-based inhibition mode. PMID:23903410

Pouyfung, Phisit; Prasopthum, Aruna; Sarapusit, Songklod; Srisook, Ekaruth; Rongnoparut, Pornpimol

2014-01-01

324

Analysis of Naphthalene Adduct Binding Sites in Model Proteins by Tandem Mass Spectrometry  

PubMed Central

The electrophilic metabolites of the polyaromatic hydrocarbon naphthalene have been shown to bind covalently to proteins and covalent adduct formation correlates with the cytotoxic effects of the chemical in the respiratory system. Although 1,2-naphthalene epoxide, naphthalene diol epoxide, 1,2-naphthoquinone, and 1,4-napthoquinone have been identified as reactive metabolites of interest, the role of each metabolite in total covalent protein adduction and subsequent cytotoxicity remains to be established. To better understand the target residues associated with the reaction of these metabolites with proteins, mass spectrometry was used to identify adducted residues following 1) incubation of metabolites with actin and protein disulfide isomerase (PDI), and 2) activation of naphthalene in microsomal incubations containing supplemental actin or PDI. All four reactive metabolites bound to Cys, Lys or His residues in actin and PDI. Cys17 of actin was the only residue adducted by all metabolites; there was substantial metabolite selectivity for the majority of adducted residues. Modifications of actin and PDI, following microsomal incubations containing 14C-naphthalene, were detected readily by 2D gel electrophoresis and phosphor imaging. However, target modifications on tryptic peptides from these isolated proteins could not be readily detected by MALDI/TOF/TOF and only three modified peptides were detected using high resolution – selective ion monitoring (HR-SIM). All the reactive metabolites investigated have the potential to modify several residues in a single protein, but even in tissues with very high rates of naphthalene activation, the extent of modification was too low to allow unambiguous identification of a significant number of modified residues in the isolated proteins. PMID:22659010

Pham, Nathalie T.; Jewell, William T.; Morin, Dexter; Buckpitt, Alan R.

2013-01-01

325

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy.  

PubMed

Epilepsy is a debilitating disease affecting 1-2% of the world's population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit histone deacetylases (HDACs) using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compound pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously determined to be a measurable manifestation of seizures. In our first screen, we tested a number of different HDAC inhibitors and found that one, 2-benzamido-1 4-naphthoquinone (NQN1), significantly decreased swim activity to levels equal to that of valproic acid, 2-n-propylpentanoic acid (VPA). We continued to screen structurally related compounds including Vitamin K3 (VK3) and a number of novel Vitamin K (VK) analogs. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compounds. Three of these compounds were subsequently tested on mouse seizure models at the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compound 2h reduced seizures particularly well in the minimal clonic seizure (6Hz) and corneal-kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogs for the prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production. PMID:24291671

Rahn, J J; Bestman, J E; Josey, B J; Inks, E S; Stackley, K D; Rogers, C E; Chou, C J; Chan, S S L

2014-02-14

326

From body art to anticancer activities: perspectives on medicinal properties of henna.  

PubMed

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

2012-12-01

327

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. PMID:22279374

Kora?, Radava R.; Khambholja, Kapil M.

2011-01-01

328

Antiparasitic activities of novel ruthenium/lapachol complexes.  

PubMed

The present study describes the synthesis, characterization, antileishmanial and antiplasmodial activities of novel diimine/(2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 4,4'-methylbipyridine (Me-bipy) and 4,4'-methoxybipyridine (MeO-bipy)/phosphine/ruthenium(II) complexes containing lapachol (Lap, 2-hydroxy-3-(3-33 methyl-2-buthenyl)-1,4-naphthoquinone) as bidentate ligand. The [Ru(Lap)(PPh3)2(bipy)]PF6 (1), [Ru(Lap)(PPh3)2(Me-bipy)]PF6 (2), [Ru(Lap)(PPh3)2(MeO-bipy)]PF6(3) and[Ru(Lap)(PPh3)2(phen)]PF6 (4) complexes, PPh3=triphenylphospine, were synthesized from the reactions of cis-[RuCl2(PPh3)2(X-bipy)] or cis-[RuCl2(PPh3)2(phen)], with lapachol. The [RuCl2(Lap)(dppb)] (5) [dppb=1,4-bis(diphenylphosphine)butane] was synthesized from the mer-[RuCl3(dppb)(H2O)] complex. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, (31)P{(1)H} and (1)H NMR, and cyclic voltammetry. The Ru(III) complex, [RuCl2(Lap)(dppb)], was also characterized by the EPR technique. The structure of the complexes [Ru(Lap)(PPh3)2(bipy)]PF6 and [RuCl2(Lap)(dppb)] was elucidated by X-ray diffraction. The evaluation of the antiparasitic activities of the complexes against Leishmania amazonensis and Plasmodium falciparum demonstrated that lapachol-ruthenium complexes are more potent than the free lapachol. The [RuCl2(Lap)(dppb)] complex is the most potent and selective antiparasitic compound among the five new ruthenium complexes studied in this work, exhibiting an activity comparable to the reference drugs. PMID:24727183

Barbosa, Marília I F; Corrêa, Rodrigo S; de Oliveira, Katia Mara; Rodrigues, Claudia; Ellena, Javier; Nascimento, Otaciro R; Rocha, Vinícius P C; Nonato, Fabiana R; Macedo, Taís S; Barbosa-Filho, José Maria; Soares, Milena B P; Batista, Alzir A

2014-07-01

329

Kinetics of naphthalene metabolism in target and non-target tissues of rodents and in nasal and airway microsomes from the Rhesus monkey  

SciTech Connect

Naphthalene produces species and cell selective injury to respiratory tract epithelial cells of rodents. In these studies we determined the apparent K{sub m}, V{sub max}, and catalytic efficiency (V{sub max}/K{sub m}) for naphthalene metabolism in microsomal preparations from subcompartments of the respiratory tract of rodents and non-human primates. In tissues with high substrate turnover, major metabolites were derived directly from naphthalene oxide with smaller amounts from conjugates of diol epoxide, diepoxide, and 1,2- and 1,4-naphthoquinones. In some tissues, different enzymes with dissimilar K{sub m} and V{sub max} appeared to metabolize naphthalene. The rank order of V{sub max} (rat olfactory epithelium > mouse olfactory epithelium > murine airways ? rat airways) correlated well with tissue susceptibility to naphthalene. The V{sub max} in monkey alveolar subcompartment was 2% that in rat nasal olfactory epithelium. Rates of metabolism in nasal compartments of the monkey were low. The catalytic efficiencies of microsomes from known susceptible tissues/subcompartments are 10 and 250 fold higher than in rat airway and monkey alveolar subcompartments, respectively. Although the strong correlations between catalytic efficiencies and tissue susceptibility suggest that non-human primate tissues are unlikely to generate metabolites at a rate sufficient to produce cellular injury, other studies showing high levels of formation of protein adducts support the need for additional studies. - Highlights: • Naphthalene is metabolized with high catalytic efficiency in susceptible tissue. • Naphthalene is metabolized at low catalytic efficiency in non-susceptible tissue. • Respiratory tissues of the non human primate metabolize naphthalene slowly.

Buckpitt, Alan, E-mail: arbuckpitt@ucdavis.edu [Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States); Morin, Dexter [Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States); Murphy, Shannon; Edwards, Patricia; Van Winkle, Laura [Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States); Center for Health and the Environment, UC Davis, Davis, CA 95616 United States (United States)

2013-07-15

330

Tanshinone IIA inhibits viral oncogene expression leading to apoptosis and inhibition of cervical cancer.  

PubMed

Human papilloma virus (HPV) is the well-established etiological factor of cervical cancer. E6 and E7 oncoproteins expressed by HPV are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Tanshinone IIA (Tan IIA) is a diterpenoid naphthoquinone found in the traditional Chinese medicine Danshen (Salvia sp.). Tan IIA has been shown to possess anti-tumor activity against several cancer types. In this study we show that Tan IIA potently inhibited proliferation of the human cervical cancer CaSki, SiHa, HeLa and C33a cells. Mechanistically in HPV positive CaSki cells, Tan IIA was found to (i) downregulate expression of HPV E6 and E7 genes and modulate associated proteins E6AP and E2F1, (ii) cause S phase cell cycle arrest, (iii) induce accumulation of p53 and alter expression of p53-dependent targets, (iv) modulate pRb and related proteins, and (v) cause p53-mediated apoptosis by moderating Bcl2, Bax, caspase-3, and PARP cleavage expressions. In vivo, Tan IIA resulted in over 66% reduction in tumor volume of cervical cancer xenograft in athymic nude mice. Tan IIA treated tumor tissues had lower expression of proliferation marker PCNA and changes in apoptosis targets were in agreement with in vitro studies, further confirming reduced proliferation and involvement of multiple targets behind anti-cancer effects. This is the first demonstration of Tan IIA to possess significant anti-viral activity by repressing HPV oncogenes leading to inhibition of cervical cancer. Together, our data suggest that Tan IIA can be exploited as a potent therapeutic agent for the prevention and treatment of cervical and other HPV-related cancers. PMID:25304375

Munagala, Radha; Aqil, Farrukh; Jeyabalan, Jeyaprakash; Gupta, Ramesh C

2015-01-28

331

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2  

PubMed Central

Acetyl Coenzyme A-dependent N-, O- and N,O-acetylation of aromatic amines and hydrazines by arylamine N-acetyltransferases is well characterised. Here, we describe experiments demonstrating that human arylamine N-acetyltransferase Type 1 and its murine homologue (Type 2) can also catalyse the direct hydrolysis of acetyl Coenzyme A in the presence of folate. This folate-dependent activity is exclusive to these two isoforms; no acetyl Coenzyme A hydrolysis was found when murine arylamine N-acetyltransferase Type 1 or recombinant bacterial arylamine N-acetyltransferases were incubated with folate. Proton nuclear magnetic resonance spectroscopy allowed chemical modifications occurring during the catalytic reaction to be analysed in real time, revealing that the disappearance of acetyl CH3 from acetyl Coenzyme A occurred concomitantly with the appearance of a CH3 peak corresponding to that of free acetate and suggesting that folate is not acetylated during the reaction. We propose that folate is a cofactor for this reaction and suggest it as an endogenous function of this widespread enzyme. Furthermore, in silico docking of folate within the active site of human arylamine N-acetyltransferase Type 1 suggests that folate may bind at the enzyme’s active site, and facilitate acetyl Coenzyme A hydrolysis. The evidence presented in this paper adds to our growing understanding of the endogenous roles of human arylamine N-acetyltransferase Type 1 and its mouse homologue and expands the catalytic repertoire of these enzymes, demonstrating that they are by no means just xenobiotic metabolising enzymes but probably also play an important role in cellular metabolism. These data, together with the characterisation of a naphthoquinone inhibitor of folate-dependent acetyl Coenzyme A hydrolysis by human arylamine N-acetyltransferase Type 1/murine arylamine N-acetyltransferase Type 2, open up a range of future avenues of exploration, both for elucidating the developmental role of these enzymes and for improving chemotherapeutic approaches to pathological conditions including estrogen receptor-positive breast cancer. PMID:24823794

Laurieri, Nicola; Dairou, Julien; Egleton, James E.; Stanley, Lesley A.; Russell, Angela J.; Dupret, Jean-Marie; Sim, Edith; Rodrigues-Lima, Fernando

2014-01-01

332

From arylamine N-acetyltransferase to folate-dependent acetyl CoA hydrolase: impact of folic acid on the activity of (HUMAN)NAT1 and its homologue (MOUSE)NAT2.  

PubMed

Acetyl Coenzyme A-dependent N-, O- and N,O-acetylation of aromatic amines and hydrazines by arylamine N-acetyltransferases is well characterised. Here, we describe experiments demonstrating that human arylamine N-acetyltransferase Type 1 and its murine homologue (Type 2) can also catalyse the direct hydrolysis of acetyl Coenzyme A in the presence of folate. This folate-dependent activity is exclusive to these two isoforms; no acetyl Coenzyme A hydrolysis was found when murine arylamine N-acetyltransferase Type 1 or recombinant bacterial arylamine N-acetyltransferases were incubated with folate. Proton nuclear magnetic resonance spectroscopy allowed chemical modifications occurring during the catalytic reaction to be analysed in real time, revealing that the disappearance of acetyl CH3 from acetyl Coenzyme A occurred concomitantly with the appearance of a CH3 peak corresponding to that of free acetate and suggesting that folate is not acetylated during the reaction. We propose that folate is a cofactor for this reaction and suggest it as an endogenous function of this widespread enzyme. Furthermore, in silico docking of folate within the active site of human arylamine N-acetyltransferase Type 1 suggests that folate may bind at the enzyme's active site, and facilitate acetyl Coenzyme A hydrolysis. The evidence presented in this paper adds to our growing understanding of the endogenous roles of human arylamine N-acetyltransferase Type 1 and its mouse homologue and expands the catalytic repertoire of these enzymes, demonstrating that they are by no means just xenobiotic metabolising enzymes but probably also play an important role in cellular metabolism. These data, together with the characterisation of a naphthoquinone inhibitor of folate-dependent acetyl Coenzyme A hydrolysis by human arylamine N-acetyltransferase Type 1/murine arylamine N-acetyltransferase Type 2, open up a range of future avenues of exploration, both for elucidating the developmental role of these enzymes and for improving chemotherapeutic approaches to pathological conditions including estrogen receptor-positive breast cancer. PMID:24823794

Laurieri, Nicola; Dairou, Julien; Egleton, James E; Stanley, Lesley A; Russell, Angela J; Dupret, Jean-Marie; Sim, Edith; Rodrigues-Lima, Fernando

2014-01-01

333

Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol  

SciTech Connect

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.

Maeda, Masayo [Department of Chemistry, Kanazawa Medical University, Uchinada, Ishikawa 920-0293 (Japan); Murakami, Manabu; Takegami, Tsutomu [Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293 (Japan); Ota, Takahide [Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293 (Japan)], E-mail: takahide@kanazawa-med.ac.jp

2008-06-01

334

The Lipids of Pneumocystis carinii  

PubMed Central

Information about a number of Pneumocystis carinii lipids obtained by the analyses of organisms isolated and purified from infected lungs of corticosteroid-immunosuppressed rats has been reported in recent years. Of the common opportunistic protists associated with AIDS (Cryptosporidium, Toxoplasma, and the microsporidia), more is currently known about the lipids of P. carinii than the others. Lipids that are synthesized by the organism but not by humans are attractive targets for drug development. Thus, the elucidation of ?7C-24-alykylated sterol and cis-9,10-epoxystearic acid biosyntheses in P. carinii is currently being examined in detail, since these have been identified as P. carinii-specific lipids. The development of low-toxicity drugs that prevent sterol C-24 alkylation and the specific inhibition of the lipoxygenase that forms cis-9,10-epoxystearic acid might prove fruitful. Although humans can synthesize coenzyme Q10, the anti-P. carinii activity and low toxicity of ubiquinone analogs such as atovaquone suggest that the electron transport chain in the pathogen may differ importantly from that in the host. Although resistance to atovaquone has been observed, development of other naphthoquinone drugs would provide a broader armamentarium of drugs to treat patients with P. carinii pneumonia. Studies of bronchoalveolar lavage fluid and of infected lungs have demonstrated that the infection causes a number of chemical abnormalities. Bronchoalveolar lavage fluid obtained after the removal of lung cellular material and the organisms has been shown to contain larger amounts of surfactant proteins and smaller amounts of phospholipids than do comparable samples from P. carinii-free lungs. Increased phospholipase activity, inhibition of surfactant secretion by type II cells, and uptake and catabolism of lipids by the pathogen may explain this phenomenon related to P. carinii pneumonia. Although not yet thoroughly examined, initial studies on the uptake and metabolism of lipids by P. carinii suggest that the organism relies heavily on exogenous lipid nutrients. PMID:9457427

Kaneshiro, Edna S.

1998-01-01

335

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. PMID:16332831

White, David C.; Geyer, Roland; Peacock, Aaron D.; Hedrick, David B.; Koenigsberg, Stephen S.; Sung, Youlboong; He, Jianzhong; Löffler, Frank E.

2005-01-01

336

A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme.  

PubMed

Glutathione reductase is an important housekeeping enzyme for redox homeostasis both in human cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid, called M(5), as a potent reversible and uncompetitive inhibitor of both human and P. falciparum glutathione reductases. Here we describe the synthesis and kinetic characterization of a fluoromethyl-M(5) analogue that acts as a mechanism-based inhibitor of both enzymes. In the course of enzymatic catalysis, the suicide substrate is activated by one- or two-electron reduction, and then a highly reactive quinone methide is generated upon elimination of the fluorine. Accordingly the human enzyme was found to be irreversibly inactivated with a k(inact) value of 0.4 +/- 0.2 min(-1). The crystal structure of the alkylated enzyme was solved at 1.7 A resolution. It showed the inhibitor to bind covalently to the active site Cys58 and to interact noncovalently with His467', Arg347, Arg37, and Tyr114. On the basis of the crystal structure of the inactivated human enzyme and stopped-flow kinetic studies with two- and four-electron-reduced forms of the unreacted P. falciparum enzyme, a mechanism is proposed which explains naphthoquinone reduction at the flavin of glutathione reductase. PMID:16910673

Bauer, Holger; Fritz-Wolf, Karin; Winzer, Andreas; Kühner, Sebastian; Little, Susan; Yardley, Vanessa; Vezin, Hervé; Palfey, Bruce; Schirmer, R Heiner; Davioud-Charvet, Elisabeth

2006-08-23

337

Plumbagin inhibits cell growth and potentiates apoptosis in human gastric cancer cells in vitro through the NF-?B signaling pathway  

PubMed Central

Aim: To investigate the effects and underlying mechanisms of plumbagin, a naphthoquinone derived from medicinal plant Plumbago zeylanica, on human gastric cancer (GC) cells. Methods: Human gastric cancer cell lines SGC-7901, MKN-28, and AGS were used. The cell viability was examined using CCK-8 viability assay. Cell proliferation rate was determined using both clonogenic assay and EdU incorporation assay. Apoptosis was detected via Annexin V/propidium iodide double-labeled flow cytometry. Western blotting was used to assess the expression of both NF-?B-regulated gene products and TNF-?-induced activation of p65, I?B?, and IKK. The intracellular location of NF-?B p65 was detected using confocal microscopy. Results: Plumbagin (2.5–40 ?mol/L) concentration-dependently reduced the viability of the GC cells. The IC50 value of plumbagin in SGC-7901, MKN-28, and AGS cells was 19.12, 13.64, and 10.12 ?mol/L, respectively. The compound (5–20 ?mol/L) concentration-dependently induced apoptosis of SGC-7901 cells, and potentiated the sensitivity of SGC-7901 cells to chemotherapeutic agents TNF-?and cisplatin. The compound (10 ?mol/L) downregulated the expression of NF-?B-regulated gene products, including IAP1, XIAP, Bcl-2, Bcl-xL, tumor factor (TF), and VEGF. In addition to inhibition of NF-?B p65 nuclear translocation, the compound also suppressed TNF-?-induced phosphorylation of p65 and IKK, and the degradation of I?B?. Conclusion: Plumbagin inhibits cell growth and potentiates apoptosis in human GC cells through the NF-?B pathway. PMID:22231395

Li, Jing; Shen, Lin; Lu, Fu-rong; Qin, You; Chen, Rui; Li, Jia; Li, Yan; Zhan, Han-zi; He, Yuan-qiao

2012-01-01

338

Proliferation and lymphocyte stimulatory capacity of Theileria-infected lymphoblastoid cells before and after the elimination of intracellular parasites.  

PubMed Central

A prominent pathogenic facet of Theileria infections is that the parasite infects lymphocytes and 'transforms' them into parasitized lymphoblastoid cells which are highly proliferative and can be cultured indefinitely in vitro. To analyse the relationship between the intracellular parasite and lymphocyte transformation we have studied the effects of eliminating parasites from these lymphoblastoid cells using the naphthoquinone derivative 993.C. Treatment of Theileria-infected lymphoblastoid cells with 993.C gradually eliminates intracellular parasites but cell proliferation is not inhibited until several days after parasite elimination. The proliferating cells no longer contain schizont particles and are medium-sized lymphocytes and small blast cells. The surface phenotype of these cells, as defined by lectins and monoclonal antibodies, remains unchanged after parasite elimination. The division of non-parasitized cells, under the culture conditions examined, was not indefinite. The compound 993.C itself does not appear to be mitogenic and possible mechanisms for this continued division are discussed. It has been previously reported that co-cultivation of irradiated Theileria-infected lymphoblastoid cells with autologous lymphocytes induces marked DNA synthesis in the latter. We examined further the relevance of this observation for immunity to Theileria by using lymphoblastoid cells treated with 993.C. Elimination of intracellular parasites by this compound does not impair the ability of these cells to stimulate DNA synthesis in autologous lymphocytes. Furthermore, lymphocytes from Theileria-immune or non-immune cattle react similarly. The reaction differs from a classical mixed lymphocyte reaction induced by antigens encoded in the main histocompatibility complex since the stimulator cells are exclusively T lymphocyte-derived cells, the magnitude of response is greater and stimulated lymphocytes are able to act as 'stimulator cells' to fresh autologous lymphocytes. Thus we question the immunological relevance of the observed lymphocyte division. The possibility that Theileria-infected lymphoblastoid cells carry viral genomes or infectious virus particles is discussed. Preliminary electron microscopic studies have not revealed any virus particles. PMID:6792058

Pinder, M; Kar, S; Withey, K S; Lundin, L B; Roelants, G E

1981-01-01

339

Proliferation and lymphocyte stimulatory capacity of Theileria-infected lymphoblastoid cells before and after the elimination of intracellular parasites.  

PubMed

A prominent pathogenic facet of Theileria infections is that the parasite infects lymphocytes and 'transforms' them into parasitized lymphoblastoid cells which are highly proliferative and can be cultured indefinitely in vitro. To analyse the relationship between the intracellular parasite and lymphocyte transformation we have studied the effects of eliminating parasites from these lymphoblastoid cells using the naphthoquinone derivative 993.C. Treatment of Theileria-infected lymphoblastoid cells with 993.C gradually eliminates intracellular parasites but cell proliferation is not inhibited until several days after parasite elimination. The proliferating cells no longer contain schizont particles and are medium-sized lymphocytes and small blast cells. The surface phenotype of these cells, as defined by lectins and monoclonal antibodies, remains unchanged after parasite elimination. The division of non-parasitized cells, under the culture conditions examined, was not indefinite. The compound 993.C itself does not appear to be mitogenic and possible mechanisms for this continued division are discussed. It has been previously reported that co-cultivation of irradiated Theileria-infected lymphoblastoid cells with autologous lymphocytes induces marked DNA synthesis in the latter. We examined further the relevance of this observation for immunity to Theileria by using lymphoblastoid cells treated with 993.C. Elimination of intracellular parasites by this compound does not impair the ability of these cells to stimulate DNA synthesis in autologous lymphocytes. Furthermore, lymphocytes from Theileria-immune or non-immune cattle react similarly. The reaction differs from a classical mixed lymphocyte reaction induced by antigens encoded in the main histocompatibility complex since the stimulator cells are exclusively T lymphocyte-derived cells, the magnitude of response is greater and stimulated lymphocytes are able to act as 'stimulator cells' to fresh autologous lymphocytes. Thus we question the immunological relevance of the observed lymphocyte division. The possibility that Theileria-infected lymphoblastoid cells carry viral genomes or infectious virus particles is discussed. Preliminary electron microscopic studies have not revealed any virus particles. PMID:6792058

Pinder, M; Kar, S; Withey, K S; Lundin, L B; Roelants, G E

1981-09-01

340

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

2012-01-01

341

Isolation of cellular membranes from lignin-producing tissues of Norway spruce and analysis of redox enzymes.  

PubMed

There are no earlier reports with successful isolation of plasma membranes from lignin-forming tissues of conifers. A method to isolate cellular membranes from extracellular lignin-producing tissue-cultured cells and developing xylem of Norway spruce was optimized. Modifications to the homogenization buffer were needed to obtain membranes from these phenolics-rich tissues. Membranes were separated by aqueous polymer two-phase partitioning. Chlorophyll a determination, marker enzyme assays and western blot analyses using antibodies for each membrane type showed that mitochondrial, chloroplastic and to a certain extent also ER and Golgi membranes were efficiently diminished from the upper phase, but tonoplast and plasma membranes distributed evenly between the upper and lower phases. Redox enzymes present in the partially purified membrane fractions were assayed in order to reveal the origin of H2 O2 needed for lignification. The membranes of spruce contained enzymes able to generate superoxide in the presence of NAD(P)H. Besides members of the flavodoxin and flavodoxin-like family proteins, cytochrome b5, cytochrome P450 and several stress responsive proteins were identified by nitroblue tetrazolium staining of isoelectric focusing gels and by mass spectrometry. Naphthoquinones juglone and menadione increased superoxide production in activity-stained gels. Some juglone-activated enzymes were preferentially using NADH. With NADH, menadione activated only some of the enzymes that juglone did, whereas with NADPH the activation patterns were identical. Duroquinone, a benzoquinone, did not affect superoxide production. Superoxide dismutase, ascorbate peroxidase, catalase and an acidic class III peroxidase isoenzyme were detected in partially purified spruce membranes. The possible locations and functions of these enzymes are discussed. PMID:24730578

Kärkönen, Anna; Meisrimler, Claudia-Nicole; Takahashi, Junko; Väisänen, Enni; Laitinen, Teresa; Jiménez Barboza, Luis Alexis; Holmström, Sami; Salonvaara, Sadette; Wienkoop, Stefanie; Fagerstedt, Kurt V; Lüthje, Sabine

2014-12-01

342

2-Methoxystypandrone represses RANKL-mediated osteoclastogenesis by down-regulating formation of TRAF6–TAK1 signalling complexes  

PubMed Central

BACKGROUND AND PURPOSE 2-Methoxystypandrone (2-MS) is a naphthoquinone isolated from Polygonum cuspidatum, a Chinese herb used to treat bone diseases. Here we have determined whether 2-MS antagonised osteoclast development and bone resorption. EXPERIMENTAL APPROACH RAW264.7 cells were treated with receptor activator of nuclear factor ?B (NF-?B) ligand (RANKL) to induce differentiation into osteoclasts. RT-PCR and Western blot were used to analyse osteoclast-associated gene expression and signalling pathways. KEY RESULTS The number of multinuclear osteoclasts, actin rings and resorption pit formation were markedly inhibited by 2-MS, targeting osteoclast differentiation at an early stage and without significant cytotoxicity. The anti-resorption effect of 2-MS was accompanied by decreasing dendritic cell-specific transmembrane protein and matrix metalloproteinase-9 (MMP-9) mRNA expression. RANKL-increased MMP-9 gelatinolytic activity was also attenuated by concurrent, but not by subsequent addition of 2-MS. 2-MS markedly inhibited not only the RANKL-triggered nuclear translocations of NF-?B, c-Fos and nuclear factor of activated T cells c1 (NFATc1), but also the subsequent NFATc1 induction. Degradation of I?B and phosphorylation of mitogen-activated protein kinases were also suppressed. RANKL facilitated the formation of singaling complexes of tumour necrosis factor receptor-associated factor 6 and transforming growth factor ?-activated kinase 1 (TRAF6–TAK1), important for osteoclastogenesis and formation of such signalling complexes was prevented by 2-MS. CONCLUSIONS AND IMPLICATIONS The anti-osteoclastogenic effects of 2-MS could reflect the block of RANKL-induced association of TRAF6–TAK1 complexes with consequent decrease of I?B-mediated NF-?B and mitogen-activated protein kinases-mediated c-Fos activation pathways and suppression of NFATc1 and other gene expression, essential for bone resorption. PMID:20735418

Chiou, WF; Liao, JF; Huang, CY; Chen, CC

2010-01-01

343

Shikonin Exerts Antitumor Activity via Proteasome Inhibition and Cell Death Induction in vitro and in vivo  

PubMed Central

Dysregulation of the ubiquitin-proteasome pathway plays an essential role in tumor growth and development. Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been reported to possess tumor cell-killing activity, and results from a clinical study using a shikonin-containing mixture demonstrated its safety and efficacy for the treatment of late-stage lung cancer. In the present study, we reported that shikonin is an inhibitor of tumor proteasome activity in vitro and in vivo. Our computational modeling predicts that the carbonyl carbons C1 and C4 of shikonin potentially interact with the catalytic site of ?5 chymotryptic subunit of the proteasome. Indeed, shikonin potently inhibits the chymotrypsin-like activity of purified 20S proteasome (IC50 12.5 ?mol/L) and tumor cellular 26S proteasome (IC50 between 2-16 ?mol/L). Inhibition of the proteasome by shikonin in murine hepatoma H22, leukemia P388 and human prostate cancer PC-3 cultures resulted in accumulation of ubiquitinated proteins and several proteasome target proapoptotic proteins (I?B-?, Bax and p27), followed by induction of cell death. Shikonin treatment resulted in tumor growth inhibition in both H22 allografts and PC-3 xenografts, associated with suppression of the proteasomal activity and induction of cell death in vivo. Finally, shikonin treatment significantly prolonged the survival period of mice bearing P388 leukemia. Our results indicate that the tumor proteasome is one of the cellular targets of shikonin, and inhibition of the proteasome activity by shikonin contributes to its anti-tumor property. PMID:19165859

Yang, Huanjie; Zhou, Ping; Huang, Hongbiao; Chen, Di; Ma, Ningfang; Cui, Cindy Qiuzhi; Shen, Shouxing; Dong, Weihua; Zhang, Xiaoyan; Lian, Wen; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao

2009-01-01

344

Synthesis and characterization of 2-(n-alkylamino)-1,4-napthoquinone: Molecular structures of ethyl and hexyl derivatives  

NASA Astrophysics Data System (ADS)

We would like to introduce seven analogues of 2-(n-alkylamino)-1,4-napthoquinone (where n-alkyl is methyl in LH-1, ethyl in LH-2, propyl in LH-3, butyl in LH-4, pentyl in LH-5, hexyl in LH-6 and heptyl in LH-7). All the said analogues have been successfully synthesized from 1,4-naphthoquinone and well characterised using different spectroscopic techniques. Furthermore, in order to understand the mechanistic aspects of formation of LH-1-LH-7 compounds we could propose the mechanism. The FT-IR spectroscopic analysis of LH-1-LH-7 compounds indicating that the presence of characteristic band of Nsbnd H group at ?3340 cm-1. This band could assigned to existence of intramolecular hydrogen bonding interactions. The 13C-NMR spectroscopic technique has been used to study structural feature of LH-1-LH-7 compounds via HSQC, COSY and DEPT experiments. Finally, the structural aspects of the LH-2-LH-6 compounds have been confirmed by single crystal X-ray diffraction studies. We could observed that LH-2 compound crystallises in monoclinic space group P21/c, whereas LH-6 crystallises in triclinic P-1 space group. The molecule of LH-2 and LH-6 compounds forms dimers via Nsbnd H⋯O hydrogen bonding interaction while polymeric chains of dimers have been seen via Csbnd H⋯O hydrogen bonding. It is very interesting to note that the molecules of LH-6 possessing a ?-? stacking interaction between C⋯N of the neighbouring chains.

Patil, Rishikesh; Chadar, Dattatray; Chaudhari, Dinkar; Peter, Justin; Nikalje, Milind; Weyhermüller, Thomas; Salunke-Gawali, Sunita

2014-10-01

345

Toxicological effects of polycyclic aromatic hydrocarbons and their derivatives on respiratory cells  

NASA Astrophysics Data System (ADS)

Polycyclic aromatic hydrocarbons (PAHs) are found in ambient aerosols and particulate matter. Experimental studies have shown that PAHs and related chemicals can induce toxicological effects. The present study aimed to investigate the effects of PAHs and their derivatives on the respiratory and immune systems and the underlying mechanisms. The human bronchial epithelial cell line BEAS-2B was exposed to PAHs and their derivatives, and the cytotoxicity and proinflammatory protein expression were then investigated. A cytotoxic effect was observed in BEAS-2B exposed to PAH derivatives such as naphthoquinone (NQ), phenanthrenequinone (PQ), 1-nitropyrene (1-NP), and 1-aminopyrene (1-AP). In addition, 1,2-NQ and 9,10-PQ showed more effective cytotoxicity than 1,4-NQ and 1,4-PQ, respectively. Pyrene showed a weak cytotoxic effect. On the other hand, naphthalene and phenanthrene showed no significant effects. Pyrene, 1-NP, and 1-AP also increased intercellular adhesion molecule-1 expression and interleukin-6 production in BEAS-2B. The increase was partly suppressed by protein kinase inhibitors such as the epidermal growth factor receptor-selective tyrosine kinase inhibitor and nuclear receptor antagonists such as the thyroid hormone receptor antagonist. The present study suggests that the toxicological effects of chemicals may be related to the different activities resulting from their structures, such as numbers of benzene rings and functional groups. Furthermore, the chemical-induced increase in proinflammatory protein expression in bronchial epithelial cells was possibly a result of the activation of protein kinase pathways and nuclear receptors. The increase may partly contribute to the adverse health effects of atmospheric PAHs.

Koike, Eiko; Yanagisawa, Rie; Takano, Hirohisa

2014-11-01

346

Opposing effects of nitroxide free radicals in Escherichia coli mutants deficient in DNA repair.  

PubMed

Nitroxide free radicals have been previously shown to function as superoxide dismutase (SOD) mimics and to protect bacterial and mammalian cells against oxidative damage, particularly from superoxide and hydrogen peroxide. Although nitroxides are generally considered to be non-toxic nor mutagenic, there is no agreement regarding their potential adverse effect. Some toxic effects were observed upon using high concentration of six-membered ring derivatives. Conflicting evidence has also been reported regarding the mutagenic activity of nitroxides toward Salmonella typhimurium. It was also demonstrated that nitroxides exert two opposing effects on exonuclease III deficient cells of Escherichia coli upon exposure to naphthoquinones. The attempts to use nitroxides as contrast agents in nuclear magnetic resonance imaging (MRI) and as a new class of anti-oxidants underscore the need to examine their potential adverse effects. Since nitroxides protected xthA cells from DNA scission caused by H2O2, it was anticipated that they would provide even greater protection for recA DNA repair-deficient cells of E. coli, which are more sensitive to H2O2-induced oxidative stress. The results of the present study showed that: (a) nitroxides exert bactericidal and bacteriostatic effects on recA but not on xthA or wild-type E. coli K12 cells; (b) nitroxides and H2O2 act synergistically on recA cells, both under aerobic and hypoxic conditions; (c) the nitroxide-induced toxicity in recA cells and the synergistic effect with H2O2 were not accompanied by a decrease in the cellular level of reduced glutathione; (d) TEMPAMINE protected against DNA scission induced by H2O2 and 1,10-ortho-phenanthroline chelate of Cu(II) in xthA cells, but potentiated DNA double-strand breakage in recA cells. PMID:8605254

Wang, G; Godinger, D; Aronovitch, J; Samuni, A

1996-02-01

347

Effect of medium composition and light on root and rhinacanthin formation in Rhinacanthus nasutus cultures.  

PubMed

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

2010-11-01

348

Secreted pitfall-trap fluid of carnivorous Nepenthes plants is unsuitable for microbial growth  

PubMed Central

Background and Aims Carnivorous plants of the genus Nepenthes possess modified leaves that form pitfall traps in order to capture prey, mainly arthropods, to make additional nutrients available for the plant. These pitchers contain a digestive fluid due to the presence of hydrolytic enzymes. In this study, the composition of the digestive fluid was further analysed with regard to mineral nutrients and low molecular-weight compounds. A potential contribution of microbes to the composition of pitcher fluid was investigated. Methods Fluids from closed pitchers were harvested and analysed for mineral nutrients using analytical techniques based on ion-chromatography and inductively coupled plasma–optical emission spectroscopy. Secondary metabolites were identified by a combination of LC-MS and NMR. The presence of bacteria in the pitcher fluid was investigated by PCR of 16S-rRNA genes. Growth analyses of bacteria and yeast were performed in vitro with harvested pitcher fluid and in vivo within pitchers with injected microbes. Key Results The pitcher fluid from closed pitchers was found to be primarily an approx. 25-mm KCl solution, which is free of bacteria and unsuitable for microbial growth probably due to the lack of essential mineral nutrients such as phosphate and inorganic nitrogen. The fluid also contained antimicrobial naphthoquinones, plumbagin and 7-methyl-juglone, and defensive proteins such as the thaumatin-like protein. Challenging with bacteria or yeast caused bactericide as well as fungistatic properties in the fluid. Our results reveal that Nepenthes pitcher fluids represent a dynamic system that is able to react to the presence of microbes. Conclusions The secreted liquid of closed and freshly opened Nepenthes pitchers is exclusively plant-derived. It is unsuitable to serve as an environment for microbial growth. Thus, Nepenthes plants can avoid and control, at least to some extent, the microbial colonization of their pitfall traps and, thereby, reduce the need to vie with microbes for the prey-derived nutrients. PMID:23264234

Buch, Franziska; Rott, Matthias; Rottloff, Sandy; Paetz, Christian; Hilke, Ines; Raessler, Michael; Mithöfer, Axel

2013-01-01

349

Functional anatomy of scent glands in Paranemastoma quadripunctatum (Opiliones, Dyspnoi, Nemastomatidae).  

PubMed

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

2011-10-01

350

Temperature-dependent quinone cytotoxicity in platelets involves arylation.  

PubMed

Menadione (MEN), a representative quinone compound, produces cytotoxicity in many cells by arylation with protein thiols and oxidative stress due to redox cycling. Previously it was demonstrated that protein arylation appears to be a primary mechanism for MEN-induced toxicity in platelets. To test the hypothesis that temperature conditions may be important in MEN-induced cytotoxicity in noncancer cells, platelets were incubated with menadione at 25, 37, or 42 degrees C. As temperature was increased, MEN significantly enhanced lactate dehydrogenase (LDH) leakage. MEN-induced depletion of protein thiol levels also increased as temperature was elevated. To investigate the mechanism of temperature-dependent MEN cytotoxicity, MEN-induced platelet toxicity was compared to two other quinone substances. Benzoquinone (BQ), which acts via arylation, produced cytotoxic effects similar to those of MEN. Dimethoxy-1,4-naphthoquinone (DMNQ), which exerts toxicity via oxidative radical generation, failed to produce cytotoxicity at all three temperatures. While MEN and DMNQ enhanced O(2) consumption in a temperature-dependent manner, BQ did not affect this parameter. MEN, which possesses an electrophilic 3-position, was found to react with thiols to form a thioether linkage, a direct indicator of arylation. In the case of MEN uptake kinetics, the amount of cellular uptake was not different at various temperatures, but concentration of MEN in extracellular medium decreased temperature dependently. This might be due to increased arylation capacity binding to cellular proteins as temperature rises. These data suggest that MEN-induced platelet cytotoxicity involves arylation that is temperature related. PMID:12227957

Kang, Young-Ah; Bae, Ok-Nam; Lee, Moo-Yeol; Chung, Seung-Min; Lee, Joo-Young; Chung, Jin-Ho

2002-09-27

351

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 Csbnd H⋯O and Nsbnd H⋯O close contacts. L-6 is a dimer formed by Nsbnd H⋯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

2013-10-01

352

Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways.  

PubMed

Metastasis is one of the most important factors related to prostate cancer therapeutic efficacy. In previous studies, shikonin, an active naphthoquinone isolated from the Chinese medicine Zi Cao, has various anticancer activities both in vivo and in vitro. However, the mechanisms underlying shikonin's anticancer activity are not fully elucidated on prostate cancer cells. In the present study, we aimed to investigate the potential effects of shikonin on prostate cancer cells and the underlying mechanisms by which shikonin exerted its actions. With cell proliferation, flow cytometric cell cycle, migration and invasion assays, we found that shikonin potently suppressed PC-3 and DU145 cell growth by cell cycle arrest at the G2 phase and metastasis in a dose-dependent manner. Mechanically, we presented that shikonin could suppress the metastasis of PC-3 and DU145 cells via inhibiting the matrix metalloproteinase-2 (MMP-2) and MMP-9 expression and activation. In addition, shikonin significantly decreased the phosphorylation of AKT and mTOR in a dose-dependent manner while it induced extracellular signal-regulated kinase (ERK), p38 mitogen activated protein kinase (MAPK) and c-Jun N terminal kinase (JNK) phosphorylation. Further investigation of the underlying mechanism revealed that shikonin also induced the production of reactive oxygen species (ROS) that was reversed by the ROS scavenger dithiothreitol (DTT). Additionally, DTT reversed the shikonin induced activation of ERK1/2, thereby maintaining MMP-2 and MMP-9 expression and restoring cell metastasis. Together, shikonin inhibits aggressive prostate cancer cell migration and invasion by reducing MMP-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways and presents a potential novel alternative agent for the treatment of human prostate cancer. PMID:24905636

Chen, Yongqiang; Zheng, Lu; Liu, Junquan; Zhou, Zhonghai; Cao, Xiliang; Lv, Xiaoting; Chen, Fuxing

2014-08-01

353

Shikonin attenuates lung cancer cell adhesion to extracellular matrix and metastasis by inhibiting integrin ?1 expression and the ERK1/2 signaling pathway.  

PubMed

Integrin ?1 facilitates cancer cell adhesion, migration and metastasis by activating intracellular signaling pathways including the ERK and PI3K signaling pathways. In previous studies, shikonin, an active naphthoquinone isolated from the Chinese medicine Zi Cao (gromwell), showed effective anticancer activity both in vivo and in vitro. However, the mechanisms underlying shikonin's anticancer activity are not fully elucidated. Increasing evidence indicates that shikonin inhibits tumor metastasis, but little is known about the effect of shikonin on lung cancer cells. To better understand the anti-metastatic role of shikonin in lung cancer, in this study we sought to investigate the effect of shikonin on lung cancer cell proliferation, adhesion to extracellular matrices (ECM), migration and invasion in non-small cell lung cancer A549 cells. We also sought to investigate the molecular mechanisms underlying shikonin's anticancer effects. Here we showed that when non-small cell lung cancer A549 cells were treated with shikonin for 24h, 8.0?M shikonin significantly inhibited cell proliferation, while cells treated with less than 2.0?M shikonin for 24h significantly suppressed cell adhesion to the ECM, invasion and migration in a dose-dependent manner. Moreover, real-time PCR and Western blot analysis showed that shikonin led to a reduction in the expression of integrin ?1 at the mRNA and protein levels. Further elucidation of the mechanisms involved revealed that shikonin repressed the phosphorylation of extracellular signal-regulated kinase (ERK1/2). Taken together, our findings provide new evidence that shikonin suppresses lung cancer invasion and metastasis by inhibiting integrin ?1 expression and the ERK1/2 signaling pathway. PMID:23562787

Wang, Heyong; Wu, Chunlian; Wan, Shengbang; Zhang, Huijun; Zhou, Songwen; Liu, Gentao

2013-06-01

354

Redox modulation of global phosphatase activity and protein phosphorylation in intact skeletal muscle  

PubMed Central

Skeletal muscles produce transient reactive oxygen species (ROS) in response to intense stimulation, disuse atrophy, heat stress, hypoxia, osmotic stress, stretch and cell receptor activation. The physiological significance is not well understood. Protein phosphatases (PPases) are known to be highly sensitive to oxidants and could contribute to many different signalling responses in muscle. We tested whether broad categories of PPases are inhibited by levels of acute oxidant exposure that do not result in loss of contractile function or gross oxidative stress. We also tested if this exposure results in elevated levels of global protein phosphorylation. Rat diaphragm muscles were treated with either 2,3-dimethoxy-1-naphthoquinone (DMNQ; 1, 10, 100 ?m; a mitochondrial O2•?/H2O2 generator) or exogenous H2O2 (5, 50, 500 ?m) for 30 min. Supernatants were assayed for serine/threonine PPase (Ser/Thr-PPase) or protein tyrosine PPase (PTP) activities. With the exception of 500 ?m H2O2, no other oxidant exposures significantly elevated protein carbonyl formation, nor did they alter the magnitude of twitch force. DMNQ significantly decreased all categories of PPase activity at 10 and 100 ?m and reduced PTP at 1 ?m. Similar reductions in Ser/Thr-PPase activity were seen in response to 50 and 500 ?m H2O2 and PTP at 500 ?m H2O2. ROS treatments resulted a dose-dependent increase in the phosphorylation states of many proteins. The data are consistent with the concept that PPases, within intact skeletal muscles, are highly sensitive to acute changes in ROS activity and that localized ROS play a critical role in lowering the barriers for effective phosphorylation events to occur in muscle cells, thus increasing the probability for cell signalling responses to proceed. PMID:19841000

Wright, Valerie P; Reiser, Peter J; Clanton, Thomas L

2009-01-01

355

NMR Studies Reveal an Unexpected Binding Site for a Redox Inhibitor of AP Endonuclease 1  

PubMed Central

AP endonuclease 1 (APE1) is a multi-faceted protein with essential roles in DNA repair and transcriptional regulation. APE1 (Ref-1) activates many transcription factors (TF), including AP-1 and NF-?B. While the mechanism of APE1 redox activity remains unknown, it may involve reduction of an oxidized Cys in the TF DNA-binding domain. Several small molecules inhibit APE1-mediated TF activation, including the quinone derivative E3330. It has been proposed some inhibitors bind near C65, a residue suggested to be important for TF activation, but the binding site has not been determined for any inhibitor. Remarkably, NMR and molecular docking studies here reveal E3330 binds in the DNA repair active site of APE1, far removed from C65. Accordingly, AP endonuclease activity is substantially inhibited by E3330 (100 ?M), suggesting that E3330 may not selectively inhibit APE1 redox activity in cells, in contrast with previous proposals. A naphthoquinone analog of E3330, RN7-60, binds a site removed from both C65 and the repair active-site. While a detailed understanding of how these inhibitors work requires further studies into the mechanism of redox activity, our results do not support proposals that E3330 binds selectively (and slowly) to locally unfolded APE1, or that E3330 promotes formation of disulfide bonds in APE1. Rather, we suggest E3330 may suppress a conformational change needed for redox activity, disrupt productive APE1-TF binding, or block the proposed redox chaperone activity of APE1. Our results provide the first structural information for any APE1 redox inhibitor, and could facilitate development of improved inhibitors for research and perhaps clinical purposes. PMID:22032234

Manvilla, Brittney A.; Wauchope, Orrette; Seley-Radtke, Katherine L.; Drohat, Alexander C.

2011-01-01

356

Phytochemical screening and anti-inflammatory activity of Cnidoscolus quercifolius (Euphorbiaceae) in mice  

PubMed Central

Background: Cnidoscolus quercifolius is a species popularly known as favela and faveleira, and belonging to the Caatinga biome (semi-arid vegetation, Brazil), where is used in folk medicine as an anti-inflammatory. Objective: The aim was to evaluate the anti-inflammatory effect of the ethanolic extract from barks (Cqb-EtOH) and leaves (Cql-EtOH) of C. quercifolius in mice using experimental models of inflammation. Materials and Methods: The preliminary phytochemical analysis of the ethanolic extract was performed. The activity was evaluated by paw edema induced by carrageenan and leukocytes migration to the peritoneal cavity induced by carrageenan methods. Results: A preliminary analysis of Cqb-EtOH revealed that it contained coumarins, flavonoids, monoterpenes/diterpenes and naphthoquinones, while the Cql-EtOH showed positive reaction to coumarins, anthracene derivatives, flavonoids, lignans and triterpenes/steroids. Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan. In the peritonitis test, acute pretreatment with Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited the leukocyte migration. Conclusions: It can be concluded that extracts from the barks and leaves of C. quercifolius have anti-inflammatory activity, which supports the popular use of this plant to treat inflammation. Thus, extracts has significant anti-inflammatory properties, which are related probably to inhibition of release of mediators of the inflammatory process. PMID:25276074

de Araújo Gomes, Leandra Macedo; de Andrade, Thayne Mayra; Silva, Juliane Cabral; de Lima, Julianeli Tolentino; Quintans-Junior, Lucindo José; da Silva Almeida, Jackson Roberto Guedes

2014-01-01

357

Effect of shikonin on multidrug resistance in HepG2: The role of SIRT1.  

PubMed

Abstract Context: Overexpression of SIRT1 is considered to enhance the resistance of HepG2 cells to irradiation. Shikonin, a naturally occurring naphthoquinone compound, displays anticancer effects and circumvents cancer drug resistance. Objectives: This study investigated the MDR reversal effect of shikonin induced by the overexpression of SIRT1. Materials and methods: The overexpression of SIRT1 in HepG2 cells was established by lentivirus infection. Five days after transduction, real-time quantitative polymerase chain reaction and western blotting were used to detect the expression of SIRT1 and MDR1/P-gp. Drug resistance was also evaluated by flow cytometry after rhodamine-123 staining. On day 5, the multidrug resistance cells were treated by shikonin (10(-7), 10(-6), and 10(-5) µmol/L) one time. The cell viability was detected by the MTT assay, and apoptosis was evaluated by Hoechst 33342 staining and caspase-3 activity 24?h after shikonin treatment. Results: Overexpression of SIRT1 decreased rhodamine-123 staining and successfully produced the R-HepG2 cell line. Compared with HepG2, the expression of MDR1/P-gp mRNA (3.45?±?0.35) and protein (1.40?±?0.05) were both upregulated in R-HepG2. Shikonin inhibited cell viability (from 93.9?±?2.1 to 66.7?±?1.5%), induced apoptosis of R-HepG2 (apoptotic ratio from 3.5?±?0.8 to 47.5?±?2.7%, caspase-3 activity from 103.5?±?1.9 to 329.2?±?14.9%, respectively), downregulated the mRNA and protein expression of SIRT1 and MDR1/P-gp, and decreased rhodamin 123 efflux. Discussion and conclusion: In the present study, we demonstrated that shikonin is able to overcome drug resistance in hepatocellular carcinoma cells, and the mechanism is related to the SIRT1-MDR1/P-gp signaling pathway. PMID:25471124

Jin, Yong-Dong; Ren, Yi; Wu, Ming-Wei; Chen, Ping; Lu, Jin

2014-12-01

358

Kinetic phases in the electron transfer from P{sup +}Q{sub A}{sup -}Q{sub B} to P{sup +}Q{sub A}Q{sub B}{sup -} and the associated processes in Rhodobacter sphaeroides R-26 reaction centers.  

SciTech Connect

Electron transfer from P{sup +}Q{sub A}{sup -}Q{sub B} to form P{sup +}Q{sub A}Q{sub B}{sup -} was measured in Rhodobacter sphaeroides R-26 reaction centers (RCs) where the native primary quinone, ubiquinone-10 (UQ{sub A}), was replaced by 2-methyl-3-phytyl-1,4-naphthoquinone (MQA). The native secondary quinone, UQ-10, was retained as UQ{sub B}. The difference spectrum of the semiquinone MQ{sub A}- minus UQ{sub B}- absorption is very similar to that of MQ- minus UQ- in solution (398-480 nm). Thus, the absorption change provides a direct monitor of the electron transfer from MQ{sub A}- to UQ{sub B}. In contrast, when both Q{sub A} and Q{sub B} are UQ-10 the spectral difference between UQ{sub A}- and UQ{sub B}- arises from electrochromic responses of RC chromophores. Three kinetic processes are seen in the near UV (390-480 nm) and near-IR (740-820 nm). Analysis of the time-correlated spectra support the conclusion that the changes at {tau}{sub 1} {approx} 3 {micro}s are mostly due to electron transfer, electron transfer and charge compensation are mixed in {tau}{sub 2} {approx} 80 {micro}s, while little or no electron transfer occurs at 200-600 {micro}s ({tau}{sub 3}) in MQAUQB RCs. The 80-{micro}s rate has been previously observed, while the fast component has not. The fast phase represents 60% of the electron-transfer reaction (398 nm). The activation energy for electron transfer is {Delta}G {approx} 3.5 kcal/mol for both {tau}{sub 1} and {tau}{sub 2} between 0 and 30 C. In isolated RCs with UQ{sub A}, if there is any fast component, it appears to be faster and less important than in the MQ{sub A} reconstituted RCs.

Li, J.-L.; Gilroy, D.; Tiede, D. M.; Gunner, M. R.; Chemistry; City Coll. of New York

1998-03-03

359

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

360

Synthesis, characterization, and photocatalytic activities of Cobalt(II)-Titanium dioxide nanorods, and electrophoretic deposition of Titanium dioxide nanoparticle/nanorod composite films for self-cleaning applications  

NASA Astrophysics Data System (ADS)

This dissertation consists of two projects. The first project is synthesis, characterization, and photocatalytic activities of Co(II)-TiO2 nanorods. We modified brookite TiO2 nanorods with cobalt(II) ions to design new photocatalysts with visible light absorption. X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS) data indicated that the local structure of Co(II)-TiO2 nanorods was shown as tetrahedral and octahedral Co(II) sites at TiO2 nanorod surface. Dimethylglyoxime (DMG) has been used to remove surface Co(II) from Co(II)-TiO2 nanorods to determine single-site Co(II) ions selectively attached to the TiO 2 nanorod surface. We proposed a mechanism that the Co-Co bond of the precursor Co2(CO)8 undergoes heterolysis followed by disproportionation of Co(I) to produce Co(II) and Co(0) precipitate. Finally, the Co(II)-TiO2 nanorods showed greater activity than TiO 2 nanorods in the degradation of 5,8-dihydroxy-1,4-naphthoquinone (DHNQ) dye under visible light irradiation. The second project is electrophoretic deposition (EPD) of TiO2 nanoparticle/nanorod composite films for self-cleaning applications. We developed novel electrolyte system for EPD of TiO2 nanoparticle/nanorod composites for self-cleaning coatings. A mixture of TiO2 powder and TiO2 nanorods was used as EPD suspension in a mixture of THF and acetone. TiO2 nanoparticle/nanorod composite films were fabricated on aluminium substrates via the EPD method, and were characterized by scanning electron microscope (SEM). SEM images showed that TiO2 nanoparticle/nanorod composite films had a uniform pore structure. The hydrophobic properties of surfaces in TiO2 nanoparticle/nanorod composite films were evaluated by water contact angle measurements. It was found that the surfaces of TiO2 nanoparticle/nanorod composite films were hydrophobic with contact angle of 103°. These hydrophobic surfaces are expected to have potential applications for self-cleaning.

Kang, Wonjun

361

Cellular injury induced by oxidative stress is mediated through lysosomal damage.  

PubMed

Cultured primary hepatocytes pretreated (protected) with the iron chelator deferoxamine or the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD) were resistant to the toxicity of 5 microM naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) during a 180-min exposure. Hepatocytes exposed to naphthazarin without any protection were abruptly depleted of intracellular reduced glutathione, and the level of cytosolic Ca2+ was rapidly increased. This was followed by lipid peroxidation, measured as accumulation of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNA) intra- and extracellularly; decrease in ATP levels; destabilization of lysosomes; and finally cell death. The stability of the lysosomal membranes was evaluated by determining retention of the lysosomotropic weak base acridine orange (AO). Naphthazarin exposure caused leakage of protons from the acidic compartment, as indicated by relocalization of AO to the cytosol. Protection of the cell cultures with deferoxamine or DPPD prevented destabilization of lysosomes and cell killing. It also reduced the loss of ATP but did not prevent the depletion of glutathione or the increase in Ca2+. In cells subjected to naphthazarin exposure, DPPD protection also completely inhibited lipid peroxidation, whereas deferoxamine pretreatment only slightly reduced the intracellular accumulation of MDA and 4-HNA but completely prevented cell rupture and the leakage of these lipid peroxidation products to the medium that took place in large amounts from unprotected cells exposed to naphthazarin. Deferoxamine is taken up by endocytosis and is thus transported to the acidic vacuolar apparatus, whereas the lipophilic DPPD is rapidly distributed throughout the cells. Inhibiting endocytosis during deferoxamine pretreatment, by incubating at +4 degrees C or by preexposure to a mixture of the endocytosis-inhibitors cytochalasin B and monensin, abolished the protective effect of deferoxamine. The findings suggest that naphthazarin-induced cell killing is not caused directly by either thiol oxidation or an increase in cytosolic free Ca2+, but rather is preceded by lysosomal destabilization, which may be prevented either by inhibition of cellular peroxidation in general or by prevention of iron-catalyzed oxidative reactions, and involves peroxidation of cellular membranes, energy depletion, and leakage of lysosomal content. DPPD would protect against cell killing by preventing lipid peroxidation of cellular membranes in general, whereas deferoxamine seems to allow a limited general cellular peroxidation but specifically prevents peroxidation and fragmentation of lysosomal membranes by chelating intralysosomal iron and, consequently, leakage of destructive lysosomal contents with ensuing cell rupture and death. Thus, a certain degree of cellular peroxidation does not appear to be lethal as long as lysosomal membranes are protected, placing lysosomes into a category of cellular loci minora resistentia. PMID:8529915

Ollinger, K; Brunk, U T

1995-11-01

362

Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial to mesenchymal transition involving PI3K/Akt/mTOR-mediated pathway in human pancreatic cancer cells  

PubMed Central

Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5?-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of PI3K/protein kinase B/mammalian target of rapamycin and p38 MAPK mediated pathways.

Wang, Feng; Wang, Qi; Zhou, Zhi-Wei; Yu, Song-Ning; Pan, Shu-Ting; He, Zhi-Xu; Zhang, Xueji; Wang, Dong; Yang, Yin-Xue; Yang, Tianxing; Sun, Tao; Li, Min; Qiu, Jia-Xuan; Zhou, Shu-Feng

2015-01-01

363

Direct quantitative determination of cyanamide by stable isotope dilution gas chromatography-mass spectrometry.  

PubMed

Cyanamide is a multifunctional agrochemical used, for example, as a pesticide, herbicide, and fertilizer. Recent research has revealed that cyanamide is a natural product biosynthesized in a leguminous plant, hairy vetch (Vicia villosa). In the present study, gas chromatography-mass spectrometry (GC-MS) equipped with a capillary column for amines was used for direct quantitative determination of cyanamide. Quantitative signals for ((14)N(2))cyanamide, ((15)N(2))cyanamide (internal standard for stable isotope dilution method), and m-(trifluoromethyl)benzonitrile (internal standard for correcting errors in GC-MS analysis) were recorded as peak areas on mass chromatograms at m/z 42 (A(42)), 44 (A(44)), and 171 (A(IS)), respectively. Total cyanamide content, ((14)N(2))cyanamide plus ((15)N(2))cyanamide, was determined as a function of (A(42)+A(44))/A(IS). Contents of ((14)N(2))cyanamide and ((15)N(2))cyanamide were then calculated by multiplying the total cyanamide content by A(42)/(A(42)+A(44)) and A(44)/(A(42)+A(44)), respectively. The limit of detection for the total cyanamide content by the GC-MS analysis was around 1ng. The molar ratio of ((14)N(2))cyanamide to ((15)N(2))cyanamide in the injected sample was equal to the observed A(42)/A(44) value in the range from 0.1 to 5. It was, therefore, possible to use the stable isotope dilution method to quantify the natural cyanamide content in samples; i.e., the natural cyanamide content was derived by subtracting the A(42)/A(44) ratio of the internal standard from the A(42)/A(44) ratio of sample spiked with internal standard, and then multiplying the resulting difference by the amount of added ((15)N(2))cyanamide (SID-GC-MS method). This method successfully gave a reasonable value for the natural cyanamide content in hairy vetch, concurring with the value obtained by a conventional method in which cyanamide was derivatized to a photometrically active compound 4-cyanimido-1,2-naphthoquinone and analyzed with reversed-phase HPLC (CNQ-HPLC method). The determination range of cyanamide in the SID-GC-MS method was almost the same as that in the CNQ-HPLC method; however, the SID-GC-MS method was much simpler than the CNQ-HPLC method. PMID:16314170

Hiradate, Syuntaro; Kamo, Tsunashi; Nakajima, Eri; Kato, Kenji; Fujii, Yoshiharu

2005-12-01

364

Synthesis and evaluation of 11?-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists  

PubMed Central

Introduction As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11?-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11?-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11?-aryl estradiol analogs or their potential as scaffolds for drug conjugation. Methods We prepared and characterized a series of 11?-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ER?-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists. Results The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ER?-LBD, ranging from 13–83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11?-substituent than upon the nature of the terminal group Conclusions We have developed a synthetic strategy that provides facile access to potent 11?-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER?-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11?-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11?-aryl estradiol analogs as potential drug delivery systems and imaging agents. PMID:22608920

Hanson, Robert N.; Hua, Edward; Hendricks, J. Adam; Labaree, David; Hochberg, Richard B.

2012-01-01

365

Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice  

PubMed Central

Aim: To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice. Methods: Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses. Results: Plumbagin (2.5–20 ?mol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of cell viability was 14.7 ?mol/L). Administration of plumbagin to breast cancer bearing mice delayed the tumor growth by 2–3 weeks and reduced the tumor volume by 44%–74%. The in vivo imaging study showed that plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts. Conclusion: Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells. PMID:24384612

Yan, Wei; Wang, Ting-yu; Fan, Qi-ming; Du, Lin; Xu, Jia-ke; Zhai, Zan-jing; Li, Hao-wei; Tang, Ting-ting

2014-01-01

366

Shikonin, a constituent of Lithospermum erythrorhizon exhibits anti-allergic effects by suppressing orphan nuclear receptor Nr4a family gene expression as a new prototype of calcineurin inhibitors in mast cells.  

PubMed

Over the last few decades, food allergy (FA) has become a common disease in infants in advanced countries. However, anti-allergic medicines available in the market have no effect on FA, and consequently effective drug therapies for FA are not yet available. We have already demonstrated that mucosal mast cells play an essential role in the development of FA in a murine model. Thus, we screened many constituents from medicinal herbs for the ability to inhibit rat basophilic leukemia-2H3 mast-like cell degranulation, and found that shikonin, a naphthoquinone dye from Lithospermum erythrorhizon, exhibited the most potent inhibitory effect among them. Furthermore, shikonin extremely inhibited the IgE/antigen-induced and calcium ionophore-induced upregulation of tumor necrosis factor (TNF)-? mRNA expression in mucosal-type bone marrow-derived mast cells (mBMMCs). Global gene expression analysis confirmed by real-time PCR revealed that shikonin drastically inhibited the IgE/antigen-induced and calcium ionophore-induced upregulation of mRNA expression of the nuclear orphan receptor 4a family (Nr4a1, Nr4a2 and Nr4a3) in mBMMCs, and knockdown of Nr4a1 or Nr4a2 suppressed the IgE/antigen-induced upregulation of TNF-? mRNA expression. Computational docking simulation of a small molecule for a target protein is a useful technique to elucidate the molecular mechanisms underlying the effects of drugs. Therefore, the simulation revealed that the predicted binding sites of shikonin to immunophilins (cyclophilin A and FK506 binding protein (FKBP) 12) were almost the same as the binding sites of immunosuppressants (cyclosporin A and FK506) to immunophilins. Indeed, shikonin inhibited the calcineurin activity to a similar extent as cyclosporin A that markedly suppressed the IgE/antigen-enhanced mRNA expression of TNF-? and the Nr4a family in mBMMCs. These findings suggest that shikonin suppresses mucosal mast cell activation by reducing Nr4a family gene expression through the inhibition of calcineurin activity. Therefore, shikonin has therapeutic potential for the treatment of allergic diseases as a new calcineurin inhibitor. PMID:25451590

Wang, Xiaoyu; Hayashi, Shusaku; Umezaki, Masahito; Yamamoto, Takeshi; Kageyama-Yahara, Natsuko; Kondo, Takashi; Kadowaki, Makoto

2014-10-29

367

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.

2010-12-01

368

Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members.  

PubMed

Complementary DNA clones encoding human aflatoxin B(1) aldehyde reductase (AKR7A2), aldehyde reductase (AKR1A1), aldose reductase (AKR1B1), dihydrodiol dehydrogenase 1 (AKR1C1) and chlordecone reductase (AKR1C4) have been expressed in Escherichia coli. These members of the aldo-keto reductase (AKR) superfamily have been purified from E. coli as recombinant proteins. The recently identified AKR7A2 was shown to differ from the AKR1 isoenzymes in being able to catalyse the reduction of 2-carboxybenzaldehyde. Also, AKR7A2 was found to exhibit a narrow substrate specificity, with activity being restricted to succinic semialdehyde (SSA), 2-nitrobenzaldehyde, pyridine-2-aldehyde, isatin, 1,2-naphthoquinone (1,2-NQ) and 9,10-phenanthrenequinone. In contrast, AKR1A1 reduces a broad spectrum of carbonyl-containing compounds, displaying highest specific activity for SSA, 4-carboxybenzaldehyde, 4-nitrobenzaldehyde, pyridine-3-aldehyde, pyridine-4-aldehyde, 4-hydroxynonenal, phenylglyoxal, methylglyoxal, 2,3-hexanedione, 1, 2-NQ, 16-ketoestrone and d-glucuronic acid. Comparison between the kinetic properties of AKR7A2 and AKR1A1 showed that both recombinant enzymes exhibited roughly similar k(cat)/K(m) values for SSA, 1,2-NQ and 16-ketoestrone. Many of the compounds which are substrates for AKR1A1 also serve as substrates for AKR1B1, though the latter enzyme was shown to display a specific activity significantly less than that of AKR1A1 for most of the aromatic and aliphatic aldehydes studied. Neither AKR1C1 nor AKR1C4 was found to possess high reductase activity towards aliphatic aldehydes, aromatic aldehydes, aldoses or dicarbonyls. However, unlike AKR1A1 and AKR1B1, both AKR1C1 and AKR1C4 were able to catalyse the oxidation of 1-acenaphthenol and, in addition, AKR1C4 could oxidize di- and tri-hydroxylated bile acids. Specific antibodies raised against AKR7A2, AKR1A1, AKR1B1, AKR1C1 and AKR1C4 have been used to show the presence of all of the reductases in human hepatic cytosol; the levels of AKR1B1 and AKR1C1 were markedly elevated in livers with alcohol-associated injury, and indeed AKR1B1 was only detectable in livers with evidence of alcoholic liver disease. Western blotting of extracts from brain, heart, kidney, liver, lung, prostate, skeletal muscle, small intestine, spleen and testis showed that AKR7A2 is present in all of the organs examined, and AKR1B1 is similarly widely distributed in human tissues. These experiments revealed however, that the expression of AKR1A1 is restricted primarily to brain, kidney, liver and small intestine. The AKR1C family members proved not to be as widely expressed as the other reductases, with AKR1C1 being observed in only kidney, liver and testis, and AKR1C4 being found in liver alone. As human kidney is a rich source of AKR, the isoenzymes in this organ have been studied further. Anion-exchange chromatography of human renal cytosol on Q-Sepharose allowed resolution of AKR1A1, AKR1B1, AKR1C1 and AKR7A2, as identified by substrate specificity and Western blotting. Immunohistochemistry of human kidney demonstrated that AKR7A2 is expressed in a similar fashion to the AKR1 family members in proximal and distal convoluted renal tubules. Furthermore, both AKR7A2 and AKR1 members were expressed in renal carcinoma cells, suggesting that these groups of isoenzymes may be engaged in related physiological functions. PMID:10510318

O'connor, T; Ireland, L S; Harrison, D J; Hayes, J D

1999-10-15