Synthetic Quinones Research Articles

Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging.

Human NAD(P)H-quinone oxidoreductase1 (HNQO1) is a two-electron reductase antioxidant enzyme whose expression is driven by the NRF2 transcription factor highly active in the prooxidant milieu found in human malignancies. The resulting abundance of NQO1 expression (up to 200-fold) in cancers and a barely detectable expression in body tissues makes it a selective marker of neoplasms. NQO1 can catalyze the repeated futile redox cycling of certain natural and synthetic quinones to their hydroxyquinones, consuming NADPH and generating rapid bursts of cytotoxic reactive oxygen species (ROS) and H2O2. A greater level of this quinone bioactivation due to elevated NQO1 content has been recognized as a tumor-specific therapeutic strategy, which, however, has not been clinically exploited. We review here the natural and new quinones activated by NQO1, the catalytic inhibitors, and the ensuing cell death mechanisms. Further, the cancer-selective expression of NQO1 has opened excellent opportunities for distinguishing cancer cells/tissues from their normal counterparts. Given this diagnostic, prognostic, and therapeutic importance, we and others have engineered a large number of specific NQO1 turn-on small molecule probes that remain latent but release intense fluorescence groups at near-infrared and other wavelengths, following enzymatic cleavage in cancer cells and tumor masses. This sensitive visualization/quantitation and powerful imaging technology based on NQO1 expression offers promise for guided cancer surgery, and the reagents suggest a theranostic potential for NQO1-targeted chemotherapy.

Antimalarial application of quinones: A recent update.

Atovaquone belongs to a naphthoquinone class of drugs and is used in combination with proguanil (Malarone) for the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum (including chloroquine-resistant P.falciparum/P.vivax). Numerous quinone-derived compounds have attracted considerable attention in the last few decades due to their potential in antimalarial drug discovery. Several semi-synthetic derivatives of natural quinones, synthetic quinones (naphtho-/benzo-quinone, anthraquinones, thiazinoquinones), and quinone-based hybrids were explored for their invitro and invivo antimalarial activities. A careful literature survey revealed that this topic has not been compiled as a review article so far. Therefore, we herein summarise the recent discovery (the year 2009-2020) of quinone based antimalarial compounds in chronological order. This compilation would be very useful towards the exploration of novel quinone-derived compounds against malarial parasites with promising efficacy and lesser side effects.

Electrochemistry of selected quinones at immiscible n-octyl-2-pyrrolidone/aqueous interface using a three-phase electrode system

Both endogenous and synthetic (e.g. drugs) quinones are essential functional moieties in various biological systems and their activity is mainly governed by their electrochemical properties. In recent years they are also more readily applied in novel energy storage devices, such as batteries and solar cells. In this work, the redox behaviour of 1-aminoanthraquinone (AQ), and 2,3-dichloro-1,4-naphthoquinone (NQ) is studied at a three-phase junction formed by n-octyl-2-pyrrolidone and aqueous electrolyte solution on a glassy carbon working electrode. We show that the two quinones behave quite differently when undergoing reduction at the three-phase junction. AQ underwent a 1-step, 2-electron reduction resulting in transfer of cations from the aqueous phase, while reduction of NQ occurred in two steps, the first of which was accompanied by a transfer of the NQ•− radical to the interface with the reduction potential dependent on the anion present in the aqueous phase due to salting out effects. After that, the quinone was able to undergo a second reduction process forming a dianion which similarly to AQ resulted in a transfer of cations from the aqueous phase. Importantly, the cation transfer potential is determined by ion-pair formation with the quinone, rather than the solvation energy of cation in the pure organic solvent.

Tattooing Dye as a Green Electrode Material for Lithium Batteries

Lawsone (2‐hydroxy‐1,4‐naphthoquinone), a naturally derived red‐orange dye, is investigated as a promising cathode material for next‐generation lithium batteries. Lithium cells based on lawsone cathode display a high discharge capacity of 280 mA h g−1 (99% theoretical capacity), a high energy density of 664 W h kg−1, and long life of 1000 cycles at 0.5 C along with good rate performance up to 5 C. These results represent significant improvements from previously reported organic cathode materials, and surpass those of conventional lithium batteries based on LiCoO2 cathodes (140 mA h g−1 and 520 W h kg−1, respectively). Its success stems from the unique 2D planar packing of lawsone molecules, with maximized overlap of adjacent p orbitals for redox active sites. The result is the simultaneous enhancement of electrical and ionic conductivities that are an order of magnitude higher than those of other synthetic quinones. Given that lawsone is derived from the henna plant and has long been used as a dye for human hair and skin, this work may open a new chapter in the design of future green batteries.

Coenzyme Q10 in the Treatment of Mitochondrial Disease

Currently, there is a paucity of available treatment strategies for oxidative phosphorylation disorders. Coenzyme Q10 (CoQ10) and related synthetic quinones are the only agents to date that have pr...

Structural Effects of Urea and Tmo on Lipid Bilayers

Lipid bilayers can display a wide range of morphologies and are simple models for the cell membrane, that not only defines the cell limits but also provides a matrix for anchoring a variety of substances, e.g, membrane proteins, glycolipids, etc., that play an essential role in the cell. Recently, we have been studying the structural effects of synthetic quinones on lipid model membranes, in order to investigate their contribution to morphologies possibly involved in the electron transfer process. Summarizing, we can say that the insertion of these synthetic additives lower the temperature of the structural phase transitions comparative to pure lipids and in many cases induce the formation of cubic phases at low temperatures, e.g. 30°C, which corresponds to an increase of the lipid matrix surface curvature. The scattering patterns of the cubic phases are clearly identifiable, despite their intrinsic low resolution. In some cases micellar cubic phases were observed. In this study we shifted our attention to the influence of small molecules such as urea and TMAO. It is accepted that they have antagonistic effects on the fluidity of lipid membranes. In red blood cells, urea slightly increases the gel-phase domains, but this effect is counteracted by TMAO. We intended to determine how these organic solutes affect the structure of a lipid membrane and determine their contribution to the possible curvature induced on them. We could see a change on the temperature of phase transitions and the formation of induced phases or structures.

Protection or cytotoxicity mediated by a novel quinonoid-polyphenol compound?

Many natural and synthetic quinones and naphthoquinones possess a variety of beneficial pharmacological properties. In plants, the cytotoxic properties of quinones serve in their defensive roles against invading bacteria, fungi and parasites. In this regard many quinones as well as polyphenols, exerting generally toxicity at high dosages, are able to induce favorable hormetic responses at a low dosage. The novel chloronaphthoquinone derivative of quercetin (CHNQ) showed a profound cytotoxicity followed by enhancement of intracellular generation of oxidants in human neonatal B-HNF-3 fibroblasts. Its synthetic precursors, quercetin and 2-chloro-3-hydroxy-[1,4]naphthoquinone, failed to induce these effects, and paradoxically, only CHNQ at a low concentration provided partial protection of the cells against oxidative challenge. Thus, the novel quinonoid-polyphenol CHNQ might have a merit in the search for new prospective agents in prevention and management of ageing and ageing-related pathologies.

Electron transfer capacity dependence of quinone-mediated Fe(III) reduction and current generation by Klebsiella pneumoniae L17

Quinone groups in exogenous electron shuttles can accelerate extracellular electron transfer (EET) from bacteria to insoluble terminal electron acceptors, such as Fe(III) oxides and electrodes, which are important in biogeochemical redox processes and microbial electricity generation. However, the relationship between quinone-mediated EET performance and electron-shuttling properties of the quinones remains incompletely characterized. This study investigates the effects of a series of synthetic quinones (SQs) on goethite reduction and current generation by a fermenting bacterium Klebsiella pneumoniae L17. In addition, the voltammetric behavior and electron transfer capacities (ETCs) of SQ, including electron accepting (EAC) and donating (EDC) capacities, is also examined using electrochemical methods. The results showed that SQ can significantly increase both the Fe(III) reduction rates and current outputs of L17. Each tested SQ reversibly accepted and donated electrons as indicated by the cyclic voltammograms. The EAC and EDC results showed that Carmine and Alizarin had low relative capacities of electron transfer, whereas 9,10-anthraquinone-2,6-disulfonic acid (AQDS), 2-hydroxy-1,4-naphthoquinone (2-HNQ), and 5-hydroxy-1,4-naphthoquinone (5-HNQ) showed stronger relative ETC, and 9,10-anthraquinone-2-carboxylic acid (AQC) and 9,10-anthraquinone-2-sulfonic acid (AQS) had high relative ETC. Enhancement of microbial goethite reduction kinetics and current outputs by SQ had a good linear relationship with their ETC, indicating that the effectiveness of quinone-mediated EET may be strongly dependent on the ETC of the quinones. Therefore, the presence of quinone compounds and fermenting microorganisms may increase the diversity of microbial populations that contribute to element transformation in natural environments. Moreover, ETC determination of different SQ would help to evaluate their performance for microbial EET under anoxic conditions.

Antifeedant and toxic effects of naturally occurring and synthetic quinones to the cabbage looper, Trichoplusia ni

We investigated the feeding deterrent effects and toxicity of naturally occurring and synthetic quinones to the cabbage looper, Trichoplusia ni. Feeding deterrent effects were determined via a leaf disc choice bioassay. Based on DC 50 values, 1,4-naphthoquinone was the most active antifeedant ( DC 50 = 1.8 μg/cm 2) followed by juglone ( DC 50 = 2.1 μg/cm 2), 2-methoxy-1,4-naphthoquinone ( DC 50 = 2.6 μg/cm 2), plumbagin ( DC 50 = 3.3 μg/cm 2), and 2,3-dimethoxy-5-mehtyl-1,4-benzoquinone ( DC 50 = 4.2 μg/cm 2) in third instar cabbage looper larvae. 2-Bromo-1,4-naphthoquinone, 2-chloro-3-morpholino-1,4-naphthoquinone, 1,8-dihydroxy-anthraquinone, 2-methyl-1,4-naphthoquinone and naphthazarin had DC 50 values ranging from 8.4 to 10.1 μg/cm 2. Juglone and plumbagin were able to provide protection to intact cabbage plants in a greenhouse experiment. Cabbage looper larvae consumed less leaf area and weighed less on cabbage plants treated with either of these naturally occurring quinones. Most of the quinones demonstrated levels of antifeedant activity greater than neem, a positive control, in laboratory bioassays. The level of activity for juglone was comparable to neem in the greenhouse experiment. There was also a reduction in the number of larvae on treated plants compared with the negative control. Structure-activity relationships suggest that the antifeedant effects of the tested quinones depend on the number and position of hydroxyl and methoxyl substituents of quinones. Most of the quinones were of medium-low toxicity to third instar cabbage looper larvae via topical administration. Some of these quinones could have potential for development as commercial insect control agents targeting the feeding behavior of insects with minimal toxicity, provided that their impacts on non-target organisms and environment are minimal.

Natural and Synthetic Naphthoquinones Active Against Trypanosoma Cruzi: An Initial Step Towards New Drugs for Chagas Disease

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

Pro-apoptotic activities of novel synthetic quinones in human cancer cell lines

Four novel quinonoid compounds are evaluated for their apoptotic potential against three cancer cell lines, i.e. MCF-7, HeLa and MG-63. APOP ercentage™ assay was used for the screening of the compounds and it was established that the apoptotic potential of these compounds is cell line specific. The compound 2 -(1′,4′- benzoquinon-2′- yl)-5- hydroxy-7- methyl-1,4- naphthoquinone (S4) was found to be most active, which has a potential to kill ∼99% of HeLa cancer cells in vitro after 72 h at a concentration of 10 μM. The compound’s ability to induce specific markers of apoptosis in HeLa cells is further confirmed by DNA fragmentation and cell cycle assays.

Natural and synthetic quinones and their reduction by the quinone reductase enzyme NQO1: from synthetic organic chemistry to compounds with anticancer potential

The quinone reductase enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes the two-electron reduction of quinones. This Perspective briefly reviews the structure and mechanism, physiological role, and upregulation and induction of the enzyme, but focuses on the synthesis of new heterocyclic quinones and their metabolism by recombinant human NQO1. Thus a range of indolequinones, some of which are novel analogues of mitomycin C, benzimidazolequinones, benzothiazolequinones and quinolinequinones have been prepared and evaluated, leading to detailed knowledge of the structural requirements for efficient metabolism by the enzyme. Potent mechanism-based inhibitors (suicide substrates) of NQO1 have also been developed. These indolequinones irreversibly alkylate the protein, preventing its function both in standard enzyme assays and also in cells. Some of these quinones are also potent inhibitors of growth of human pancreatic cancer cells, suggesting a potential role for such compounds as therapeutic agents.

Trypanosoma cruzi: Activities of lapachol and α- and β-lapachone derivatives against epimastigote and trypomastigote forms

Derivatives of natural quinones with biological activities, such as lapachol, α- and β-lapachones, have been synthesized and their trypanocidal activity evaluated in vitro in Trypanosoma cruzi cells. All tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity as compared with current trypanocidal drugs, nifurtimox and benznidazole. The results presented here show that the anti- T. cruzi activity of the α-lapachone derivatives can be increased by the replacement of the benzene ring by a pyridine moiety. Free radical production and consequently oxidative stress through redox cycling or production of electrophilic metabolites are the potential biological mechanism of action for these synthetic quinones.

Synthesis of Hydroxy and Methoxy Perylene Quinones, Their Spectroscopic and Computational Characterization, and Their Antiviral Activity¶

ABSTRACTHydroxy and methoxy perylene quinones are synthesized in an attempt to isolate the essential spectroscopic and biological features of light‐induced antiviral agents such as hypericin and hypocrellin. Unlike their naturally occurring counterparts, these synthetic quinones bear the carbonyl, hydroxyl, and methoxy groups in the “bay region.” The hydroxy and methoxy compounds have rich absorption spectra with broad features in the visible (∼450–800 nm) and relatively more intense and narrow features at wavelengths ≤350 nm. High‐level ab initio quantum mechanical calculations assign the features in the absorption spectra to electronic transitions from So to S2 and to higher‐lying electronic states. The calculations indicate that in the ground state the trans dihydroxy isomer is 12.5 kcal/mol lower in energy than the cis dihydroxy isomer and is thus the only species present. The lowest‐energy trans methoxy ground state isomer and the lowest‐energy cis methoxy ground state isomer are found to be degenerate. An additional cis methoxy isomer 6.3 kcal/mol higher in energy than the global minimum is assumed to contribute to the spectrum and is also considered. Finally, the synthetic compounds exhibit similar light‐induced antiviral activity to each other, but significantly less than that of hypericin.

Synthesis of Hydroxy and Methoxy Perylene Quinones, Their Spectroscopic and Computational Characterization, and Their Antiviral Activity¶

Abstract Hydroxy and methoxy perylene quinones are synthesized in an attempt to isolate the essential spectroscopic and biological features of light-induced antiviral agents such as hypericin and hypocrellin. Unlike their naturally occurring counterparts, these synthetic quinones bear the carbonyl, hydroxyl, and methoxy groups in the “bay region.” The hydroxy and methoxy compounds have rich absorption spectra with broad features in the visible (∼450–800 nm) and relatively more intense and narrow features at wavelengths ≤350 nm. High-level ab initio quantum mechanical calculations assign the features in the absorption spectra to electronic transitions from S0 to S2 and to higher-lying electronic states. The calculations indicate that in the ground state the trans dihydroxy isomer is 12.5 kcal/mol lower in energy than the cis dihydroxy isomer and is thus the only species present. The lowest-energy trans methoxy ground state isomer and the lowest-energy cis methoxy ground state isomer are found to be degener...

Synthesis of Hydroxy and Methoxy Perylene Quinones, Their Spectroscopic and Computational Characterization, and Their Antiviral Activity

Hydroxy and methoxy perylene quinones are synthesized in an attempt to isolate the essential spectroscopic and biological features of light-induced antiviral agents such as hypericin and hypocrellin. Unlike their naturally occurring counterparts, these synthetic quinones bear the carbonyl, hydroxyl, and methoxy groups in the "bay region." The hydroxy and methoxy compounds have rich absorption spectra with broad features in the visible (approximately 450-800 nm) and relatively more intense and narrow features at wavelengths < or = 350 nm. High-level ab initio quantum mechanical calculations assign the features in the absorption spectra to electronic transitions from S0 to S2 and to higher-lying electronic states. The calculations indicate that in the ground state the trans dihydroxy isomer is 12.5 kcal/mol lower in energy than the cis dihydroxy isomer and is thus the only species present. The lowest-energy trans methoxy ground state isomer and the lowest-energy cis methoxy ground state isomer are found to be degenerate. An additional cis methoxy isomer 6.3 kcal/mol higher in energy than the global minimum is assumed to contribute to the spectrum and is also considered. Finally, the synthetic compounds exhibit similar light-induced antiviral activity to each other, but significantly less than that of hypericin.

A new type-II NADH dehydrogenase from the archaeon Acidianus ambivalens: characterization and in vitro reconstitution of the respiratory chain.

A new type-II NADH dehydrogenase (NDH-II) was isolated from the hyperthermoacidophilic archaeon Acidianus ambivalens. This enzyme is a monomer with an apparent molecular mass of 47 kDa, containing a covalently bound flavin, and no iron-sulfur clusters. Upon isolation, NDH-II loses activity, which can, nevertheless, be restored by incubation with phospholipids. Catalytically, it is a proficient NADH:caldariella quinone oxidoreductase (130 mmol NADH oxidized/mg protein(-1)/min(-1)) but it can also donate electrons to synthetic quinones, strongly suggesting its involvement in the respiratory chain. The apparent Km for NADH was found to be approximately 6 microM, both for the purified and membrane-integrated enzyme, thus showing that detergent solubilization and purification did not affect the substrate binding site. Further, it is the first example of a type-II NADH dehydrogenase that contains the flavin covalently attached, which may be related to the need to stabilize the otherwise labile cofactor in a thermophilic environment. A fully operative minimal version of Acidianus ambivalens respiratory system was successfully reconstituted into artificial liposomes, using three basic components isolated from the organism: the type-II NADH dehydrogenase, caldariella quinone, the organism-specific quinone, and the aa3 type quinol oxidase. This system, which mimics the in vivo chain, is efficiently energized by NADH, driving oxygen consumption by means of the terminal oxidase.

Characterization and Partial Purification of Microsomal NAD(P)H:Quinone Oxidoreductases

Quinone oxidoreductases are flavoproteins that catalyze two-electron reduction and detoxification of quinones. This leads to the protection of cells against toxicity, mutagenicity, and cancer due to exposure to environmental and synthetic quinones and its precursors. Two cytosolic forms of quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2)] were previously identified, purified, and cloned. A role of cytosolic NQO1 in protection of cells from oxidative stress, cytotoxicity, and mutagenicity of quinones was established. Currently, we have characterized and partially purified the NQO activity from rat liver microsomes. This activity was designated as microsomal NQO (mNQO). The mNQO activity showed significantly higher affinity for NADH than NADPH as electron donors and catalyzed reduction of 2,6-dichlorophenolindophenol and menadione. The mNQO activity was insensitive to dicoumarol, a potent inhibitor of cytosolic NQO1. Western analysis of microsomal proteins revealed 29- and 18-kDa bands that cross-reacted with polyclonal antibodies raised against cytosolic NQO1. The mNQO activity was partially purified by solubilization of microsomes with detergent Chaps, ammonium sulfate fractionation, and DEAE-Sephacel column chromatography. The microsomal mNQO proteins are expected to provide additional protection after cytosolic NQOs against quinone toxicity and mutagenicity.

Vibrational modes of ubiquinone in cytochrome bo(3) from Escherichia coli identified by Fourier transform infrared difference spectroscopy and specific (13)C labeling.

In this study we present the infrared spectroscopic characterization of the bound ubiquinone in cytochrome bo(3) from Escherichia coli. Electrochemically induced Fourier transform infrared (FTIR) difference spectra of DeltaUbiA (an oxidase devoid of bound ubiquinone) and DeltaUbiA reconstituted with ubiquinone 2 and with isotopically labeled ubiquinone 2, where (13)C was introduced either at the 1- or at the 4-position of the ring (C=O groups), have been obtained. The vibrational modes of the quinone bound to the discussed high-affinity binding site (Q(H)) are compared to those from the synthetic quinones in solution, leading to the assignment of the C=O modes to a split signal at 1658/1668 cm(-)(1), with both carbonyls similarly contributing. The FTIR spectra of DeltaUbiA reconstituted with the labeled quinones indicate an essentially symmetrical and weak hydrogen bonding of the two C=O groups from the neutral quinone with the protein and distinct conformations of the 2- and 3-methoxy groups. Perturbations of the vibrational modes of the 5-methyl side groups are discussed for a signal at 1452 cm(-)(1). Only negligible shifts of the aromatic ring modes can be reported for the reduced and the protonated form of the quinone. Alterations of the protein upon quinone binding are reflected in the electrochemically induced FTIR difference spectra. In particular, difference signals at 1640-1633 cm(-)(1) and 1700-1670 cm(-)(1) indicate variations of beta-sheet secondary structure elements and loops, bands at 1706 and 1678 cm(-)(1) are tentatively attributed to individual amino acids, and a difference signal a 1540 cm(-)(1) is discussed to reflect an influence on C=C modes of the porphyrin ring or on deprotonated propionate groups of the hemes. Further tentative assignments are presented and discussed. The (13)C labeling experiments allow the assignment of the vibrational modes of a bound ubiquinone 8 in the electrochemically induced FTIR difference spectra of wild-type bo(3).

Influence of β-naphthoflavone on 7,12-dimethylbenz(a)anthracene (DMBA) DNA adduction in rainbow trout and on tumorigenicity

Dihydrodiol dehydrogenase (DDH) isoenzymes were purified from rabbit liver (Klein et al., Eur. J. Biochem., 205 (1992) 1155), and the major forms CF-1, CF-5 and CM-2 were tested for their substrate specificity with dihydrodiol and quinone metabolites of polycyclic aromatic hydrocarbons. CF-5, which was shown to correspond to aldehyde reductase in rabbit liver, was found to efficiently oxidize aromatic dihydrodiol metabolites (phenanthrene-1,2-dihydrodiol, benz[a]anthracene-3,4-dihydrodiol) while CF-1, corresponding to carbonyl reductase, and CM-2 were much less active. All three enzyme forms were found to reduce polycyclic K-region o-quinones of benz[a]anthracene, chrysene and benzo[a]pyrene. CF-1 was the least active, and CM-2 was the most active form with reaction velocities of > 10 μmol/min·mg protein. Among a range of synthetic quinones tested, benz[a]anthracene-8,9-quinone and benzo[a]pyrene 9,10-quinone were also good substrates for the three enzymes, as well as p-benzoquinone and naphthalene-1,4-quinone. The reduction of polycyclic o-quinones, but not of p-benzoquinone, by enzyme CM-2 was accompanied by the oxidation of large amounts of NADPH and the consumption of molecular oxygen which is indicative of a redox-cycling process. Thus, the formation of catechol metabolites from dihydrodiols and o-quinones may be catalyzed by the same enzymes in rabbit liver, and the reaction rate of the enzymatic reduction is strongly dependent on the structural type of the polycyclic quinone.