- Synthesis of 4,8-dimethoxy-1-naphthol via an acetyl migration
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Based on acetyl migration, an efficient synthesis of 4,8-dimethoxy-1-naphthol (1) has been achieved with high overall yield. Compared with the reported method, there were several advantages. First, the reaction conditions were mild. Second, the workup of each step was much simpler. Third, juglone as the starting material in the synthesis was readily available. The solvent and reaction temperature greatly influenced the migration process.
- Zhang, Qijing,Dong, Jinyun,Cui, Qing,Li, Shaoshun,Cui, Jiahua
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- Enantioselective Total Synthesis of (?)-Spiroxins A, C, and D
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Spiroxins A, C, and D are metabolites that have been identified in the marine fungal strain LL-37H248. Their unique polycyclic structures and intriguing biological activities make them attractive targets for the synthetic community. Based on a scalable en
- Chen, Chong-Chong,Hu, Xiangdong,Shu, Xin,Yang, Jiayi,Yu, Tao
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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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- Synthesis, biological evaluation, and correlation of cytotoxicity versus redox potential of 1,4-naphthoquinone derivatives
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A series of 1,4-naphthoquinone derivatives of lawsone (1), 6-hydroxy-1,4-naphthoquinone (2), and juglone (3) were synthesized by alkylation, acylation, and sulfonylation reactions. The yields of lawsone derivatives 1a-1k (type A), 6-hydroxy-1,4-naphthoqui
- Shen, Chien-Chang,Afraj, Shakil N.,Hung, Chia-Cheng,Barve, Balaji D.,Kuo, Li-Ming Yang,Lin, Zhi-Hu,Ho, Hisu-O.,Kuo, Yao-Haur
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supporting information
(2021/04/12)
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- Anti-novel coronavirus naphthoquinone compound and medical application thereof
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The invention discloses an anti-novel coronavirus naphthoquinone compound and a medical application of the naphthoquinone compound. The structure of the compound is shown as a formula (I), wherein R1is hydrogen, methyl, ethyl, acetyl or propionyl; and R2 is hydrogen, methyl or ethyl. The compound disclosed by the invention has very strong activity of resisting the novel coronavirus, and can be used for inhibiting 3CL hydrolase (3C-like proteinase, 3CLpro) of the 2019-nCoV novel coronavirus. The in-vitro activity determination experiments show that the enzyme inhibition rate of part of the compounds reaches 99% under the concentration of 1 [mu] M. The naphthoquinone compound disclosed by the invention is clear in structure, simple and convenient in preparation method and high in yield, andhas important significance for developing efficient and low-toxicity novel anti-novel coronavirus drugs.
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Paragraph 0031-0034
(2020/06/20)
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- Novel juglone and plumbagin 5-O derivatives and their in vitro growth inhibitory activity against apoptosis-resistant cancer cells
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Juglone 1 an plumbagin 2 are plant secondary metabolites nowadays well known for their anticancer properties. In this study we synthesized analogues of 1 and 2 deriving from the functionalization of the OH group in position 5 with different side chains in form of esters and ethers. Therefore the growth inhibitory activities of these adducts were evaluated in vitro on six cancer cell lines using the MTT colorimetric assays along with the two natural parent compounds. The data revealed that these latter displayed the strongest growth inhibitory activities in vitro. Quantitative videomicroscopy analyses were then carried out on human U373 glioblastoma cells, which are characterized by various level of resistance to pro-apoptotic stimuli. We compared the naturally occurring reference compounds 1 and 2 with the derivatives exerting the best activities in terms of IC50 growth inhibitory values. These analyses showed that both juglone and plumbagin had a cytostatic effect on U373 cells and were able to overcome the intrinsic resistance of U373 cancer cells to pro-apoptotic stimuli.
- Fiorito, Serena,Genovese, Salvatore,Taddeo, Vito Alessandro,Mathieu, Véronique,Kiss, Robert,Epifano, Francesco
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supporting information
p. 334 - 337
(2016/01/09)
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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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- New naphthoquinone derivatives against glioma cells
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This work was aimed to the development of a set of new naphtoquinone derivatives that can act against glioma. The compounds were tested in order to find out their ability to inhibit the growth of glioma cells, and the results of these assays were correlated with electrochemical analysis and NMR-based reoxidation kinetic studies, suggesting that a redox mechanism underlies and may explain the observed biological behavior. In addition to a full description of the synthetic pathways, electrochemistry, NMR and single crystal X-ray diffraction data are provided.
- Redaelli, Marco,Mucignat-Caretta, Carla,Isse, Abdirisak Ahmed,Gennaro, Armando,Pezzani, Raffaele,Pasquale, Riccardo,Pavan, Valeria,Crisma, Marco,Ribaudo, Giovanni,Zagotto, Giuseppe
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p. 458 - 466
(2015/05/05)
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- Inhibitory effect of novel 5-O-acyl juglones on mammalian DNA polymerase activity, cancer cell growth and inflammatory response
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We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on juglone (5-hydroxy-1,4-naphthoquinone), which is a 1,4-naphthoquinone derivative, and chemically synthesized novel juglones conjugated with C2:0 to C22:6 fatty acid (5-O-acyl juglones). The chemically modified juglones enhanced mammalian pol inhibition and their cytotoxic and anti-inflammatory activities. The juglone conjugated with oleic acid (C18:1-acyl juglone) showed the strongest inhibition of DNA replicative pol α activity and human colon carcinoma (HCT116) cell growth in 10 synthesized 5-O-acyl juglones. C12:0-Acyl juglone was the strongest inhibitor of DNA repair-related pol λ, as well as the strongest suppression of the production of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in the compounds tested. Moreover, this compound caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. C12:0- and C18:1-Acyl juglones selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. These data indicate that the novel 5-O-acyl juglones target anti-cancer and/or anti-inflammatory agents based on mammalian pol inhibition. Moreover, the results suggest that acylation of juglone is an effective chemical modification to improve the anti-cancer and anti-inflammation of vitamin K3 derivatives, such as juglone.
- Maruo, Sayako,Kuriyama, Isoko,Kuramochi, Kouji,Tsubaki, Kazunori,Yoshida, Hiromi,Mizushina, Yoshiyuki
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scheme or table
p. 5803 - 5812
(2011/11/05)
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- Reaction of dihydrolipoic acid with juglone and related naphthoquinones: unmasking of a spirocyclic 1,3-dithiane intermediate en route to naphtho[1,4]dithiepines
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The reaction of dihydrolipoic acid (DHLA) with 5-hydroxy-1,4-naphthoquinone (juglone) gives rise to the novel naphtho[1,4]dithiepine derivatives through ring expansion of an unstable spirocyclic 1,3-dithiane intermediate, which was isolated and completely characterized. Reported herein is also the characterization of novel reaction products of DHLA with other naphthoquinones and the extension of the study to the spirocyclic adduct formed by reaction with a representative 2-substituted naphthoquinone.
- Greco, Giorgia,Panzella, Lucia,Pezzella, Alessandro,Napolitano, Alessandra,d'Ischia, Marco
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experimental part
p. 3912 - 3916
(2010/07/05)
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- Green photochemistry: Solarchemical synthesis of 5-amido-1,4- naphthoquinones
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Dye sensitized photooxygenations of 5-amido-1-naphthols were investigated with artificial light and sunlight, and the corresponding 5-amido-1,4- naphthoquinones were isolated in moderate to excellent yields. Under sunny conditions the yields were higher for almost all cases studied. The energy demand of the equipment used was determined, revealing significant energy savings for solar exposures.
- Haggiage, Elodie,Coyle, Emma E.,Joyce, Kieran,Oelgemoeller, Michael
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body text
p. 318 - 321
(2010/04/22)
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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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- A CONVENIENT SYNTHESIS OF JUGLONE VIA NEUTRAL SALCOMINE OXIDATION
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1,5-Dihydroxynaphthalene and its derivatives can be oxidized by molecular oxygen in the presence of catalytic amounts of salcomine under neutral conditions to afford the corresponding 1,4-naphthoquinones as the major products.
- Wakamatsu, Takeshi,Nishi, Takahide,Ohnuma, Takeshi,Ban, Yoshio
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p. 1167 - 1174
(2007/10/02)
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