Fungal quinones: diversity, producers, and applications of quinones from Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium.

Quinones represent an important group of highly structurally diverse, mainly polyketide-derived secondary metabolites widely distributed among filamentous fungi. Many quinones have been reported to have important biological functions such as inhibition of bacteria or repression of the immune response in insects. Other quinones, such as ubiquinones are known to be essential molecules in cellular respiration, and many quinones are known to protect their producing organisms from exposure to sunlight. Most recently, quinones have also attracted a lot of industrial interest since their electron-donating and -accepting properties make them good candidates as electrolytes in redox flow batteries, like their often highly conjugated double bond systems make them attractive as pigments. On an industrial level, quinones are mainly synthesized from raw components in coal tar. However, the possibility of producing quinones by fungal cultivation has great prospects since fungi can often be grown in industrially scaled bioreactors, producing valuable metabolites on cheap substrates. In order to give a better overview of the secondary metabolite quinones produced by and shared between various fungi, mainly belonging to the genera Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium, this review categorizes quinones into families such as emodins, fumigatins, sorbicillinoids, yanuthones, and xanthomegnins, depending on structural similarities and information about the biosynthetic pathway from which they are derived, whenever applicable. The production of these quinone families is compared between the different genera, based on recently revised taxonomy. KEY POINTS: • Quinones represent an important group of secondary metabolites widely distributed in important fungal genera such as Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium. • Quinones are of industrial interest and can be used in pharmacology, as colorants and pigments, and as electrolytes in redox flow batteries. • Quinones are grouped into families and compared between genera according to the revised taxonomy.

Synthesis of new N,S-acetal analogs derived from juglone with cytotoxic activity against Trypanossoma cruzi.

A series of 11 new N,S-acetal juglone derivatives were synthesized and evaluated against T. cruzi epimastigote forms. These compounds were obtained in good to moderate yields using a microwave irradiation protocol. Among all compounds, two N,S-acetal analogs, showed significant trypanocidal activity. Notably, one compound 11g exhibited selectivity index 10-fold higher than the reference drug benznidazole for epimastigote. The compound 11h was more effective for amastigote forms. Both prototypes exhibited S.I. higher than the benznidazole description. Thus, both compounds proving to be useful candidate molecules to further studies in infected animals.

Design, Synthesis and Cancer Cell Growth Inhibition Evaluation of New Aminoquinone Hybrid Molecules.

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI50 < 10 nM).

Ethnobotanical uses, phytochemistry and biological activity of the genus Euclea: A review.

Euclea (Ebenaceae) is a genus of flowering shrubs and trees widely distributed in Africa, the Comoro Islands, and Arabia. This review aimed to evaluate the ethnobotanical uses, phytochemistry, and biological activities of the genus Euclea on available research reports. This was achieved through PubMed, Medline, Google Scholar, Science Direct, Taylor and Francis Online, Wiley Online Library which provides access to scientific and medical research. The extensive literature survey revealed that plants that belong to this genus are used as folkloric medicine for the treatment of diabetes mellitus, toothache, diarrhea, cancer, malaria, leprosy, and genital and oral diseases in the case of HIV/AIDS-related diseases. To date, more than 40 secondary metabolites have been isolated and identified from these plants, especially from E natalensis and E. divinorum. Among these, naphthoquinones, terpenes, and flavonoids are potential secondary metabolites with profound biological activities. Euclea plant extracts and their bioactive compounds possess outstanding pharmacological properties, especially antimalarial, antidiabetic, anticancer, antimicrobial, and antioxidant properties.

Pentas longiflora Oliv. (Rubiaceae), a plant used in the treatment of Pityriasis Versicolor in Rwanda: Chemical composition and standardization of leaves and roots.

In Rwanda, the roots of Pentas longiflora Oliv. (Rubiaceae) have been used for a long time to treat Pityriasis versicolor. However, many people reported the use of leaves instead of roots. This research was conducted to compare the phytochemical composition and establish chromatographic methods for the standardization of roots and leaves extracts of P. longiflora. During this process, three new pentalongin glycosides (pentalonginoside A, pentalonginoside B, and pentalonginoside C) and two known glycosides of the same type (harounoside and clarinoside), as well as rutin, luteolin-7-rutinoside were isolated from methanol extract of leaves. In addition, pentalongin and psychorubrin, previously isolated from ethylacetate roots extract, were also identified in Pentas longiflora ethylacetate leaves extract. The presence of the antifungal compound pentalongin in leaves may explain the traditional use of leaves in the treatment of Pytiriasis versicolor. Furthermore, harounoside, psychorubrin, and pentalongin were selected as markers for HPLC fingerprints of MeOH extract. The accuracy and risk profile demonstrated the reliability of the validated method. In general, considerable variations of concentration in plant metabolites, including pentalongin, were observed between samples from different sites. The content in pentalongin (expressed as juglone) in collected samples ranged between 1.7 and 70.0 mg/100 g. The highest concentration (70.0 ± 17 mg/100 g) was registered in the cultivated samples from Mukoni. This important variation of pentalongin concentrations according to sampling sites, shows that in order to guarantee equivalent efficacy, finished products with P. longiflora should be standardized based on their pentalongin content.

Green Extraction Strategies for Sea Urchin Waste Valorization.

Commonly known as "purple sea urchin," Paracentrotus lividus occurs in the Mediterranean Sea and the eastern Atlantic Ocean. This species is a highly appreciated food resource and Italy is the main consumer among the European countries. Gonads are the edible part of the animal but they represent only a small fraction (10-30%) of the entire sea urchin mass, therefore, the majority ends up as waste. Recently, an innovative methodology was successfully developed to obtain high-value collagen from sea urchin by-products to be used for tissue engineering. However, tissues used for the collagen extraction are still a small portion of the sea urchin waste (<20%) and the remaining part, mainly the carbonate-rich test and spines, are discarded. Residual cell tissues, tests, and spines contain polyunsaturated fatty acids, carotenoids, and a class of small polyphenols, called polyhydroxynaphthoquinones (PHNQ). PHNQ, due to their polyhydroxylated quinonoid nature, show remarkable pharmacologic effects, and have high economic significance and widespread application in several cosmetic and pharmaceuticals applications. A green extraction strategy aimed to obtain compounds of interest from the wastes of sea urchins was developed. The core strategy was the supercritical CO2 technique, characterized by low environmental impacts. Fatty acids and carotenoids were successfully and selectively extracted and identified depending on the physical parameters of the supercritical CO2 extraction. Finally, the exhausted powder was extracted by solvent-based procedures to yield PHNQ. The presence of Spinochrome A and Spinochrome B was confirmed and extracts were characterized by a remarkably high antioxidant activity, measured through the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay. Overall, the selective and successive extraction methods were validated for the valorization of waste from sea urchins, demonstrating the feasibility of the techniques targeting added-value compounds.

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells.

Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF6 (1) and [Ru(Lap)(dppm)(phen)]PF6 (2) [Lap = lapachol, dppm = 1,1'-bis(diphosphino)methane, bipy = 2,2'-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex (2) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex (2) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (2), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy.

Corrigendum: All Three Endogenous Quinone Species of Escherichia coli Are Involved in Controlling the Activity of the Aerobic/Anaerobic Response Regulator ArcA.

[This corrects the article DOI: 10.3389/fmicb.2016.01339.].

Recent Progress on Organic Electrodes Materials for Rechargeable Batteries and Supercapacitors.

Rechargeable batteries are essential elements for many applications, ranging from portable use up to electric vehicles. Among them, lithium-ion batteries have taken an increasing importance in the day life. However, they suffer of several limitations: safety concerns and risks of thermal runaway, cost, and high carbon footprint, starting with the extraction of the transition metals in ores with low metal content. These limitations were the motivation for an intensive research to replace the inorganic electrodes by organic electrodes. Subsequently, the disadvantages that are mentioned above are overcome, but are replaced by new ones, including the solubility of the organic molecules in the electrolytes and lower operational voltage. However, recent progress has been made. The lower voltage, even though it is partly compensated by a larger capacity density, may preclude the use of organic electrodes for electric vehicles, but the very long cycling lives and the fast kinetics reached recently suggest their use in grid storage and regulation, and possibly in hybrid electric vehicles (HEVs). The purpose of this work is to review the different results and strategies that are currently being used to obtain organic electrodes that make them competitive with lithium-ion batteries for such applications.

NQO1 induction mediated by photodynamic therapy synergizes with ß-Lapachone-halogenated derivative against melanoma.

The elevated expression of NQO1 in many human solid tumors along with its ability to activate quinone-based anticancer agents makes it an excellent target for enzyme-directed drug development. NQO1 plays an important role in melanogenesis and given its correlation with a poor patient outcome we propose this enzyme as an intriguing target for molecular-based therapeutic regimen against melanoma. Unfortunately, the natural product ß-Lapachone (ß-Lap), whose antitumor activity is based on NQO1, reported dose-limiting toxicity which hampered its pre-clinical and clinical use. Therefore, new effective and safe therapeutic NQO1-bioactivatable agents for melanoma treatment are desirable. Regarding NQO1, we demonstrated that halogenated ß-Lap derivative named PFB is an excellent substrate and effective tumor-selective anticancer compound. In addition, PFB resulted more attractive than the parent ß-Lap for treating metastatic-derived melanoma cells. In this context, it would be interesting to design strategies to induce NQO1 activity in cancer cells as a promising combinatorial approach with bioreductive drugs. In this sense, we had reported that photodynamic therapy (PDT) significantly upregulated NQO1 expression. Based on this event, here we demonstrated that the cytotoxic regimen consisting of PFB plus PDT improved synergistic therapeutic combination on melanoma cells. In conclusion, our contribution provides a strong rationale for using therapies that associate photo- and chemotherapy to effectively treat melanoma with modular NQO1 status.

Reaction of hydroxylated naphtoquinones/antraquinones with pentafluoropyridine.

In this study, the reaction of pentafluoropyridine with hydroxylated naphtoquinones and hydroxylated antraquinones was investigated under basic conditions in DMF. One or two hydroxyl group in naphtoquinones and antraquinones react with pentafluoropyridine to give mono and di-tetrafluoropyridyl naphtoquinones/antraquinones. All the compounds were characterized using (1)H, (13)C and (19)F-NMR spectroscopy.

All Three Endogenous Quinone Species of Escherichia coli Are Involved in Controlling the Activity of the Aerobic/Anaerobic Response Regulator ArcA.

The enteron Escherichia coli is equipped with a branched electron transfer chain that mediates chemiosmotic electron transfer, that drives ATP synthesis. The components of this electron transfer chain couple the oxidation of available electron donors from cellular metabolism (e.g., NADH, succinate, lactate, formate, etc.) to the reduction of electron acceptors like oxygen, nitrate, fumarate, di-methyl-sulfoxide, etc. Three different quinones, i.e., ubiquinone, demethyl-menaquinone and menaquinone, couple the transfer of electrons between the dehydrogenases and reductases/oxidases that constitute this electron transfer chain, whereas, the two-component regulation system ArcB/A regulates gene expression, to allow the organism to adapt itself to the ambient conditions of available electron donors and acceptors. Here, we report that E. coli can grow and adjust well to transitions in the availability of oxygen, with any of the three quinones as its single quinone. In all three 'single-quinone' E. coli strains transitions in the activity of ArcB are observed, as evidenced by changes in the level of phosphorylation of the response regulator ArcA, upon depletion/readmission of oxygen. These results lead us to conclude that all quinol species of E. coli can reduce (i.e., activate) the sensor ArcB and all three quinones oxidize (i.e., de-activate) it. These results also confirm our earlier conclusion that demethyl-menaquinone can function in aerobic respiration.

New naphthoquinone derivatives against glioma cells.

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.

Antraquinonas e naftoquinonas do caule de um espécime de reflorestamento de Tectona grandi (Verbenaceae) / Anthraquinones and naphtoquinones from the bark of Tectona grandis (Verbenaceae) reforestation specimen

O fracionamento do extrato hexânico do caule de um espécime de reflorestamento de Tectona grandis (Verbenaceae), através de procedimentos fitoquímicos clássicos, levou ao isolamento das naftoquinonas lapachol e desidro-a-lapachona e das antraquinonas tectoquinona e obtusifolina. As estruturas das substâncias foram caracterizadas através da análise de métodos espectrométricos de RMN. Este é o primeiro estudo fitoquímico de um espécime de reflorestamento de Tectona grandis, no Brasil, sendo o objetivo principal deste trabalho a comprovação da presença de tectoquinona em espécimes cultivados.

The hexane extract of the bark of Tectona grandis (Verbenaceae) afforded two anthraquinones and two naphtoquinones. Their caracterizations were obtained through NMR spectroscopic techniques. This is the first phytochemical study of the bark of Tectona grandis reforestation specimen in Brazil. The main interest in this work is proving the presence of tectoquinone in reforestation specimen.

Estudo quimico de Zeyheria montana M. (bolsa de pastor)

Do extrato hexânico das raízes de Zeyheria montana M., uma Bignoniácea conhecida como bolsa‑de‑pastor, empregada popularmente contra doenças de pele, foram isolados os seguintes compostos: lapachol, α‑lapachona, desidro‑α‑lapachona, 4‑hidróxi­-α‑lapachona, β‑sitosterol, ácido esteárico e uma mistura de ácidos graxos. Estas substancias foram identificadas por métodos espectrométricos usuais e/ou comparação com amostras autênticas. No cromatograma do extrato etanólico, obtido por CLAE, foram identificados os picos correspondentes às naftoquinonas isoladas e ao ácido esteárico. A ocorrência de naftoquinonas nas raizes de Z. montana e a atividade antimicrobiana comprovada para o lapachol e a α‑lapachona justificam o uso popular desta espécie.

Zeyheria montana M. (Bignoniaceae) is a widespread species in the Cerrado area of Minas Gerais, Brazil, and is popularly known as bolsa‑de‑pastor. In the Brazilian tradicional medicine its roots are used for the treatment of skin diseases. Several species of Bignoniaceae contain naphthoquinones, and lapachol was previously reported in the stem wood of Z. digitalis. This paper describes the isolation of three naphtoquinones from Z. montana stem barks, namely α‑lapachone, dehydro‑α‑lapachone and 4‑hydroxy‑α‑lapachone, besides lapachol, stearic acid and β‑sitosterol. Furthermore, we report the HPLC fingerprint for the species, which allowed the identification of the isolated compounds, except β‑sitosterol. Since the in vitro antimicrobial activity of lapachol and α‑lapachone has been previously described, the presence of these naphthoquinones in the roots of Z. montana corroborates its popular use for the treatment of skin diseases.