1,4-Naphthoquinone

Methyl-ketones in the scent glands of Opiliones: a chemical trait of cyphophthalmi retrieved in the dyspnoan Nemastoma triste.[Pubmed:29670318]

Chemoecology. 2018;28(2):61-67.

The homologous and phylogenetically old scent glands of harvestmen-also called defensive or repugnatorial glands-represent an ideal system for a model reconstruction of the evolutionary history of exocrine secretion chemistry ("phylogenetic chemosystematics"). While the secretions of Laniatores (mainly phenols, benzoquinones), Cyphophthalmi (naphthoquinones, chloro-naphthoquinones, methyl-ketones) and some Eupnoi (naphthoquinones, ethyl-ketones) are fairly well studied, one open question refers to the still largely enigmatic scent gland chemistry of representatives of the suborder Dyspnoi and the relation of dyspnoan chemistry to the remaining suborders. We here report on the secretion of a nemastomatid Dyspnoi, Nemastoma triste, which is composed of straight-chain methyl-ketones (heptan-2-one, nonan-2-one, 6-tridecen-2-one, 8-tridecen-2-one), methyl-branched methyl-ketones (5-methyl-heptan-2-one, 6-methyl-nonan-2-one), naphthoquinones (1,4-Naphthoquinone, 6-methyl-1,4-Naphthoquinone) and chloro-naphthoquinones (4-chloro-1,2-naphthoquinone, 4-chloro-6-methyl-1,2-naphthoquinone). Chemically, the secretions of N. triste are remarkably reminiscent of those found in Cyphophthalmi. While naphthoquinones are widely distributed across the scent gland secretions of harvestmen (all suborders except Laniatores), methyl-ketones and chloro-naphthoquinones arise as linking elements between cyphophthalmid and dyspnoan scent gland chemistry.

Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity.[Pubmed:29735338]

Bioorg Med Chem Lett. 2018 Jun 15;28(11):2023-2028.

To establish the structure-activity relationship of 5-hydroxy-1,4-Naphthoquinones toward anticancer activity, a series of its derivatives were prepared and tested for the activity (IC50 in microM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among them 2 (IC50: 2.3; 2.0; 1.4microM), 6 (IC50: 1.9; 2.2; 1.3microM), 9 (IC50: 0.7; 1.7; 0.9microM) and 10 (IC50:1.7; 1.0; 1.2microM) showed moderate to excellent activity. Our perception toward the DNA substitution of alkoxy groups at the C2 position of these naphthoquinones for the anticancer activity led us to investigate their reactivity of substitution toward dimethylamine as a nucleophile. The ease of the substitution of alkoxy groups at the C2 position with dimethylamine is strongly accelerated by hydroxyl group at C5 position and is well correlated with the found anticancer activity results.

Dual targeting of the cancer antioxidant network with 1,4-naphthoquinone fused Gold(i) N-heterocyclic carbene complexes.[Pubmed:29619196]

Chem Sci. 2017 Sep 1;8(9):5918-5929.

To achieve a systems-based approach to targeting the antioxidant pathway, 1,4-Naphthoquinone annulated N-heterocyclic carbene (NHC) [bis(1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] [silver(i) dichloride] (1), [bis(1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] chloride (2), and 1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i) chloride (3)) were designed, synthesized, and tested for biological activity in a series of human cancer cell lines. The solution phase of complexes 1-3 were assigned using several spectroscopy techniques, including NMR spectroscopic analysis. Complexes 1 and 3 were further characterized by single crystal X-ray diffraction analysis. Electrochemical and spectroelectrochemical studies revealed that quinone reductions are reversible and that the electrochemically generated semiquinone and quinone dianions are stable under these conditions. Complex 1, containing two NHC-quinone moieties (to accentuate exogenous ROS via redox cycling) centered around a Au(i) center (to inactivate thioredoxin reductase (TrxR) irreversibly), was found to inhibit cancer cell proliferation to a much greater extent than the individual components (i.e., Au(i)-NHC alone or naphthoquinone alone). Treatment of A549 lung cancer cells with 1 produced a 27-fold increase in exogenous reactive oxygen species (ROS) which was found to localize to the mitochondria. The inhibition of TrxR, an essential mediator of ROS homeostasis, was achieved in the same cell line at low administrated concentrations of 1. TrxR inhibition by 1 was similar to that of auranofin, a gold(i) containing complex known to inhibit TrxR irreversibly. Complex 1 was found to induce cell death via an apoptotic mechanism as confirmed by annexin-V staining. Complex 1 was demonstrated to be efficacious in zebrafish bearing A549 xenografts. These results provide support for the suggestion that a dual targeting approach that involves reducing ROS tolerance while concurrently increasing ROS production can perturb antioxidant homeostasis, enhance cancer cell death in vitro, and reduce tumor burden in vivo, as inferred from preliminary zebra fish model studies.

Oxidation of Naphthalene with a Manganese(IV) Bis(hydroxo) Complex in the Presence of Acid.[Pubmed:29701293]

Angew Chem Int Ed Engl. 2018 Jun 25;57(26):7764-7768.

Naphthalene oxidation with metal-oxygen intermediates is a difficult reaction in environmental and biological chemistry. Herein, we report that a Mn(IV) bis(hydroxo) complex, which was fully characterized by various physicochemical methods, such as ESI-MS, UV/Vis, and EPR analysis, X-ray diffraction, and XAS, can be employed for the oxidation of naphthalene in the presence of acid to afford 1,4-Naphthoquinone. Redox titration of the Mn(IV) bis(hydroxo) complex gave a one-electron reduction potential of 1.09 V, which is the most positive potential for all reported nonheme Mn(IV) bis(hydroxo) species as well as Mn(IV) oxo analogues. Kinetic studies, including kinetic isotope effect analysis, suggest that the naphthalene oxidation occurs through a rate-determining electron transfer process.

New cytokinin derivatives possess UVA and UVB photoprotective effect on human skin cells and prevent oxidative stress.[Pubmed:29604584]

Eur J Med Chem. 2018 Apr 25;150:946-957.

Eleven 6-furfurylaminopurine (kinetin, Kin) derivatives were synthesized to obtain biologically active compounds. The prepared compounds were characterized using (1)H NMR, mass spectrometry combined with HPLC purity determination and elemental C, H, N analyses. The biological activity of new derivatives was tested on plant cells and tissues in cytokinin bioassays, such as tobacco callus, detached wheat leaf chlorophyll retention bioassay and Amaranthus bioassay. The selected compounds were subsequently tested on normal human dermal fibroblasts (NHDF) and keratinocyte cell lines (HaCaT) to exclude possible phototoxic effects and, on the other hand, to reveal possible UVA and UVB photoprotective activity. The protective antioxidant activity of the prepared cytokinin derivatives was further studied and compared to previously prepared antisenescent compound 6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (Kin-THF) using induced oxidative stress (OS) on nematode Caenorhabditis elegans damaged by 5-hydroxy-1,4-Naphthoquinone (juglone), a generator of reactive oxygen species. The observed biological activity was interpreted in relation to the structure of the prepared derivatives. The most potent oxidative stress protection of all the prepared compounds was shown by 6-(thiophen-2-ylmethylamino)-9-(tetrahydrofuran-2-yl)purine (6) and 2-chloro-6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (9) derivatives and the results were comparable to Kin-THF. Compounds 6 and 9 were able to significantly protect human skin cells against UV radiation in vitro. Both the derivatives 6 and 9 showed higher protective activity in comparison to previously known structurally similar compounds Kin and Kin-THF. The obtained results are surprising due to the fact that the prepared compounds showed to be inactive in the ORAC assay which proved that the compounds did not act as direct antioxidants as they were unable to directly scavenge oxygen radicals.

The Application of 2-Benzyl-1,4-naphthoquinones as Pronucleophiles in Aminocatalytic Synthesis of Tricyclic Derivatives.[Pubmed:29644859]

J Org Chem. 2018 May 4;83(9):5019-5026.

This study demonstrates an unprecedented reactivity of 2-substituted-1,4-Naphthoquinones. By applying the principle of vinylogy, they have been employed as vinylogous pronucleophiles in the organocatalytic cascade reaction for the first time. This novel catalytic activation of 1,4-Naphthoquinones enables access to carboannulated naphthalen-1(4 H)-one derivatives of biological importance. The site-selectivity and stereoselectivity of a process proved possible to control by the proper choice of reaction conditions.

Oral spray containing plant-derived compounds is effective against common oral pathogens.[Pubmed:29573647]

Arch Oral Biol. 2018 Jun;90:80-85.

OBJECTIVES: Plant-derived compounds are a good source of therapeutic agents and inhibitors of inflammatory process. Dental caries, periodontal diseases and candidiasis are common oral infections caused by virulent biofilms. The objectives of this study were to develop oral spray containing plant-derived compounds; alpha-mangostin (alpha-MG) and/or lawsone methyl ether (2-methoxy-1,4-Naphthoquinone) (LME) and determine its antimicrobial, anti-biofilm, and anti-inflammatory activities. DESIGN: Oral spray formulations were prepared containing alpha-MG (5mg/ml) and/or LME (250mug/ml). Antimicrobial activity against Candida albicans, Streptococcus mutans, and Porphyromonas gingivalis and anti-biofilm formation activities were determined as well as cytotoxicity and anti-inflammatory effects. RESULTS: The oral spray demonstrated antimicrobial activity against all three of the oral pathogens tested with stronger effects on C. albicans and S. mutans than P. gingivalis. The formulation containing alpha-MG (2.5mg/ml) and LME (125 ug/ml) reduced growth of the microorganisms about 1-2 Log CFU/ml at 1-3h and the killing effects were complete at 24h. Based on biofilm assay, the oral spray containing both alpha-MG and LME showed greater inhibitory effects than those with alpha-MG or LME. In addition, the oral spray containing both alpha-MG and LME demonstrated more inhibition of nitric oxide production than alpha-MG alone. All the formulations were safe and demonstrated greater anti-inflammatory activity at lower concentration (<6.25mug/ml) than at a higher concentration. CONCLUSION: Oral spray containing alpha-MG and/or LME is effective against common oral pathogens without significant cytotoxicity. Thus, it has the potential to prevent the infections and may serve as adjunctive treatment to conventional therapy.

1,4-Naphthoquinone is a potential pharmacophore for inhibition of both MAO (monoamine oxidase) and DNA topoisomerase activities, this latter associated with antitumor activity.

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