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Given the importance of energy storage and its hybridization with renewable technologies for the energy transition, the development of redox flow batteries (RFB) is receiving particular attention. Among the various emerging technologies, aqueous organic redox flow batteries (AORFBs) are of particular interest, as the objectives in terms of durability, cost, and safety can be achieved thanks to the possibilities offered by molecular engineering. While anthraquinones have been widely explored as negolytes, few works report the use of naphthoquinones. This work aims to exploit an innovative in situ and cost-effective method for the one-pot synthesis of water-soluble naphthoquinones for application as a negolyte in redox flow batteries. As exemplified with alizarin, the energy of the naphthoquinone synthetic reaction in fuel cell mode can be recovered and the electrolyte solution used directly in redox flow batteries without purification. A 0.3 M naphthoquinone solution paired with 0.6 M ferrocyanide demonstrated good stability compared with other naphthoquinones, with a capacity fade rate of 0.017%/cycle (0.84%/day) over 320 cycles. Additionally, the system exhibited one of the highest energy efficiencies (82%) and a power density of 80-105 mW cm -2 at 50% SOC. These first results are promising for further exploration of new water-soluble naphthoquinones efficiently synthesized from hydroxyanthraquinones for application in AORFBs.

Nanoprecipitation, which is achieved through the diffusion and precipitation of drug molecules in blended solvent and antisolvent phases, is a classic route for constructing nanodrugs (NDs) and previously directed by diffusion-controlled theory. However, the diffusion-controlled mechanism is out of date in the recent preparation of self-delivery supramolecular NDs (SDSNDs), characterized by the construction of drug nanoparticles through supramolecular interactions in the absence of carriers and surfactants. Herein, a "reaction"-like complement, contributed from supramolecular interactions, is proposed for the preparation of naphthoquinone SDSNDs. Different from the diffusion-controlled process, the formation rate of SDSNDs via the "reaction"-like process is almost constant and highly dependent on the supramolecular interaction-determined Gibbs free energy of molecular binding. Thus, the formation rate and drug availability of SDSNDs are greatly improved by engineering the supramolecular interactions, which facilitates the preparation of SDSNDs with expected sizes, components, and therapeutic functions. As a deep understanding of supramolecular-interaction-involved nanoprecipitation, the current "reaction"-like protocol not only provides a theoretical supplement for classic nanoprecipitation but also highlights the potential of nanoprecipitation in shaping self-assembled, coassembled, and metal-ion-associated SDSNDs.

Cryogenic negative ion photoelectron (NIPE) spectra of the radical anion of 2,7-naphthoquinone (NQ•-) have been taken at 20 K, using 193, 240, 266, 300, and 355 nm lasers for electron detachment. The electron affinity of the NQ diradical is determined from the first resolved peak in the NIPE spectrum to be 2.880 ± 0.010 eV. CASPT2/aug-cc-pVDZ calculations predict with reasonable accuracy the positions of the 0-0 bands in the three lowest electronic states of NQ. In addition, the Franck-Condon factors calculated from the CASPT2/aug-cc-pVDZ optimized geometries, vibrational frequencies, and normal modes successfully simulate the vibrational structures in these bands. The NIPE spectrum of NQ•- confirms that, as predicted, ³B2 is the ground state, and the ¹B2 and ¹A1 states are, respectively, 12.7 and 16.4 kcal/mol higher in energy than the triplet ground state. The experimental value of ΔEST = 12.7 kcal/mol in NQ and the finding that ¹B2 is the lower energy of the two singlet states confirm the results of the previous calculations on NQ. These calculations predicted an increase in ΔEST on the substitution of both methylene groups in 2,7-naphthoquinodimethane (NQDM) by oxygens in NQ, thus providing a dramatic contrast to the decrease of 17.5 kcal/mol in ΔEST found for substitution of one methylene group by one oxygen on going from trimethylenemethane (TMM) to oxyallyl (OXA). [ABSTRACT FROM AUTHOR]

An enantioselective nucleophilic epoxidation of 2-substituted 1,4-naphthoquinones in the presence of a newly developed guanidine-bisurea bifunctional organocatalyst with tert-butyl hydroperoxide (TBHP) as an oxidant is presented. 1,4-Naphthoquinones bearing substituents at C6, C7, and C2 were available for the reaction, and the corresponding epoxides were obtained with 88:12-95:5 er in 71-98% yields. DFT calculations indicated that substituents at C2 and C6 in the terminal Ar group of the catalyst 9k play a key role in controlling the stereochemical outcome. [ABSTRACT FROM AUTHOR]

The solid-liquid equilibria (SLE) in the ternary system of 2-methyl-1,4-naphthoquinone (2-MNQ) + phthalic anhydride (PA) + 1,4-dioxane were determined experimentally by using the isothermal dissolution equilibriam method within temperatures 283.15, 293.15, and 303.15 K, respectively. The ternary phase diagram could be helpful in the separation of 2-MNQ and PA. On the basis of the experimental data on solubilities the phase diagrams of the system were plotted. Two pure solid phases were formed at 283.15, 293.15 and 303.15 K, including pure PA and pure 2-MNQ, which were confirmed and determined by Schreinemakers' wet residue method. The phase diagram at 283.15 K is similar to those at 293.15 and 303.15 K and the crystalline regions of 2-MNQ and PA decrease with increasing temperature. NRTL and Wilson model were employed to correlate and calculate the solubility data for the ternary system. A comparison between the two models shows that the NRTL model agrees better with the experimental data than those with the Wilson model. In addition, the densities of equilibrium liquid phase were obtained at the corresponding temperatures versus composition in the system. [ABSTRACT FROM AUTHOR]

An Fe(III)-promoted oxidative annulation reaction was developed for the synthesis of 1,2-naphthoqui-nones. A variety of substituted arylglyoxals and internal alkynes undergo the transformation in the presence of FeCl3 at room temperature to afford the 1,2-naphthoquinone products in good yields in a short reaction time. Interestingly, the products show unusual pseudomigration of the substituent on the arene ring of arylglyoxals. A possible mechanism involving Fe(III)-promoted formation of a vinyl cation from arylglyoxal and alkyne, electrophilic addition of the vinyl cation to the ipso carbon of the aryl group to give a spiral intermediate, and then migration of the keto carbon to the ortho carbon was proposed as key steps and verified using quantum mechanics. [ABSTRACT FROM AUTHOR]

(-)-Lomaiviticin A (4) is a complex C2-symmetric bacterial metabolite that contains two diazofluorene functional groups. The diazofluorene consists of naphthoquinone, cyclopentadiene, and diazo substituents fused through a σ- and Π-bonding network. Additionally, (-)-lomaiviticin A (4) is a potent cytotoxin, with half-maximal inhibitory potency (IC50) values in the low nanomolar range against many cancer cell lines. Because of limitations in supply, its mechanism of action had remained a "black box" since its isolation in the early 2000s. In this Account, I describe how studies directed toward the total synthesis of (-)-lomaiviticin A (4) provided a platform to elucidate the emergent properties of this metabolite and thereby connect chemical reactivity with cellular phenotype. We first developed a convergent strategy to prepare the diazofluorene (9 + 10 → 13). We then adapted this chemistry to the synthesis of lomaiviticin aglycon (21/22) and the natural monomeric diazofluorene (-)-kinamycin F (3). The key step in the lomaiviticin aglycon (21/22) synthesis involved the stereoselective oxidative coupling of two monomeric diazofluorenes (2 x 18 → 20) to establish the cojoining carbon-carbon bond of the target. As the absolute stereochemistry of the aglycon and carbohydrate residues of (-)-lomaiviticin A (4) were unknown, we developed a semisynthetic route to the metabolite that proceeds in one step and 42% yield by diazo transfer to the more abundant isolate (-)-lomaiviticin C (6). This allowed us to complete the stereochemical assignment of (-)-lomaiviticin A (4) and provided a renewable source of material. Using this material, we established that the remarkable cytotoxic effects of (-)-lomaiviticin A (4) derive from the induction of highly toxic double-strand breaks (DSBs) in DNA. At the molecular level, 1,7-nucleophilic additions to each electrophilic diazofluorene trigger homolytic decomposition pathways that produce sp2 radicals at the carbon atoms of each diazo group. These radicals abstract hydrogen atoms from the deoxyribose of DNA, a process known to initiate strand cleavage. NMR spectroscopy and molecular mechanics simulations were used to elucidate the mode of DNA binding. These studies showed that both diazofluorenes of (-)-lomaiviticin A (4) penetrate into the duplex. This mode of non-covalent binding places each diazo carbon atom in close proximity to each DNA strand. Throughout these studies, isolates containing one diazofluorene, such as (-)-lomaiviticin C (6) and (-)-kinamycin C (2), were used as controls. Consistent with our mechanistic model, these compounds do not induce DSBs in DNA and are several orders of magnitude less potent. Reactivity studies suggest that (-)-lomaiviticin A (4) is more electrophilic than simple monomeric diazofluorenes. We attribute this to through-space delocalization of the developing negative charge in the transition state for 1,7-addition. Consistent with this mechanism of action, (-)-lomaiviticin A (4) displays selective low-picomolar potencies toward DNA DSB repair-deficient cell types. The emergent properties of (-)-lomaiviticin A (4) derive from the specific arrangement of diazo, naphthoquinone, cyclopentadiene, and ketone functional groups. These functional groups work together to yield, essentially, a masked vinyl radical that can be exposed under biological conditions. Furthermore, the rotational symmetry of the metabolite, deriving from dimerization, allows it to interact with the antiparallel symmetry of DNA and affect cleavage of the duplex. [ABSTRACT FROM AUTHOR]

The first enantioselective total syntheses of engelharquinone (2) and its epoxide 3 have been achieved. The key steps include (1) catalytic asymmetric 1,4-addition of a naphthylboronic acid derivative to a masked naphthoquinone derivative by using a chiral Rh-complex and (2) thiolate-promoted stereospecific construction of the bicyclo[3.2.1]octadienone scaffold. [ABSTRACT FROM AUTHOR]

Coprisidins A and B (1 and 2) were isolated from a gut-associated Streptomyces sp. in the dung beetle Copris tripartitus. Using a combination of spectroscopic techniques, the structures of the compounds were determined to be the first examples of natural naphthoquinone-oxindole alkaloids. Coprisidin A was found to inhibit the action of Na+/K+-ATPase, and coprisidin B showed activity for the induction of NAD(P)H:quinone oxidoreductase 1. [ABSTRACT FROM AUTHOR]

A modular aerobic oxidation of amines to imines has been achieved using an ortho-naphthoquinone (o-NQ) catalyst. The cooperative catalyst system of o-NQ and Cu(OAc)2 enabled the formation of homocoupled imines from benzylamines, while the presence of TFA helped the formation of cross-coupled imines in excellent yields. The current mild aerobic oxidation protocol could also be applied to the oxidation of secondary amines to imines or ketimines with the help of cocatalyst, Ag2CO3, with excellent yields. [ABSTRACT FROM AUTHOR]

S-Bridged pyranonaphthoquinone dimers, naquihexcins A and B (1 and 2), together with a related analogue (−)-BE-52440A (3) were obtained from the culture of a sponge-derived Streptomyces sp. HDN-10-293. Naquihexcin A (1) bears a rare unsaturated hexuronic acid moiety, and (−)-BE-52440A (3) has been discovered from natural resources. Compound 3 showed cytotoxicity against NB4 and HL-60 cells, while 1 could inhibit the proliferation of the adriamycin resistant human breast cancer cell line MCF-7 ADM. [ABSTRACT FROM AUTHOR]

We describe the isolation, structure elucidation, and total synthesis of the novel marine natural product rifsaliniketal and the total synthesis of the structurally related variants salinisporamycin and saliniketals A and B. Rifsaliniketal was previously proposed, but not observed, as a diverted metabolite from a biosynthetic precursor to rifamycin S. Decarboxylation of rifamycin provides salinisporamycin, which upon truncation with loss of the naphthoquinone ring leads to saliniketals. Our synthetic strategy hinged upon a Pt(II)-catalyzed cycloisomerization of an alkynediol to set the dioxabicyclo[3.2.1]octane ring system and a fragmentation of an intermediate dihydropyranone to forge a stereochemically defined (E,Z)-dienamide unit. Multiple routes were explored to assemble fragments with high stereocontrol, an exercise that provided additional insights into acyclic stereocontrol during stereochemically complex fragment-assembly processes. The resulting 11-14 step synthesis of saliniketals then enabled us to explore strategies for the synthesis and coupling of highly substituted naphthoquinones or the corresponding naphthalene fragments. Whereas direct coupling with naphthoquinone fragments proved unsuccessful, both amidation and C-N bond formation tactics with the more electron-rich naphthalene congeners provided an efficient means to complete the first total synthesis of rifsaliniketal and salinisporamycin. [ABSTRACT FROM AUTHOR]

The unsaturated phosphonates were utilized as Hauser acceptors successfully for the first time. The products phosphonylated 1,4-dihydroxynaphthalenes were isolated in good yields in short reaction time and were further oxidized to the corresponding 1,4-naphthoquinones in quantitative yields. The reaction provides an efficient and straightforward approach for the synthesis of pharmacologically privileged disubstituted naphthalene-1,4-diols and naphtha-1,4-diones bearing a phosphonate group at the 2-position and various (het)aryl groups at the 3-position. [ABSTRACT FROM AUTHOR]

To develop in vivo monitoring meter for pH measurements is still the bottleneck for understanding the role of pH plays in the brain diseases. In this work, a selective and sensitive electrochemical pH meter was developed for real-time ratiometric monitoring of pH in different regions of rat brains upon ischemia. First, 1,2-naphthoquinone (1,2-NQ) was employed and optimized as a selective pH recognition element to establish a 2H+/2e- approach over a wide range of pH from 5.8 to 8.0. The pH meter demonstrated remarkable selectivity toward pH detection against metal ions, amino acids, reactive oxygen species, and other biological species in the brain. Meanwhile, an inner reference, 6-(ferrocenyl)hexanethiol (FcHT), was selected as a built-in correction to avoid the environmental effect through coimmobilization with 1,2-NQ. In addition, three-dimensional gold nanoleaves were electrodeposited onto the electrode surface to amplify the signal by ~4.0-fold and the measurement was achieved down to 0.07 pH. Finally, combined with the microelectrode technique, the microelectrochemical pH meter was directly implanted into brain regions including the striatum, hippocampus, and cortex and successfully applied in real-time monitoring of pH values in these regions of brain followed by global cerebral ischemia. The results demonstrated that pH values were estimated to 7.21 ± 0.05, 7.13 ± 0.09, and 7.27 ± 0.06 in the striatum, hippocampus, and cortex in the rat brains, respectively, in normal conditions. However, pH decreased to 6.75 ± 0.07 and 6.52 ± 0.03 in the striatum and hippocampus, upon global cerebral ischemia, while a negligible pH change was obtained in the cortex. [ABSTRACT FROM AUTHOR]

Oxidative stress is a commonly cited mechanism of toxicity of environmental agents. Ubiquitous environmental chemicals such as the diesel exhaust component 1,2-naphthoquinone (1,2-NQ) induce oxidative stress by redox cycling, which generates hydrogen peroxide (H2O2). Cysteinyl thiolate residues on regulatory proteins are subjected to oxidative modification by H2O2 in physiological contexts and are also toxicological targets of oxidant stress induced by environmental contaminants. We investigated whether exposure to environmentally relevant concentrations of 1,2-NQ can induce H2O2-dependent oxidation of cysteinyl thiols in regulatory proteins as a readout of oxidant stress in human airway epithelial cells. BEAS-2B cells were exposed to 0-1000 µM 1,2-NQ for 0-30 min, and levels of H2O2 were measured by ratiometric spectrofluorometry of HyPer. H2O2-dependent protein sulfenylation was measured using immunohistochemistry, immunoblotting, and isotopic mass spectrometry. Catalase overexpression was used to investigate the relationship between H2O2 generation and protein sulfenylation in cells exposed to 1,2-NQ. Multiple experimental approaches showed that exposure to 1,2-NQ at concentrations as low as 3 µM induces H2O2-dependent protein sulfenylation in BEAS-2B cells. Moreover, the time of onset and duration of 1,2-NQ-induced sulfenylation of the regulatory proteins GAPDH and PTP1B showed significant differences. Oxidative modification of regulatory cysteinyl thiols in human lung cells exposed to relevant concentrations of an ambient air contaminant represents a novel marker of oxidative environmental stress. [ABSTRACT FROM AUTHOR]

A multisensorwhich is based on a novel multifunctional triad molecule,ferrocenyl naphthoquinone fused crown ether (Fc–cnq) bearing ferrocene, quinone, and crown ether functional groups together,was synthesized and characterized in this study. Sensing performanceof a trace amount of water and the selective cation binding capabilitiesof this multisensor were carried out by the electrochemical, spectroelectrochemical,and spectrophotometric titration techniques in acetonitrile (CH3CN). It was shown that the potential separation (E(Fc)1/2– E(2)1/2) between the second reduction of naphthoquinone andthe oxidation processes of ferrocene in the triad molecule Fc–cnqwas proportional to the amount of water due to the hydrogen-bondinginteractions between water and the doubly reduced species (Fc–cnq2–). This property enabled Fc–cnqto detect the trace amount of water in CH3CN. The half-wavepotential (E(Fc)1/2) of theferrocene in Fc–cnqwas used as an internal referencepotential, and it defined the accuracy of the detection. In addition,by using the UV–vis spectrophotometric titration techniquein CH3CN, it was also shown that the Fc–cnqmultisensor could bind Ba2+and Ca2+cationsselectively. We proposed that the intramolecular charge-transfer (CT)transition which occurred between the donor ferrocene and the acceptornaphthoquinone was the principle mechanism for the selective bindingproperty of this multisensor. Quantum chemical calculations were alsoperformed to investigate optical and electronic properties of the Fc–cnqmolecule. [ABSTRACT FROM AUTHOR]

A small library of 2-phenoxy-1,4-naphthoquinoneand 2-phenoxy-1,4-anthraquinonederivatives was initially developed to optimize the antitrypanosomatidprofile of the multitarget hit compound B6 (1). The wholeseries was evaluated against the three most important human trypanosomatidpathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14and 21) showedgood activity, despite a concomitant mammalian cytotoxicity. Furthermore,a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumorproperties of quinones, the anticancer potential of some selectedderivatives was investigated. Intriguingly, the tested compounds displayedantitumor activity, while being less toxic against noncancerous cells.The observed cytotoxic potency was ascribed to a multitarget mechanismof action accounting for hGAPDH inhibition and mitochondrialtoxicity. Overall, the development of further derivatives, able tofinely modulate multiple pathways of cancer or parasite cell metabolism,might lead to more effective treatments against these devastatingdiseases. [ABSTRACT FROM AUTHOR]

The photophysical and photochemical reactions of β-lapachone were studied using femtosecond transient absorption, nanosecond transient absorption, and nanosecond time-resolved resonance Raman spectroscopy techniques and density functional theory calculations. In acetonitrile, β-lapachone underwent an efficient intersystem crossing to form the triplet state of β-lapachone. However, in water-rich solutions, the singlet state of β-lapachone was predominantly quenched by the photoinduced protonation of the carbonyl group at the β position (O9). After protonation, a series of fast reaction steps occurred to eventually generate the triplet state α-lapachone intermediate. This triplet state of α-lapachone then underwent intersystem crossing to produce the ground singlet state of α-lapachone as the final product. 1,2-Naphthoquinone is examined in acetonitrile and water solutions in order to elucidate the important roles that water and the pyran ring play during the photoconversion from β-lapachone to α-lapachone. β-Lapachone can also be converted to α-lapachone in the ground state when a strong acid is added to an aqueous solution. Our investigation indicates that β-lapachone can be converted to α-lapachone by photoconversion in aqueous solutions by a protonation-assisted singlet excited state reaction or by an acid-assisted ground state reaction. [ABSTRACT FROM AUTHOR]

o- and/or p-naphthoquinone methides (NQMs) can be selectively prepared by the ring opening of 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene derivatives based on a substituent effect at the 4 position of the substrates. The 4-alkyl- or silyl-substituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene was transformed to o-NQM (1-naphthoquinone-2-methide), which underwent Friedel–Crafts 1,4-addition of the α,β-unsaturated carbonyl moiety to provide the 2-benzyl-1-naphthol as the biarylmethane and [4 + 2]-cycloaddition with a dienophile to give the fused heterocyclic arene. Meanwhile, the 4-unsubstituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene could be converted to the corresponding 4-benzyl-1-naphthol by the Friedel–Crafts 1,6-addition of p-NQM (1-naphthoquinone-4-methide) generated by the site-selective ring opening of the 1,4-epoxy moiety. Furthermore, the 4-(siloxymethyl)-(1,4-bis(siloxymethyl))-1,4-epoxy-1,4-dihydronaphthalene was transformed into a 2,4-bisbenzyl-1-naphthol or pentacyclic derivative via both the o- and p-NQM intermediates. [ABSTRACT FROM AUTHOR]

Ambient particulate matter (PM) can cause adverse health effects via their ability to produce reactive oxygen species (ROS). Humic-like substances (HULIS), a complex mixture of amphiphilic organic compounds, have been demonstrated to contain the majority of redox activity in the water-extractable organic fraction of PM. Reduced organic nitrogen compounds, such as alkaloids resulting from biomass burning emissions, are among HULIS constituents. In this study, we examined the redox activities of pyridine, imidazole and their alkyl derivatives using a cell-free dithiothreitol (DTT) assay under simulated physiological conditions (37 °C, pH = 7.40). These compounds were found to have little redox activity on their own as measured by the DTT assay, but they enhanced ROS generation catalyzed by 1,4-naphthoquinone (as a model quinone compound) and HULIS isolated from multiple aerosol samples. The enhancement effect by the individual nitrogen-containing bases was determined to be proportional to their amount in the assay solutions. It is postulated that the underlying mechanism involves the unprotonated N atom acting as a H-bonding acceptor to facilitate hydrogen-atom transfer in the ROS generation cycle. The enhancement capability was found to increase with their basicity (i.e., pKa of their conjugated acids, BH+), consistent with the proposed mechanism for enhancement. Among the imidazole homologues, a linear relationship was observed between the enhancement factors (in log scale) of the unprotonated form of the imidazole compounds (B) and the pKa of their conjugated acids (BH+). This relationship predicts that the range of alkylimidazole homologues (C6-C13) observed in atmospheric HULIS would be 1.5-4.4 times more effective than imidazole in facilitating HULIS-mediated ROS generation. Our work reveals that the ability of atmospheric PM organics to catalyze generation of ROS in cells could be affected by coexisting redox inactive organic constituents and suggests further work deploying multiple assays be conducted to quantify redox capabilities and enhancement effects of the HULIS components. [ABSTRACT FROM AUTHOR]

Sulfhydration by a hydrogen sulfideanion and electrophile thiolationby reactive sulfur species (RSS) such as persulfides/polysulfides(e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate(1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol(1,2-NQH2-SH) and a generator of reactive oxygen species(ROS), we demonstrate that protein thiols can be modified by a reactivesulfenic acid to form disulfide adducts that undergo rapid cleavagein the presence of glutathione (GSH). As expected, 1,2-NQH2-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2-NQ-SH,resulting in a redox cycling reaction that produces ROS through achemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SHand 1,2-NQH2-SH were detected by derivatization experimentswith dimedone. 1,2-NQH2-SOH modified Keap1 at Cys171 toproduce a Keap1-S-S-1,2-NQH2adduct. Subsequent exposureof A431 cells to 1,2-NQ or 1,2-NQH2-SAc caused an extensivechemical modification of cellular proteins in both cases. Proteinadduction by 1,2-NQ through a thio ether (C–S–C) bondslowly declined through a GSH-dependent S-transarylation reaction,whereas that originating from 1,2-NQH2-SAc through a disulfide(C–S–S–C) bond was rapidly restored to the freeprotein thiol in the cells. Under these conditions, 1,2-NQH2-SAc activated Nrf2 and upregulated its target genes, which wereenhanced by pretreatment with buthionine sulfoximine (BSO), to depletecellular GSH. Pretreatment of catalase conjugated with poly(ethyleneglycol) suppressed Nrf2 activation by 1,2-NQH2-SAc. Theseresults suggest that RSS-mediated reversible electrophilic signalingtakes place through sulfenic acids formation under oxidative stress. [ABSTRACT FROM AUTHOR]

The photolysis of 2-azido-1,4-naphthoquinone (1) in argon matrices at 8 K results in the corresponding triplet vinylnitrene 32, which was detected directly by IR spectroscopy. Vinylnitrene 322 is stable in argon matrices but forms 2-cyanoindane-1,3-dione (3) upon further irradiation. Similarly, the irradiation of azide 1 in 2-methyltetrahydrofuran (MTHF) matrices at 5 K resulted in the ESR spectrum of vinylnitrene 322, which is stable up to at least 100 K. The zero-field splitting parameters for nitrene 322, D/hc = 0.7292 cm-1 and E/hc = 0.0048 cm-1, verify that it has significant 1,3-biradical character. Vinylnitrene 32 (λmax ∼ 460 nm, τ = 22 μs) is also observed directly in solution at ambient temperature with laser flash photolysis of 1. Density functional theory (DFT) calculations support the characterization of vinylnitrene 32 and the proposed mechanism for its formation. Because vinylnitrene 32 is relatively stable, it has potential use as a building-block for high-spin assemblies. [ABSTRACT FROM AUTHOR]

Bimolecular fluorescence-quenchingreactions involving electron-transferbetween electronically excited 5,10,15,20-tetraphenyl-21H,23H-porphine (TPP*) and 1,4-benzoquinone (BQ) or1,4-naphthoquinone (NQ) were investigated using a set of alkane solventsthat enabled the rapid reaction kinetics to be probed over a wideviscosity range, while minimizing changes in other relevant solventparameters. Relative diffusion coefficients and reaction distanceswere recovered directly from analysis of fluorescence decay curvesmeasured on a nanosecond time scale. The electron transfer from TPP*to BQ requires reactant contact, consistent with tightly associatedexciplex formation in these nonpolar solvents. In contrast, electrontransfer from TPP* to NQ displays a clear distance dependence, indicativeof reaction via a much looser noncontact exciplex. This differenceis attributed to the greater steric hindrance associated with contactbetween the TPP*/NQ pair. The diffusion coefficients recovered fromfluorescence decay curve analysis are markedly smaller than the correspondingmeasured bulk relative diffusion coefficients. Classical hydrodynamicstheory was found to provide a satisfactory resolution of this apparentdiscrepancy. The calculated hydrodynamic radii of TPP and NQ correlatevery well with the van der Waals values. The hydrodynamic radius obtainedfor BQ is a factor of 6 times smaller than the van der Waals value,indicative of a possible tight cofacial geometry in the (TPP+/BQ–)* exciplex. The present work demonstratesthe utility of a straightforward methodology, based on widely availableinstrumentation and data analysis, that is broadly applicable fordirect determination of kinetic parameter values for a wide varietyof rapid bimolecular fluorescence quenching reactions in fluid solution. [ABSTRACT FROM AUTHOR]

Wereport the identification of multitarget anti-Alzheimer compoundsdesigned by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase(AChE) inhibitory potencies and interesting capabilities to blockamyloid-β (Aβ) aggregation. The X-ray analysis of oneof those compounds in complex with AChE allowed rationalizing theoutstanding activity data (IC50= 0.72 nM). Two of thecompounds showed negligible toxicity in immortalized mouse corticalneurons 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, followingNQO1 induction. Furthermore, in Neuro2A, they were able to completelyrevert the decrease in viability induced by Aβ. Importantly,they crossed the blood-brain barrier, as demonstrated in exvivoexperiments with rats. When ex vivoresults were combined with in vitrostudies, thesetwo compounds emerged to be promising multitarget lead candidatesworthy of further pursuit. [ABSTRACT FROM AUTHOR]

A novel ligand-free, transition metal-free direct C-H functionalization of quinones with diaryliodonium salts has been developed for the first time. The transformation was promoted only through the use of a base and gave aryl quinone derivatives in moderate to good yields. This methodology provided an effective and easy way to synthesize β-secretase inhibitors. The radical trapping experiments showed that this progress was the radical mechanism. [ABSTRACT FROM AUTHOR]

A Rh-catalyzed oxidative dehydrogenative cross-coupling of 1,4-naphthquinones with alkenes was achieved by using a substituent-enabled C(sp²)-H functionalization (SEF) strategy. The method shows high functional group tolerance, broad substrate scope, and great potential for further functional transformations. [ABSTRACT FROM AUTHOR]

Wereport two kinds of evident hydrogen bonded chains constructing twobinary cocrystals of 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (CL-20)with para-benzoquinone (1) and 1,4-naphthoquinone(2): one kind is the CL-20 molecule chains linked by R22(6) hydrogen bonds, and the other is connected by CL-20 and coformer(1or 2) molecules alternately through R21(5) hydrogen bonds. All chains extend to the entire cocrystals CL-20/1and CL-20/2with crossing points of CL-20 molecules.In contrast to the unremarkable intermolecular interactions in observedCL-20 polymorphs and cocrystals, these two kinds of chains in CL-20/1and CL-20/2are evident and can be readilyunderstood using the definition of supramolecular synthons. Moreover,the thermal behaviors, impact sensitivity, and detonation propertiesof these two energetic cocrystals are reported. [ABSTRACT FROM AUTHOR]

A novelmetal-free catalytic annulation was developed through aLewis base-catalyzed asymmetric allylic alkylation and the ensuingunprecedented asymmetric intramolecular acylcyanation of alkenes.This protocol provides a unique and facile access to prepare enantioenricheddensely functionalized dihydronaphthoquinones accompanied by enantiomericallypure 3,3-disubstituted phthalides bearing quaternary carbon centers. [ABSTRACT FROM AUTHOR]

One-pot synthesis of tetracyclic naphthoxazole derivatives from electron-deficient naphthoquinones and alkynes was achieved via Rh(III)-catalyzed C--H activation and Csp³--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. [ABSTRACT FROM AUTHOR]

A highlyregioselective Diels–Alder approach toward thebioactive natural products hygrocin B and divergolide C is presented.The route uses an unusual benzoquinone–azepinone dienophileprepared in 8 steps from ethyl 8-methoxy-1-naphthoate, by a routewhich includes, as key steps, a Birch alkylation and a Beckmann rearrangementof a tetralone oxime, both of which are demonstrated on multigramscale. The naphthoquinone–azepinone core is suitably functionalizedfor addition of the ansa-chain, found in the natural products. [ABSTRACT FROM AUTHOR]

Pd(OAc)2was found to be an efficient catalyst for themacrocyclization of 1,2-diazonaphthoquinones and cyclicethers. This transformation serves as an efficient method for thesynthesis of protected 1,2-naphthalenediols. [ABSTRACT FROM AUTHOR]

Oxidative arylation of naphthoquinones has been developed through combination of o-iodoxybenzoic acid with arylhydrazines under mild conditions at open atmosphere. Arylated naphthoquinones with different electronic properties were obtained in moderate to good yields. The postulated radical mediated mechanism is supported by radical trapping experiments. Developed protocol for direct arylation of naphthoquinones has been extended toward short, high yielding, and an effective synthesis of antitumor-antibiotic precursor such as benzocarbazoledione. [ABSTRACT FROM AUTHOR]

A new method formanganous acetate tetrahydrate mediated formalintermolecular [2 + 2 + 2 + 1] cycloaddition was developed for thesynthesis of fused cycloheptatriene derivatives from N-(acylmethyl)pyridinium iodides and naphthoquinone. Thismethod provides an innovative route for the efficient and convenientconstruction of fused seven-membered carbocycles from simple startingmaterials. [ABSTRACT FROM AUTHOR]

Novel naphthoquinones were designed,synthesized, and tested assubstrate-based inhibitors against the membrane-embedded protein quinol/fumaratereductase (QFR) from Wolinella succinogenes, a targetclosely related to QFRs from the human pathogens Helicobacterpyloriand Campylobacter jejuni. For a betterunderstanding of the hitherto structurally unexplored substrate bindingpocket, a structure–activity relationship (SAR) study was carriedout. Analogues of lawsone (2-hydroxy-1,4-naphthoquinone 3a) were synthesized that vary in length and size of the alkyl sidechains (3b–k). A combined study onthe prototropic tautomerism of 2-hydroxy-1,4-naphthoquinones seriesindicated that the 1,4-tautomer is the more stable and biologicallyrelevant isomer and that the presence of the hydroxyl group is crucialfor inhibition. Furthermore, 2-bromine-1,4-naphthoquinone (4a–c) and 2-methoxy-1,4-naphthoquinone (5a–b) series were also discovered as novel andpotent inhibitors. Compounds 4aand 4bshowedIC50values in low micromolar range in the primary assayand no activity in the counter DT-diaphorase assay. [ABSTRACT FROM AUTHOR]

An efficient one-pot four-component domino protocol for the combinatorial synthesis of novel 1,4-dihydropyrano[2,3-c]pyrazol-6-amines has been achieved. This transformation presumably occurs via cyclization-Knoevenagel condensation-Michael addition-tautomerism-intramolecular O-cyclization-elimination sequence of reactions. The significant features of this reaction include expedient one-pot process, short reaction time, no column chromatographic purification, excellent yield, and readily available starting materials. [ABSTRACT FROM AUTHOR]

An efficient diastereoselective oxa-Pictet–Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (+)-frenolicin B and epi-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs. [ABSTRACT FROM AUTHOR]

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

2H,3'H-Spiro[benzofuran-3,2'-naphthoquinones], constituting a new spiroheterocyclic skeleton, were synthesized starting from 2-aryloxymethyl-1,4-naphthoquinones by means of a palladium(II)-catalyzed reaction, which is a new spirocyclic transformation. Under optimal conditions, i.e. 10 mol % of palladium(II) acetate, 15 mol % of 3,5-dichloropyridine, and 5 mol % of trifluoroacetic acid in acetic acid at 110 °C, various 2H,3'H-spiro[benzofuran-3,2'-naphthoquinones] were synthesized in yields strongly dependent on the substitution pattern of the aryloxy group. Unsubstituted or ortho-substituted 2-aryloxymethyl-1,4-quinones were found to rearrange toward the corresponding 2-(4-hydroxyaryl)-1,4-quinones upon treatment with trifluoroacetic acid. [ABSTRACT FROM AUTHOR]

A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recycled up to 10 times without any decrease in enantioselectivity (average 96% ee) and adapted to continuous flow operation (24 h). A single flow experiment involving six different nitroalkenes in a sequential manner highlights the applicability of this methodology for rapid access to chemical diversity. [ABSTRACT FROM AUTHOR]

When produced at physiological levels, reactive oxygen species (ROS) can act as signaling molecules to regulate normal vascular function. Produced under pathological conditions, ROS can contribute to the oxidative damage of cellular components (e.g., DNA and proteins) and trigger cell death. Moreover, the reaction of superoxide with nitric oxide (NO) produces the strong oxidant peroxynitrite and decreases NO bioavailability, both of which may contribute to activation of cell death pathways. The effects of ROS generated from the 1,4-naphthoquinones alone and in combination with NO on the activation status of poly(ADP-ribose) polymerase (PARP) and cell viability were examined. Treatment with redox cycling quinones activates PARP, and this stimulatory effect is attenuated in the presence of NO. Mitochondria play a central role in cell death signaling pathways and are a target of oxidants. We show that simultaneous exposure of endothelial cells to NO and ROS results in mitochondrial dysfunction, ATP and NAD+ depletion, and cell death. Alone, NO and ROS have only minor effects on cellular bioenergetics. Further, PARP inhibition does not attenuate reduced cell viability or mitochondrial dysfunction. These results show that concomitant exposure to NO and ROS impairs energy metabolism and triggers PARP-independent cell death. While superoxide-mediated PARP activation is attenuated in the presence of NO, PARP inhibition does not modify the loss of mitochondrial function or adenine and pyridine nucleotide pools and subsequent bioenergetic dysfunction. These findings suggest that the mechanisms by which ROS and NO induce endothelial cell death are closely linked to the maintenance of mitochondrial function and not overactivation of PARP. [ABSTRACT FROM AUTHOR]

The synthesis of optically active, carboannulated dihydronaphthoquinone and naphthoquinone derivatives with up to four stereogenic centers is demonstrated by H-bond-directed, trienamine-mediated [4 + 2]-cycloadditions. The outcome of the reaction between 2,4-dienals and 1,4-naphthoquinones is controlled by the substituent in the 2-position of the 1,4-naphthoquinone. In the case of sterically demanding 2-substituted derivatives, dihydronaphthoquinones are obtained. However, when a hydrogen atom is present in the 2-position, a subsequent oxidation of the initially formed cycloadducts occurs yielding naphthoquinones. [ABSTRACT FROM AUTHOR]

A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 ± 250 and 290 ± 54 nM, respectively. Dose-response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn2+ and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 ± 8.2 fmol min-1 mg-1) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 ± 0.3 nmol min-1 mg-1). Zn2+, 1,2-naphthoquinone, and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 μM, and 100 nM, respectively. Dephosphorylation of the reporter, following loading into living single cells, occurred at rates of at least 2 pmol min-1 mg-1. When single cells were exposed to 1,2-naphthoquinone (50 μM), Zn2+ (100 μM), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

A highly efficient and stereoselective synthesis of coumarin-, 1,3-cyclohexanedione-, and 1,4-naphthoquinone-fused 2,8-dioxabicyclo[3.3.1]nonanes is described. This was achieved via a sequential Michael addition/bicyclization reaction from easily accessible 3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one derivatives. Three chemical bonds (one C-C bond and two C-O bonds), two six-membered cycles, and two stereogenic centers were formed in a one-pot operation. [ABSTRACT FROM AUTHOR]

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

Aggregation of amyloid beta (Aβ) is the hallmarkof Alzheimer’sdisease (AD). Small molecules inhibiting Aβ can be valuabletherapeutics for AD. We have previously reported that 1,4-naphthoquinon-2-yl-l-tryptophan (NQTrp), reduces aggregation and oligomerizationof Aβ in vitro and in vivo. In silico analysis further showedthat certain functional groups of NQTrp, not in the aromatic rings,are also involved in binding and inhibiting Aβ. To better understandthe exact mode of action and identify the groups crucial for NQTrpinhibitory activity, we conducted structure–activity analysis.Four derivatives of NQTrp were studied in silico: a D-isomer, two single-methylated and one double-methylated derivative.In silico results showed that the NQTrp groups involved in hydrogenbonds are the anilinic NH (i.e., the NH linker between the quinoneand tryptophan moieties), the quinonic carbonyls, and the carboxylicacid. These predictions were supported by in vitro results. Our resultsshould aid in designing improved small-molecule inhibitors of Aβaggregation for treating AD. [ABSTRACT FROM AUTHOR]

Three conformational polymorphs of 2-(1,4-dihydro-1,4-dioxonaphthalen-3-ylthio)benzoic acid (L), an acetonitrile solvate of L, and cocrystal of Lwith 2,2′-bipyridine arestructurally characterized. The two polymorphs Iand IIhave Z′ = 1 and possess R22(8) type of dimeric structure in which the two aromaticrings are in trans disposition across the cyclic hydrogen bonded motifs.However, the dihedral angles between the aromatic ring and 2-methyl1,4-naphthoquinone rings are −129.38° and 126.56°,respectively. The polymorph IIIhas Z′ = 2; it shows R22(8) type of dimericstructures which are formed by two symmetry independent molecules.In its crystal lattice, the aromatic rings across the cyclic hydrogenbond motifs are in cis dispositions. Dihedral angles between the aromaticring and 2-methyl 1,4-naphthoquinone ring in the two symmetry independentmolecules are 114.82° and 125.27°, respectively. The acetonitrilesolvate of 1has Z′ = 3. In itscrystal lattice, it has two symmetry independent molecules formingR22(8) hydrogen bonds to form dimeric assembliesand another cyclic R22(8) type hydrogen bondgeometry between molecules which constitute the third set of symmetryindependent molecules. The 2-(1,4-dihydro-1,4-dioxonaphthalen-3-ylthio)benzoicacid also forms a 2:1 cocrystal with 2,2′-bipyridine; in thiscocrystal the two nitrogen atoms are trans to each other and theyparticipate in hydrogen bonds with carboxylic acids. [ABSTRACT FROM AUTHOR]

A very facile reaction between photochemically generated o-naphthoquinone methides (oNQMs) and thiols is employed for reversible light-directed surface derivatization and patterning. A thiol-functionalized glass slide is covered with an aqueous solution of a substrate conjugated to 3-(hydroxymethyl)-2-naphthol (NQMP). Subsequent irradiation via shadow mask results in the efficient conversion of NQMP into reactive oNQM species in the exposed areas. The latter react with thiol groups on the surface, producing thioether links between the substrate and the surface. Unreacted oNQM groups are rapidly hydrated to regenerate NQMP. The short lifetime of oNQM in aqueous solution prevents its migration from the site of irradiation, thus allowing for the spatial control of the surface derivatization. A two-step procedure was employed for protein patterning: photobiotinylation of the surface with an NQMP-biotin conjugate followed by staining with FITC-avidin. The orthogonality of oNQM-thiol and azide click chemistry allowed for the development of a sequential click strategy, which might be useful for the immobilization of light-sensitive compounds. The thioether linkage produced by the reaction of oNQM and a thiol is stable under ambient conditions but can be cleaved by UV irradiation, regenerating the free thiol. This feature allows for the removal or replacement of immobilized substrates. [ABSTRACT FROM AUTHOR]