- The compound 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via reactive oxygen species-regulated mitogen-activated protein kinase, protein kinase B, and signal transducer and activator of transcription 3 signaling in human gastric cancer cells
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(Table presented.). It is reported that 1,4-naphthoquinones and their derivatives have potent antitumor activity in various cancers, although their clinical application is limited by observed side effects. To improve the therapeutic efficacy of naphthoquinones in the treatment of cancer and to reduce side effects, we synthesized a novel naphthoquinone derivative, 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ). In this study, we explored the effects of NTDMNQ on apoptosis in gastric cancer cells with a focus on reactive oxygen species (ROS) production. Our results demonstrated that NTDMNQ exhibited the cytotoxic effects on gastric cancer cells in a dose-dependent manner. NTDMNQ significantly induced mitochondrial-related apoptosis in AGS cells and increased the accumulation of ROS. However, pre-treatment with N-acetyl-L-cysteine (NAC), an ROS scavenger, inhibited the NTDMNQ-induced apoptosis. In addition, NTDMNQ increased the phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and Signal Transducer and Activator of Transcription 3 (STAT3); these effects were blocked by mitogen-activated protein kinase (MAPK) inhibitor and NAC. Taken together, the present findings indicate that NTDMNQ-induced gastric cancer cell apoptosis via ROS-mediated regulation of the MAPK, Akt, and STAT3 signaling pathways. Therefore, NTDMNQ may be a potential treatment for gastric cancer as well as other tumor types.
- Wang, Jia-Ru,Shen, Gui-Nan,Luo, Ying-Hua,Piao, Xian-Ji,Shen, Meng,Liu, Chang,Wang, Yue,Meng, Ling-Qi,Zhang, Yi,Wang, Hao,Li, Jin-Qian,Xu, Wan-Ting,Liu, Yang,Sun, Hu-Nan,Han, Ying-Hao,Jin, Mei-Hua,Cao, Long-Kui,Jin, Cheng-Hao
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- 6-Substituted 1,4-Naphthoquinone Oxime Derivatives (III): Synthesis and Cytotoxic Evaluation
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As a continuous study, a set of 23 new 6-substituted 1,4-naphthoquinone oxime derivatives are synthesized and screened for their in vitro cytotoxic activity. Four of those oxime derivatives demonstrate more potent cytotoxic activity towards K562, HCT-15, and HCT-116 cell lines than a reference drug 5-Fu. In particular, compound 21g exhibits the strongest inhibitory activity against K562 cell lines with IC50 values of 1.25 μM. According to flow cytometry data, compound 21g can arrest cell cycle at S phase and induce a strong apoptotic response in K562 cells. The preliminary structure-activity relationship study shows that the nature of substituents in positions 6 and 1' of 1,4-naphthoquinone derivatives significantly affect their cytotoxic activity.
- Huang,Liu,Meng,Li
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- Synthesis of cis- and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone
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Cis- and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (1a, 1b) were for the first time synthesized from 5,8-dihydroxy-1,4-naphthoquinone (naphthazazine) (6) as a starting material and racemic triol (3) was first synthesized from 7. The configuration of 1a was determined by X-ray analysis.
- Arima,Yamada,Takeda,Takayanagi,Harigaya
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- The design of 1,4-naphthoquinone derivatives and mechanisms underlying apoptosis induction through ROS-dependent MAPK/Akt/STAT3 pathways in human lung cancer cells
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The natural compound 1,4-naphthoquinone has potent anti-tumor activity. However, the clinical application of 1,4-naphthoquinone and its derivatives has been limited by their side effects. In this study, we attempted to reduce the toxicity of 1,4-naphthoquinone by synthesizing two derivatives: 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ). Then we evaluated the cytotoxicity and molecular mechanisms of these compounds in lung cancer cells. EPDMNQ and ENDMNQ significantly inhibited the viabilities of three lung cancer cell lines and induced A549 cell cycle arrest at the G1 phase. In addition, they induced the apoptosis of A549 lung cancer cells by increasing the phosphorylation of p38 and c-Jun N-terminal kinase (p-JNK), and decreasing the phosphorylation of extracellular signal-related kinase (p-ERK), protein kinase B (Akt), and signal transducer and activator of transcription 3 (STAT3). Furthermore, they increased reactive oxygen species (ROS) levels in A549 cells; however, pretreatment with the ROS inhibitor N-acetyl-L-cysteine significantly inhibited EPDMNQ- and ENDMNQ-mediated apoptosis and reversed apoptotic proteins expression. In conclusion, EPDMNQ and ENDMNQ induced G1 phase cell cycle arrest and apoptosis in A549 cells via the ROS-mediated activation of mitogen activated protein kinase (MAPK), Akt and STAT3 signaling pathways.
- Zhang, Yi,Luo, Ying-Hua,Piao, Xian-Ji,Shen, Gui-Nan,Wang, Jia-Ru,Feng, Yu-Chao,Li, Jin-Qian,Xu, Wan-Ting,Zhang, Yu,Zhang, Tong,Wang, Chang-Yuan,Jin, Cheng-Hao
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- Discovery of juglone and its derivatives as potent SARS-CoV-2 main proteinase inhibitors
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SARS-CoV-2 as a positive-sense single-stranded RNA coronavirus caused the global outbreak of COVID-19. The main protease (Mpro) of the virus as the major enzyme processing viral polyproteins contributed to the replication and transcription of SARS-CoV-2 in host cells, and has been characterized as an attractive target in drug discovery. Herein, a set of 1,4-naphthoquinones with juglone skeleton were prepared and evaluated for the inhibitory efficacy against SARS-CoV-2 Mpro. More than half of the tested naphthoquinones could effectively inhibit the target enzyme with an inhibition rate of more than 90% at the concentration of 10 μM. In the structure-activity relationships (SARs) analysis, the characteristics of substituents and their position on juglone core scaffold were recognized as key ingredients for enzyme inhibitory activity. The most active compound, 2-acetyl-8-methoxy-1,4-naphthoquinone (15), which exhibited much higher potency in enzyme inhibitions than shikonin as the positive control, displayed an IC50 value of 72.07 ± 4.84 nM towards Mpro-mediated hydrolysis of the fluorescently labeled peptide. It fit well into the active site cavity of the enzyme by forming hydrogen bonds with adjacent amino acid residues in molecular docking studies. The results from in vitro antiviral activity evaluation demonstrated that the most potent Mpro inhibitor could significantly suppress the replication of SARS-CoV-2 in Vero E6 cells within the low micromolar concentrations, with its EC50 value of about 4.55 μM. It was non-toxic towards the host Vero E6 cells under tested concentrations. The present research work implied that juglone skeleton could be a primary template for the development of potent Mpro inhibitors.
- Cui, Jiahua,Jia, Jinping
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supporting information
(2021/08/25)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF PROSTATE CARCINOMA
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Disclosed herein are 1,4-naphthoquinone analogs, pharmaceutical compositions that include one or more of such 1,4-naphthoquinone analogs, and methods of treating and/or ameliorating diseases and/or conditions associated with a cancer, such as prostate can
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Paragraph 0272-0273; 0278
(2016/06/01)
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- Synthesis, antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study
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The synthesis of 1,4-naphthoquinone derivatives is of great interest since these compounds exhibit strong activity as antimalarial, antibacterial, antifungal and anticancer agents. A series of 50 naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida krusei, Candida parapsilosis and Cryptococcus neoformans using the broth microdilution method. The Candida species were the most susceptible microorganisms. Halogen derivatives of 1,4-naphthoquinone presented strong activity, e.g., 2-bromo-5-hydroxy-1,4-naphthoquinone, which exhibited inhibition at an MIC of 16?μg/mL in S. aureus, and 2-chloro-5,8-dihydroxy-1,4-naphthoquinone, with an MIC of 2?μg/mL in C. krusei. These compounds showed higher activity against fungi, but the antibacterial activities were very low. The study of structure–activity relationships is very important in the search for new antimicrobial drugs due to the limited therapeutic arsenal.
- Sánchez-Calvo, Juan M.,Barbero, Gara R.,Guerrero-Vásquez, Guillermo,Durán, Alexandra G.,Macías, Mariola,Rodríguez-Iglesias, Manuel A.,Molinillo, José M. G.,Macías, Francisco A.
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p. 1274 - 1285
(2016/07/06)
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- Enantioselective Total Syntheses of (R)- A nd (S)-Naphthotectone, and Stereochemical Assignment of the Natural Product
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Both isomers of naphthotectone, an isoprenoid quinone from Verbenaceae Tectona grandis possessing interesting biological activities, were enantioselectively obtained by two different synthetic routes in which the carbon side-chain of the naphthoquinone core was introduced using either a Sonogashira or a Heck coupling reaction. In both cases, the naphthoquinone core of the final products was obtained by a late-stage anodic treatment. (R)-Naphthotectone was obtained in six steps from leuconaphthazarin with an overall yield of 38 % and an enantiomeric excess of 86 %. This compound was found to have the same absolute configuration as the natural product at its C-3′ stereogenic center. (S)-Naphthotectone was obtained in five steps from leuconaphthazarin with an overall yield of 36 % and an enantiomeric excess of 80 %. Naphthotectone was synthesized in both racemic and enantioenriched forms by two different synthetic strategies using Pd coupling reactions and anodic treatment as key steps. The stereochemistry of the natural product has been assigned.
- Guerrero-Vásquez, Guillermo A.,Galarza, Flávia A. D.,Molinillo, José M. G.,Andrade, Carlos Kleber Z.,Macías, Francisco A.
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p. 1599 - 1604
(2016/04/05)
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- Synthesis and cytotoxic activity of a small naphthoquinone library: First synthesis of juglonbutin
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A synthetic protocol has been designed to synthesize grecoketidone (2k), 5-hydroxylapachol (2g), and the recently discovered natural products juglonbutin (2o) and its derivatives, leading to a small library of different 1,4-naphthoquinones with the intention of finding new active compounds. Within our collection, 2-O-alkylated naphthoquinones with an ester functionality in the side-chain and a free OH group at C-5 showed the best activities. Compounds 2f, 2m, and 2n showed GI50 values against 12 tumor cell lines in the lower micromolar range and juglonbutin (2o) showed remarkably efficient inhibition of the glycogen synthase kinase 3β with an IC50 value of 2.03 μM. Furthermore, studies on the mode of action of the most active cytotoxic compounds have been carried out. To the best of our knowledge, this is the first report on the synthesis of juglonbutin (2o) and its biological activity. Copyright
- Broetz, Elke,Herrmann, Jennifer,Wiese, Jutta,Zinecker, Heidi,Maier, Armin,Kelter, Gerhardt,Imhoff, Johannes F.,Mueller, Rolf,Paululat, Thomas
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p. 5318 - 5330
(2014/09/30)
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- A convenient and efficient synthesis of naphthazarin
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A convenient and efficient synthetic method of the important intermediate naphthazarin is presented starting from 1, 4, 5, 8-tetramethoxynaphthalene in an overall yield of 87%. Compared with the reported synthesis, this method has several advantages. Firstly, the reaction conditions are milder; secondly, the workup of each step is simpler and the yield is considerably higher; thirdly, all the reactions involved in the method are more suitable for large-scale preparations.
- Peng, Ying,Zhou, Wen,Zhang, Min,Wang, Cheng-Dong,Chen, Qian,Jiang, Sheng-Jie,Li, Shao-Shun
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experimental part
p. 24 - 25
(2011/04/26)
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- PESTICIDES
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Disclosed herein are novel compounds and salts thereof having inhibitory activity against the biosynthesis of triglycerides, pesticidal compositions comprising the same as active ingredients, and a method for killing insects using the same. Functioning to inhibit the activity of diacyl CoA: glycerol acyltransferase, the novel compounds deny insects triglycerides, which are essential for their growth, thereby having a potent pesticidal effect. The compounds are safe for humans and may be used as environment- friendly pesticides.
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- Direct amination of naphthazarin, juglone, and some derivatives
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Mono- and diamino-derivatives of naphthazarin, 2-methoxynaphthazarin, juglone and their methylethers were prepared by reaction with ammonia. The structure of the products was established by NMR studies. Some compounds were tested for cytotoxic activity. C
- Arnone, Alberto,Merlini, Lucio,Nasini, Gianluca,De Pava, Orso Vajna
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p. 2569 - 2577
(2008/02/10)
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- Convenient Synthesis of 1,4-Naphthoquinones from Polymethoxynaphthalenes. Oxidative Demethylation with Silver-Catalyzed Ammonium Peroxodisulfate
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The oxidative demethylation of polymethoxynaphthalenes such as 1,4-di, 1,4,5-tri, 1,4,5,8-tetra-, and 1,2,4,5,8-pentamethoxynaphthalenes with silver-catalyzed ammonium peroxodisulfate gave the corresponding 1,4-naphthoquinones in good yield under mild reaction conditions.
- Tanoue, Yasuhiro,Sakata, Kazunori,Hashimoto, Mamoru,Morishita, Shin-ichi,Hamada, Moritsugu
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p. 2593 - 2595
(2007/10/02)
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- Monosubstituted Tetramethoxynaphthalenes
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As a new intermediates for the syntheses of monosubstituted naphthazarins and anthracyclines, several tetramethoxynaphthalenes having a substituent such as CH3, COOH, CN, Br, OAc, OH, and OMe groups were prepared from 1,4,5,8-tetramethoxynaphthalene and 2-formyl-1,4,5,8-tetramethoxynaphthalene.
- Tanoue, Yasuhiro,Terada, Akira,Torisu, Kazuhiko,Taniguchi, Hiroshige
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p. 1211 - 1214
(2007/10/02)
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- SYNTHETIC STUDIES ON NOGALAMYCIN CONGENERS ; CHIRAL SYNTHESIS OF THE CDEF-RING SYSTEM OF NOGALAMYCIN
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The chiral synthesis of the (+)-naphthoquinone (4), the CDEF-ring system of nogalamycin congeners, has been accomplished following the synthetic scheme developed for the model (-)-DEF-ring system (3) in the preceding paper.This synthesis features (1) stereoselective construction of the C5'-asymmetric center by introducing the naphthalene moiety into the (-)-methyl ketone (5), the glycoside part, (2) regioselective oxidation of the 1,4,5,8-tetramethoxynaphthalene moiety with cerium(III) ammonium nitrate, and (3) efficient formation of bicyclic acetal system.
- Kawasaki, Motoji,Matsuda, Fuyuhiko,Terashima, Shiro
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p. 5713 - 5726
(2007/10/02)
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- The 2- or 6-(α-Hydroxyalkyl- and α-Oxoalkyl)-5,8-dimethoxy-1,4-naphtoquinones from the Oxidative Demethylation of 2-(α-Hydroxyalkyl- and α-Oxoalkyl)-1,4,5,8-tetramethoxynaphthalenes with Cerium(IV) Ammonium Nitrate, and the Further Demethylations to Naphthazarins
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Oxidative demethylation of 2-(α-hydroxyalkyl- and α-oxoalkyl)-1,4,5,8-tetramethoxynaphthalene with (NH4)2Ce(NO3)6 gave two isomeric dimethoxynaphthoquinones: 2-substituted and 6-substituted 5,8-dimethoxy-1,4-naphthoquinones.Further demethylations of the former isomer to the corresponding dihydroxynaphthoquinones required an AgO-40percentHNO3 reagent, while the latter isomers needed AlCl3 as the demethylation reagent.Some comments regarding the mechanism of these oxidative demethylations with (NH4)2Ce(NO3)6 are given.
- Tanoue, Yasuhiro,Terada, Akira
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p. 2039 - 2046
(2007/10/02)
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- Mise au point. Reaction de metallation ortho dirigee des composes aromatiques. Nouvelles methodologies et applications en synthese organique
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In recent years, the aromatic directed metalation reaction has developed into a broadly useful protocol for the regiospecific construction of polysubstituted aromatics and has been applied in efficient total syntheses of diverse classes of natural products.In this review, both methodological and total synthesis advences using primarily the tertiary carboxamide and carbamate as metalation directors are presented.First, general aspects such as the nature of the directed metalation group (DMG) (scheme 1), the effect of two meta-related DMGs on the metalation process (scheme 2), the relative directed metalation abilities of different DMGs (scheme 3), and the scope of reaction with various electrophiles (scheme 4) are first discussed.Next, the advantage of the directed metalation tactic for the synthesis of several classes of natural products (anthramycin, scheme 7 ; angular anthracyclinones, scheme 8 ; and cannabifuran, schemes 10 and 11) are conceptualized and briefly described.Further, the significance of silicon functionality in context of directed metalation chemistry is demonstrated by its use for protection of prefferentially reactive aromatic C-H and C-methyl sites (scheme 12), ipso desilylation (scheme 13), generation of o-quinodimethanes (scheme 14), and overcoming normal Friedel-Crafts regioselectivity in carboannelation (schemes 16-18).Aspects of the tertiary carbamate as a ortho metalation director (scheme 19) are delineated : the development of an anionic ortho-Fries rearrangement (scheme 21) ; a new, also anionic, ortho-tolyl carbamate rearrangement leading to benzofuranones (scheme 22) ; its comparison with tertiary amide a methoxymethoxy as a DMG (scheme 23) ; its use for the generation of benzamide benzyne intermediates (scheme 24) ; metalation of O-pyridyl carbamates (scheme 25) and its synthetic ramifications (schemes 26-28) ; and its application in conjunction with amide metalation for the synthesis of the ochratoxin metaolites (scheme 29).Dimetalation of benzamides (scheme 32), phthalamides (scheme 33), p,p- and o,o-aryl dicarbamates (schemes 34 and 35) are supported by reactions with various electrophiles.To conclude, recent work aimed at connecting the aromatic directed metalation strategy to other modern synthetic methods is described.Coupling the directed metalation process with the radical-induced annelation provides new routes to benzofurans (scheme 36) and furopyridines (scheme 37) and is applied to the preparation of a key synthon for the mould metabolite, aflatoxin (scheme 38).Anionic aromatic and heteroaromatic ring annelation processes which depend upon ortho metalated precursors lead to naphthalene (schemes 39-41) and 4-quinolone (scheme 42) derivatives.Aryl boronic acids with ortho-DMGs, synthesized by metalation-boronation and ipso borodesilylation methods, are cross coupled with aryl bromides under palladium (O) catalysis leading to new routes for the preparation of unsymmetrical biaryls (scheme 45).
- Snieckus, Victor
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- Dimeric Naphthoquinones, XVIII. - Ammonium Cerium(IV) Nitrate as Oxidising Agent: peri-Hydroxylation of Juglones giving Naphthazarins
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5,8-Dialkoxy-1-naphthols (type 6a) which are easily accessible starting from juglones (5a) are oxidised under mild conditions using ammonium cerium(IV) nitrate, yielding with high p-selectivity the corresponding 1,4-naphthoquinones (7a).By dealkylation of the latter, substituted 1,8-dihydroxy-1,4-naphthoquinones (1a) are obtained in good yields.
- Laatsch, Hartmut
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p. 1655 - 1668
(2007/10/02)
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- Regiospecific Synthesis of Quinizarin and Naphthazarin Derivatives by Cycloaddition
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The diene (E)-1,1,4-trimethoxybuta-1,3-diene underwent regiospecific cycloaddition to derivatives of 2(3)-chloro-1,4-naphthoquinone.The resulting adducts were aromatized to give 1,4-dioxygenated anthraquinones.The latter were obtained as derivatives of quinizarin dimethyl ether or of quinizarin monomethyl ether depending on the conditions of aromatization.Cycloaddition of the diene to non-halogenated naphthoquinones proceeded similarly, orientation being controlled by substituents in the benzenoid ring.Analogous reaction of the diene with benzoquinones gave 5,8-dioxygenated naphthoquinones (naphthazarins), generally in limited yield.The procedure has been applied to synthesis of the mould metabolites helminthosporin and cynodontin
- Cameron, Donald W.,Feutrill, Geoffrey I.,McKay, Peter G.
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p. 2095 - 2109
(2007/10/02)
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