Rapanone

Anti-melanoma potential of two benzoquinone homologues embelin and rapanone - a comparative in vitro study.[Pubmed:32169436]

Toxicol In Vitro. 2020 Jun;65:104826.

Rapanone and embelin are simple alkyl benzoquinone derivatives, mainly distributed in the Primulaceae. They have an interesting scope of biological activities including cytotoxicity. As melanoma is one of the most common types of cancer, in many cases resistant to current treatment regimens, the aim of this study was to assess and compare anti-melanoma activity of the two benzoquinones. Cytotoxicity of both compounds towards different melanoma cell lines (A375, HTB140, WM793) and selectivity with respect to normal keratinocytes (HaCaT) were investigated. Furthermore, interactions with a reference chemotherapeutic, doxorubicine, were assessed. Finally, analysis of anti-inflammatory, antioxidant and anti-tyrosinase activities of both benzoquinones was conducted as well. Rapanone showed selective and higher than doxorubicine cytotoxic potential against primary melanoma cell line, WM793. Although embelin was also highly cytotoxic, its selectivity was much poorer. Interestingly, in case of HTB140 and HaCaT cell lines a combination of each benzoquinone with doxorubicine potentiated the cytotoxic potential in a synergistic manner. Embelin revealed higher albumin anti-denaturation potential than Rapanone but lower than diclofenac sodium. Anti-hyaluronidase effect of both benzoquinones was higher than quercetin. Both compounds showed antioxidant potential although significantly lower as compared to vitamin C. Finally, neither embelin nor Rapanone had any inhibitory effect on tyrosinase.

Rapanone, a naturally occurring benzoquinone, inhibits mitochondrial respiration and induces HepG2 cell death.[Pubmed:31756542]

Toxicol In Vitro. 2020 Mar;63:104737.

Rapanone is a natural occurring benzoquinone with several biological effects including unclear cytotoxic mechanisms. Here we addressed if mitochondria are involved in the cytotoxicity of Rapanone towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In the HepG2, Rapanone (20-40 muM) induced a concentration-dependent mitochondrial membrane potential dissipation, ATP depletion, hydrogen peroxide generation and, phosphatidyl serine externalization; the latter being indicative of apoptosis induction. Rapanone toxicity towards primary rats hepatocytes (IC50 = 35.58 +/- 1.50 muM) was lower than that found for HepG2 cells (IC50 = 27.89 +/- 0.75 muM). Loading of isolated mitochondria with Rapanone (5-20 muM) caused a concentration-dependent inhibition of phosphorylating and uncoupled respirations supported by complex I (glutamate and malate) or the complex II (succinate) substrates, being the latter eliminated by complex IV substrate (TMPD/ascorbate). Rapanone also dissipated mitochondrial membrane potential, depleted ATP content, released Ca(2+) from Ca(2+)-loaded mitochondria, increased ROS generation, cytochrome c release and membrane fluidity. Further analysis demonstrated that Rapanone prevented the cytochrome c reduction in the presence of decylbenzilquinol, identifying complex III as the site of its inhibitory action. Computational docking results of Rapanone to cytochrome bc1 (Cyt bc1) complex from the human sources found spontaneous thermodynamic processes for the quinone-Qo and Qi binding interactions, supporting the experimental in vitro assays. Collectively, these observations suggest that Rapanone impairs mitochondrial respiration by inhibiting electron transport chain at Complex III and promotes mitochondrial dysfunction. This property is potentially involved in Rapanone toxicity on cancer cells.

Bioactive benzoquinones content variability in red-berry and white-berry varieties of Ardisia crenata Sims. and assessment of cytotoxic activity.[Pubmed:31135229]

Nat Prod Res. 2019 May 28:1-5.

Ardisia crenata Sims (Myrsinaceae) occurs in two varieties differing in the fruit color, the red berries being common while the white ones are rare. The roots of red-berried A. crenata are a valued TCM product which contains bioactive benzoquinones such as embelin and Rapanone. In this study we compared their profiles in different organs of the plant to provide an insight in the pattern of their accumulation within the two varieties. Moreover, cytotoxic activity against human melanoma and prostate cancer cells was evaluated. Quantitative HPLC revealed that the white-berried variety differs profoundly in the content of Rapanone, with its total level of 606.5 mg/100 g d.w., as compared to 16.2 mg/100 g d.w. in A. crenata 'red'. Embelin was less distributed and found in minor amounts in both varieties. This is the first report on Rapanone content in various parts of Ardisia crenata and on benzoquinones in the white-berried variety.

Metabolome responses of the sea cucumber Apostichopus japonicus to multiple environmental stresses: Heat and hypoxia.[Pubmed:30660290]

Mar Pollut Bull. 2019 Jan;138:407-420.

Economically important marine organisms face severe environmental challenges, such as high temperature and low dissolved oxygen, from global climate change. Adverse environmental factors impact the survival and growth of economically important marine organisms, thereby negatively influencing the aquaculture industry. However, little is known about the responses of sea cucumbers to combined environmental co-stressors till now. In this study, ultra-performance liquid chromatography (UPLC) was utilized to obtain metabolic profiles of sea cucumbers. Changes in the concentrations of 84, 68, and 417 metabolites related to the responses of sea cucumbers to heat (26 degrees C), hypoxia (2mg/L) and the combined stress, respectively, were observed and analyzed. Representative biomarkers were discussed in detail, including deltaline, fusarin C, halichondrin B and Rapanone. The concentration of metabolites involved in the regulation of energy metabolism, including amino acid, carbohydrate and lipid metabolism were significantly changed, and the tricarboxylic acid (TCA)-cycle was significantly altered under heat plus hypoxia. We interpreted these changes partly as an adaptation mechanism in response to environmental stress. Based on the decreased accumulation of glutamine, we hypothesized that heat stress is the main factor that interferes with the process of glutamic acid-glutamine metabolism. The present study showed that combined environmental stressors have a more extensive impact on the metabolites of the respiratory tree in sea cucumbers than single stress. These results would facilitate further development of the sea cucumber as an echinoderm model to study mechanisms of response to adverse environments, as well as to help advance knowledge of the adaptation of marine organisms to global climate change.

Discerning the antioxidant mechanism of rapanone: A naturally occurring benzoquinone with iron complexing and radical scavenging activities.[Pubmed:28237732]

J Inorg Biochem. 2017 May;170:134-147.

Oxidative stress resulting from iron and reactive oxygen species (ROS) homeostasis breakdown has been implicated in several diseases. Therefore, molecules capable of binding iron and/or scavenging ROS may be reasonable strategies for protecting cells. Rapanone is a naturally occurring hydroxyl-benzoquinone with a privileged chelating structure. In this work, we addressed the antioxidant properties of Rapanone concerning its iron-chelating and scavenging activities, and its protective potential against iron and tert-butyl hydroperoxide-induced damage to mitochondria. Experimental determinations revealed the formation of Rapanone-Fe(II)/Fe(III) complexes. Additionally, the electrochemical assays indicated that Rapanone oxidized Fe(II) and O2(-), thus inhibiting Fenton-Haber-Weiss reactions. Furthermore, Rapanone displayed an increased 2,2-diphenyl-1-picrylhydrazyl radical scavenging ability in the presence of Fe(II). The above results explained the capacity of Rapanone to provide near-full protection against iron and tert-butyl hydroperoxide induced mitochondrial lipid peroxidation in energized organelles, which fail under non-energized condition. We postulate that Rapanone affords protection against iron and reactive oxygen species by means of both iron chelating and iron-stimulated free radical scavenging activity.

Cytotoxicity of Plumbagin, Rapanone and 12 other naturally occurring Quinones from Kenyan Flora towards human carcinoma cells.[Pubmed:27998305]

BMC Pharmacol Toxicol. 2016 Dec 21;17(1):60.

BACKGROUND: Cancer is a major public health concern globally and chemotherapy remains the principal mode of the treatment of various malignant diseases. METHODS: This study was designed to investigate the cytotoxicity of 14 naturally occurring quinones including; 3 anthraquinones, 1 naphthoquinone and 10 benzoquinones against 6 human carcinoma cell lines and normal CRL2120 fibroblasts. The neutral red uptake (NR) assay was used to evaluate the cytotoxicity of the compounds, whilst caspase-Glo assay was used to detect caspases activation. Cell cycle and mitochondrial membrane potential (MMP) were all analyzed via flow cytometry meanwhile levels of reactive oxygen species (ROS) were measured by spectrophotometry. RESULTS: Anthraquinone: emodin (2), naphthoquinone: plumbagin (4), and benzoquinones: Rapanone (9), 2,5-dihydroxy-3-pentadecyl-2,5-cyclohexadiene-1,4-dione (10), 5-O-methylembelin (11), 1,2,4,5-tetraacetate-3-methyl-6-(14-nonadecenyl)-cyclohexadi-2,5-diene (13), as well as doxorubicin displayed interesting activities with IC50 values below 100 muM in the six tested cancer cell lines. The IC50 values ranged from 37.57 muM (towards breast adenocarcinoma MCF-7 cells) to 99.31 muM (towards small cell lung cancer A549 cells) for 2, from 0.06 muM (MCF-7 cells) to 1.14 muM (A549 cells) for 4, from 2.27 muM (mesothelioma SPC212 cells) to 46.62 muM (colorectal adenocarcinoma DLD-1 cells) for 9, from 8.39 muM (SPC212 cells) to 48.35 muM (hepatocarinoma HepG2 cells) for 10, from 22.57 muM (MCF-7 cells) to 61.28 muM (HepG2 cells) for 11, from 9.25 muM (MCF-7 cells) to 47.53 muM (A549 cells) for 13, and from 0.07 muM (SPC212 cells) to 1.01 muM (A549 cells) for doxorubicin. Compounds 4 and 9 induced apoptosis in MCF-7 cells mediated by increased ROS production and MMP loss, respectively. CONCLUSION: The tested natural products and mostly 2, 4, 9, 10, 11 and 13 are potential cytotoxic compounds that deserve more investigations towards developing novel antiproliferative drugs against human carcinoma.

Antibacterial activities and structure-activity relationships of a panel of 48 compounds from Kenyan plants against multidrug resistant phenotypes.[Pubmed:27386347]

Springerplus. 2016 Jun 27;5(1):901.

In the current study forty eight compounds belonging to anthraquinones, naphthoquinones, benzoquinones, flavonoids (chalcones and polymethoxylated flavones) and diterpenoids (clerodanes and kauranes) were explored for their antimicrobial potential against a panel of sensitive and multi-drug resistant Gram-negative and Gram-positive bacteria. The minimal inhibitory concentration (MIC) determinations on the tested bacteria were conducted using modified rapid INT colorimetric assay. To evaluate the role of efflux pumps in the susceptibility of Gram-negative bacteria to the most active compounds, they were tested in the presence of phenylalanine arginine beta-naphthylamide (PAbetaN) (at 30 microg/mL) against selected multidrug resistance (MDR) bacteria. The anthraquinone, emodin, naphthaquinone, plumbagin and the benzoquinone, Rapanone were active against methicillin resistant Staphylococcus aureus (MRSA) strains of bacteria with MIC values ranging from 2 to 128 mug/mL. The structure activity relationships of benzoquinones against the MDR Gram-negative phenotype showed antibacterial activities increasing with increase in side chain length. In the chalcone series the presence of a hydroxyl group at C3' together with a methoxy group and a second hydroxyl group in meta orientation in ring B of the chalcone skeleton appeared to be necessary for minimal activities against MRSA. In most cases, the optimal potential of the active compounds were not attained as they were extruded by bacterial efflux pumps. However, the presence of the PAbetaN significantly increased the antibacterial activities of emodin against Gram-negative MDR E. coli AG102, 100ATet; K. pneumoniae KP55 and KP63 by >4-64 g/mL. The antibacterial activities were substantially enhanced and were higher than those of the standard drug, chloramphenicol. These data clearly demonstrate that the active compounds, having the necessary pharmacophores for antibacterial activities, including some quinones and chalcones are substrates of bacterial efflux pumps and therefore should be combined to efflux pump inhibitors in the fight against MDR bacterial infections.

Discovery of the rapanone and suberonone mixture as a motif for leishmanicidal and antifungal applications.[Pubmed:24331757]

Bioorg Med Chem. 2014 Jan 1;22(1):135-40.

Leishmaniasis and fungal infections are significant diseases impacting worldwide public health. Treatments have developed greatly over time, however, there is a necessity to discover less toxic drugs, which have greater efficacy and are more economically accessible. This work conducted a screening of Cerrado species extracts: Connarus suberosus Planch. (Connaraceae), Neea theifera Oerst. (Nyctaginaceae) and Myrcia linearifolia Cambess. (Myrtaceae) against Leishmania (Leishmania) amazonensis, dermatophytes and yeasts. Leishmanicidal and antifungal tests were conducted using MTT colorimetric assay and CLSI methodology, respectively. Connarus suberosus extracts presented the most promising results against the aforementioned microorganisms, which has not been described in the literature. The root bark EtOAc extract was selected for chemical fractionation resulting in a mixture of Rapanone (1) and a previously unreported compound named as suberonone (2); a mixture of beta-sitosterol (3) and stigmasterol (4); oleic acid (5); geranilgeraniol (6); and two derivatives obtained from 1 and 2 mixture. The Rapanone and suberonone mixture demonstrated a MIC of 15.62 mug/mL against Candida albicans ATCC 10231.

First synthesis of N-(3-carboxylpropyl)-5-amino-2-hydroxy-3- tridecyl-1,4-benzoquinone, an unusual quinone isolated from Embelia ribes.[Pubmed:17999537]

J Org Chem. 2007 Dec 21;72(26):10298-301.

The first synthesis of the unusual nitrogen-containing 3-alkyl-1,4-benzoquinone, N-(3-carboxylpropyl)-5-amino-2-hydroxy-3-tridecyl-1,4-benzoquinone, isolated from Embelia ribes, is reported. The key steps are a microwave-assisted combined Mitsunobu reaction-Claisen rearrangement to introduce the alkyl side chain into 2,5-dimethoxyphenol, followed by alkene reduction, oxidation to the quinone, and sequential displacement of the methoxy groups with hydroxide and GABA tert-butyl ester. Two other naturally occurring benzoquinones, O-methylRapanone and Rapanone, were also prepared en route.

Cytotoxic activity of five compounds isolated from Colombian plants.[Pubmed:15030931]

Fitoterapia. 2004 Mar;75(2):225-7.

Cytotoxic effect of five known compounds, khellin, berberine, lupeol, scopolin, Rapanone, obtained from Colombian plants, were determined against human tumor cell lines as an indicator of the potential anticancer activity of these compounds. Berberine and Rapanone presented interesting cytotoxicity.

Inhibition of acute and chronic inflammatory responses by the hydroxybenzoquinonic derivative rapanone.[Pubmed:11745012]

Planta Med. 2001 Dec;67(9):791-5.

Rapanone (2,5-dihydroxy-3-tridecyl-1,4-benzoquinone), a natural compound isolated from Myrsine guianensis growing in the Andean highlands of Colombia, was studied in different in vitro and in vivo models as a potential antioxidant and anti-inflammatory drug. Rapanone showed a mild anti-lipoperoxidative profile in rat liver microsomes and inhibited potently degranulation (IC(50) of 9.8 microM) and superoxide chemiluminescence (IC(50) of 3.0 microM) in human neutrophils. In addition, Rapanone is a selective and potent human synovial PLA(2) inhibitor (IC(50) of 2.6 microM). In vivo experiments using the carrageenan paw oedema and the zymosan air pouch model in mice as well as the adjuvant arthritis model in rats have proved that Rapanone is very efficient in controlling the inflammatory process by different administration routes.

Alterations in the reproduction of mice induced by rapanone.[Pubmed:10940592]

J Ethnopharmacol. 2000 Aug;71(3):521-5.

Oral administration of Rapanone to a group of female mice at doses of 60 and 120 mg/kg, reduced the percentage of pregnancies compared to control group, suggesting an anovulatory effect. Postcoital administration induced uterine alteration in both the first and second gestation periods. These results seem to indicate inhibition of trophoblast implantation in the first period, and an abortive effect and/or reabsorption in the second. Daily administration of Rapanone to a group of male mice resulted in fertility alteration, which is attributed to an antispermatogenic effect. Rapanone did not show acute toxic effects at the doses tested in this research.

Biological activities of benzoquinones from Badula barthesia and Embelia angustifolia.[Pubmed:23195841]

Phytomedicine. 1998 May;5(3):199-203.

In our screening program for antihypertensive plant constituents extracts of the leaves and bark of Badula barthesia showed strong in vitro inhibition of angiotensin converting enzyme (ACE). Rapanone (1), 2,5-dihydroxy-3-tridecyl-1,4-benzoquinone, was isolated as an active constituent of the leaves. The IC(50) values of Rapanone and three 3-alkyl-2,5-dihydroxybenzoquinones, (2)-(4), (Z)-2,5-dihydroxy-3-(pentadec-8-enyl)-1,4-benzoquinone, (Z,Z)-2,5-dihydroxy-3-(heptadeca-8,11-dienyl)-1,4-benzoqui-none and (Z)-2,5-dihydroxy-3-(heptadec-8-enyl)-1,4-benzoquinone recently isolated from Embelia angustifolia were determined. The following IC(50) +/- S.D. values have been obtained (1) 36 +/- 4.6 muM, (2) 19 +/- 6.2 muM, (3) 19 +/- 8.7 muM and (4) 16 +/- 3.0 mu.M. The IC(50) value for the reference compound Captopril was determined to 12 +/- 2.6 nM. The antimicrobial activity of the four compounds was determined by thin layer chromatography agar overlay technique as minimum growth inhibitory amount in mug. One yeast, Candida albicans, and four bacteria, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were used as test organisms.