naphthoquinones and dunnione

Three new naphthoquinones, 5,6,7-trimethoxydunnione (

Topics: Antioxidants; Ethanol; Hexanes; Lamiales; Naphthoquinones; Plant Extracts

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Extracellular Traps; Female; Mice; Mice, Inbred BALB C; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Sirtuin 1; Thrombophilia; Thromboplastin; Thrombosis

Topics: Animals; Antimalarials; Disease Models, Animal; HeLa Cells; Humans; Mice; Molecular Structure; Naphthoquinones; Quinone Reductases; Reactive Oxygen Species; Structure-Activity Relationship; Substrate Specificity

Topics: Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Gene Expression Regulation; Inflammation; Kidney Diseases; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Oxidative Stress; Protective Agents; Rats; Rats, Wistar

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Dinoprostone; Edema; Hyperalgesia; Magnoliopsida; Mice; Molecular Structure; Naphthoquinones; Plant Tubers

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

Topics: Acetylation; Animals; Cisplatin; Cochlea; Cytoprotection; Disease Models, Animal; Hearing; Hearing Loss; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Poly (ADP-Ribose) Polymerase-1; Protective Agents; Signal Transduction; Sirtuin 1; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Chemical investigation of the tubers of Sinningia allagophylla led to the isolation of two new chromenes, (2S)-12-hydroxylapachenole (1) and (3R)-3,4-dihydro-3-hydroxy-4-oxo-8-methoxylapachenole (2), and three new dimeric chromenes, allagophylldimers A-C (3-5). Thirteen known compounds, 6-methoxy-7,8-benzocoumarin (6), lapachenole, 8-methoxylapachenole, tectoquinone, 7-hydroxytectoquinone, dunniol, α-dunnione, dunnione, 8-hydroxydunnione, aggregatin E, cedrol, oleanolic acid, and halleridone, were also identified. 6-Methoxy-7,8-benzocoumarin (6) has been isolated for the first time from a natural source.

Topics: Benzofurans; Benzopyrans; Brazil; Cyclohexanones; Molecular Structure; Naphthalenes; Naphthoquinones; Plant Tubers; Plants, Medicinal; Polycyclic Sesquiterpenes; Terpenes

Natural product (±)-dunnione (2) and its ortho-quinone analogues (3-8) were synthesized and found to be substrates for NQO1. The structure-activity relationship study revealed that the biological activity was favored by the presence of methyl group at the C ring and methoxy group at the A ring. The docking studies supported the rationalization of the metabolic studies. Deeper location in the active site of NQO1, interactions with hydrophobic pocket and C-H…π interactions with the adjacent Phe178 residue contributed to the better catalytic efficiency and specificity to NQO1. Cytotoxicity studies and determination of superoxide (O2(-)) production in the presence and absence of the NOQ1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling.

Topics: Binding Sites; Catalytic Domain; Cell Line, Tumor; Cell Survival; Enzyme Inhibitors; Humans; Kinetics; Molecular Docking Simulation; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Quinones; Reactive Oxygen Species; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Superoxides

Naphthoquinones are considered privileged structures for anticancer drug molecules. The Heck reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with 1-bromo-3-methyl-2-butene offered easy access to lapachol. Several naturally occurring linear and angular heterocyclic quinoids (α-lapachone, β-lapachone, dunnione, and related analogues) were prepared from lapachol. Furthermore, we demonstrated that the synthetic naphthoquinones inhibit cell proliferation in human leukemia HL-60 cells. In particular, angular-type derivatives were found to possess moderate cytotoxicity and to elevate the levels of intracellular glutathione disulfide (GSSG). Our work highlights the significant potential of naturally occurring angular-series naphthoquinones as antileukemic agents.

Topics: Alkenes; Antineoplastic Agents; Cell Proliferation; Crystallography, X-Ray; Dimerization; Glutathione; HL-60 Cells; Humans; Molecular Conformation; Naphthoquinones; Structure-Activity Relationship

Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD(+)) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD(+) in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD(+) levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage.

Topics: Animals; Antineoplastic Agents; Apoptosis; Body Weight; Cisplatin; Cytokines; Inflammation Mediators; Intestine, Small; Male; Mice; Mice, Inbred C57BL; NAD; Naphthoquinones; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Sirtuin 1; Transcription Factor RelA

A new naphthoquinone, 6-methoxy-7-hydroxy-a-dunnione (1), along with four known compounds (2, 4, 10, and 11) were isolated from Sinningia canescens (Mart.) Wiehler tubers, while S. warmingii (Hiern.) Chautems furnished eight known compounds (3-10). The known compounds were identified as 7-hydroxy- α-dunnione (2), lapachenole (3), tectoquinone (4), 7-methoxytectoquinone (5), 1-hydroxytectoquinone (6), 7-hydroxytectoquinone (7), aggregatin C (8), aggregatin D (9), halleridone (10), and cedrol (11). In addition, S. canescens yielded a volatile fraction, which was analyzed by GC/FID and GC/MS. This fraction was constituted mainly by sesquiterpene hydrocarbons (82.6%). The major components were β-santalene (14.6%), β-cedrene (10.4%), and trans-cadina-1(6)-4-diene (10.0%).

Topics: Benzofurans; Benzopyrans; Cyclohexanones; Gas Chromatography-Mass Spectrometry; Magnoliopsida; Naphthoquinones; Polycyclic Sesquiterpenes; Terpenes

Two new furanonaphthoquinones, (3R)-7-methoxy-α-dunnione (5) and (3R)-6-hydroxy-7-methoxy-α-dunnione (6), along with the known (3R)-dunnione (1), (3R)-α-dunnione (2), (3R)-7-hydroxy-α-dunnione (3), and 1-hydroxy-2-methylanthraquinone (4), were isolated from in vitro cultures of Streptocarpus dunnii. The structures of compounds 5 and 6 were established by spectroscopic means. This is the first report of hydroxylated furanonaphthoquinones in a Streptocarpus species. Compounds 1-3 demonstrated cytotoxic activity against a range of breast cancer and pancreatic tumor cell lines.

Topics: Anthraquinones; Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; Female; Furans; Humans; Magnoliopsida; Molecular Structure; Naphthoquinones; Nuclear Magnetic Resonance, Biomolecular; Seedlings; Seeds; South Africa; Structure-Activity Relationship

This paper reports the investigation of the insecticidal and fungicidal activity of dunnione, a natural product obtained inadvertently as a by-product of a synthesis programme. Dunnione exhibits no insecticidal activity but has an unusually broad spectrum of antifungal activity. In vitro and in vivo (preventative) activities were comparable to those of several long-established fungicides (eg carbendazim). However, in whole-plant assays, its eradicant activity was unexpectedly low, probably due to poor dose-transfer from leaf surface to fungus. The level of residual activity appears to be influenced by the formulation. Finally, its potential as a lead structure was assessed, and several analogues synthesised which exhibited high activity in the in vitro assays. Mode-of-action studies revealed that dunnione exerts its action primarily through initiation of redox cycling. This contrasts to the activity of BTG 505, the biochemical/chemical precursor, which does not initiate redox cycling but instead exhibits both insecticidal and fungicidal activity by inhibiting mitochondrial Complex III.

Topics: Animals; Biological Assay; Biological Factors; Carbon Isotopes; Cell Respiration; Electron Transport Complex I; Electron Transport Complex III; Fungi; Fungicides, Industrial; Insect Control; Insecta; Insecticides; Magnetic Resonance Spectroscopy; Molecular Structure; NADH, NADPH Oxidoreductases; Naphthoquinones; Oxidation-Reduction; Quantitative Structure-Activity Relationship