Raspberry Ketone Research Articles

Simple HPLC-Fluorescence Determination of Raspberry Ketone in Fragrance Mist after Pre-Column Derivatization with 4-Hydrazino-7-nitro-2,1,3-benzoxadiazole

Raspberry ketone {RK, 4-(4-hydroxyphenyl)butan-2-one} is a natural compound contained in raspberry, and is added to cosmetics for skin whitening. It is very important to measure the RK level in cosmetics for quality assessment, since RK structurally resembles 4-(4-hydroxyphenyl)-2-butanol, which causes leukoderma on consumers’ skin. Here, we present a simple HPLC-fluorescence method for determination of RK in a fragrance mist by pre-column derivatization with 4-hydrazino-7-nitro-2,1,3-benzoxadiazole hydrazine (NBD-H), which reacts with the carbonyl group of RK. The NBD-RK derivative was eluted from a reversed-phase ODS column, and detected with excitation at 470 nm and emission at 550 nm. The retention time of NBD-RK derivative obtained by reaction with NBD-H at 80°C for 20 min was 10.3 min. The standard curve was linear in the range of 0.2 to 10 μg/mL, with a correlation coefficient (r2) value of 0.9980. The lower limit of detection was 0.018 μg/mL (absolute amount of 1.8 pmol). The coefficients of variation were less than 8.1%. The content of RK in fragrance mist (1.00 mL) was 1.18 ± 0.07 mg (range: 1.12 to 1.28 mg, n = 5). Recovery tests were satisfactory (83.9% ± 3.9%; range: 79.6 to 88.8%, n = 5).

Decarboxylative Csp(3)-Csp(3) coupling for benzylation of unstable ketone enolates: synthesis of p-(acylethyl)phenols.

A new decarboxylative Csp(3)-Csp(3) coupling approach for the benzylation of ketone enolates has been developed. A variety of raspberry ketone derivatives were conveniently synthesized in good to excellent yields under mild conditions. A crossover reaction shed light on the mechanism of this tandem reaction.

Further research on the biological activities and the safety of raspberry ketone is needed

Raspberry ketone supplements have grabbed consumer attention with the possibility that they might help burn fat and aid weight loss. While raspberry ketone occurs naturally, and is found in raspberry fruit, most is synthetically produced for use in commercial products as flavorings, fragrances, or dietary supplements. Currently, the amount of raspberry ketone in dietary supplements (currently sold in the US) is well above the maximum concentration recommended for food and fragrance products, so additional toxicology work is needed to ensure that such concentrations of raspberry ketone are safe. In addition to safety data, clinical studies are also needed to validate any health benefits. Without research on the effects of consuming high concentrations of raspberry ketone, consumers should be wary of unsubstantiated claims and mindful of potential harm to their health.

Zeolitic behaviour of paratoluenesulfonic acid-modified clay in Friedel-Crafts synthesis of raspberry ketone

AbstractDuring solventless alkylation of phenol with 4-hydroxy-2-butanone under microwave irradiation, paratoluenesulfonic acid (pTSA)-modified montmorillonite clays gave, regioselectively, 4-(4′-hydroxyphenyl)-2-butanone (raspberry ketone). The duration for this reaction under microwave irradiation is much shorter than that of the conventional method. A comparative study of the alkylation reaction over a montmorillonite clay sample treated with 0.5 M-pTSA (0.5 M-pTSA clay) with that of Al-exchanged montmorillonite (Al3+-Mont) and beta-zeolite (HB) was carried out. The results show that the reaction time to reach equilibrium and the product distribution pattern for the reaction over 0.5 M-pTSA clay were similar to those values for the HB. Micropores formed on the clay surface during the pTSA treatment were found to enhance the rate of formation of C-alkylation. Micropores appear to enable better access to the active sites during the course of reaction.

Biobased Fat Mimicking Molecular Structuring Agents for Medium-Chain Triglycerides (MCTs) and Other Edible Oils.

To develop sustainable value-added materials from biomass, novel small-molecule sugar ester gelators were synthesized using biocatalysis. The facile one-step regiospecific coupling of the pro-antioxidant raspberry ketone glucoside and unsaturated or saturated long- and medium-chain fatty acids provides a simple approach to tailor the structure and self-assembly of the amphiphilic product. These low molecular weight molecules demonstrated the ability to self-assemble in a variety of solvents and exhibited supergelation, with a minimum gelation concentration of 0.25 wt %, in numerous organic solvents, as well as in a range of natural edible oils, specifically a relatively unstudied group of liquids: natural medium-chain triglyceride oils, notably coconut oil. Spectroscopic analysis details the gelator structure as well as the intermolecular noncovalent interactions, which allow for gelation. X-ray diffraction studies indicate fatty acid chain packing of gelators is similar to that of natural fats, signifying the crystalline nature may lead to desirable textural properties and mouthfeel.

Bioconversion to Raspberry Ketone is Achieved by Several Non-related Plant Cell Cultures.

Bioconversion, i.e., the use of biological systems to perform chemical changes in synthetic or natural compounds in mild conditions, is an attractive tool for the production of novel active or high-value compounds. Plant cells exhibit a vast biochemical potential, being able to transform a range of substances, including pharmaceutical ingredients and industrial by-products, via enzymatic processes. The use of plant cell cultures offers possibilities for contained and optimized production processes which can be applied in industrial scale. Raspberry ketone [4-(4-hydroxyphenyl)butan-2-one] is among the most interesting natural flavor compounds, due to its high demand and significant market value. The biosynthesis of this industrially relevant flavor compound is relatively well characterized, involving the condensation of 4-coumaryl-CoA and malonyl-CoA by Type III polyketide synthase to form a diketide, and the subsequent reduction catalyzed by an NADPH-dependent reductase. Raspberry ketone has been successfully produced by bioconversion using different hosts and precursors to establish more efficient and economical processes. In this work, we studied the effect of overexpressed RiZS1 in tobacco on precursor bioconversion to raspberry ketone. In addition, various wild type plant cell cultures were studied for their capacity to carry out the bioconversion to raspberry ketone using either 4-hydroxybenzalacetone or betuligenol as a substrate. Apparently plant cells possess rather widely distributed reductase activity capable of performing the bioconversion to raspberry ketone using cheap and readily available precursors.

Different effects of five depigmentary compounds, rhododendrol, raspberry ketone, monobenzone, rucinol and AP736 on melanogenesis and viability of human epidermal melanocytes.

Numerous medications are used to treat hyperpigmentation. However, several reports have indicated that repeated application of some agents, such as rhododendrol (RD), raspberry ketone (RK) and monobenzone (MB), can be toxic to melanocytes. Although these agents had severe side effects in human trials, no current in vitro methods can predict the safety of such drugs. This study assessed the in vitro effects of five depigmentary compounds including leukoderma-inducing agents. In particular, we determined the effects of different concentrations and exposure times of different depigmentary agents on cell viability and melanogenesis in the presence and absence of ultraviolet B (UVB) radiation. Concentrations of RD, RK and MB that inhibit melanogenesis are similar to concentrations that are cytotoxic; however, concentrations of rucinol (RC) and AP736 that inhibit melanogenesis are much lower than concentrations that are cytotoxic. Furthermore, the concentrations that cause toxic effects depend on exposure duration, and prolonged exposure to RD, RK and MB had more cytotoxic effects than prolonged exposure to RC and AP736. The cytotoxic effects of RD and RK appear to be mediated by apoptosis due to increased expression of caspase-3 and caspase-8; UVB radiation increased the cytotoxicity of these agents and also increased caspase activity. Our results indicate that different leukoderma-inducing compounds have different effects on the viability of normal epidermal melanocytes and suggest that the in vitro assay used here can be used to predict whether an investigational compound that induces leukoderma may lead to adverse effects in human trials.

A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols

BackgroundTyrosinase is able to oxidize a great number of phenols and catechols to form ortho-quinones. Ortho-quinones are highly reactive compounds that exert cytotoxicity through binding with thiol enzymes and the production of reactive oxygen species. Certain phenolic (and catecholic) compounds are known to induce contact/occupational leukoderma through activation to ortho-quinones. ObjectiveWe report a convenient screening method to follow the oxidation of those leukoderma-inducing phenols by mushroom tyrosinase. MethodsOxidation of phenolic compounds by mushroom tyrosinase was followed periodically by UV–vis spectrophotometry. The production of ortho-quinones were confirmed by their absorptions around 400–420nm. HPLC analysis after reduction with NaBH4 detected the corresponding catechols. ResultsLeukoderma-inducing phenols, rhododendrol, raspberry ketone, 4-methoxyphenol, 4-benzyloxyphenol, 4-tert-butylphenol, and 4-tert-butylcatechol, were readily oxidized by mushroom tyrosinase to form ortho-quinones. On the other hand, phenolic skin whitening tyrosinase inhibitors, ellagic acid, 4-n-butylresorcinol, potassium 4-methoxysalicylate, and 2,2′-dihydroxy-5,5′-di-n-propylbiphenyl, were not oxidized by mushroom tyrosinase, while arbutin was only slowly oxidized. ConclusionThis study has provided a convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols. A common chemical feature of the latter group of compounds is that they are readily oxidized by tyrosinase to form reactive ortho-quinone species. The present results point out the necessity that tyrosinase inhibitors should also be examined as substrates if they are phenolic compounds.

Mechanistic Approaches of PHE and PPF Columns for Separation of Rasberry Ketone and Caffeine

High-Performance Liquid Chromatography (HPLC) separation mechanisms of raspberry ketone and caffeine on phenyl columns (PhE and PPF) are described. The π–π interactions played major role in separation phenomenon. PhE column resulted into better separation than PPF due poor π–π interactions in later column. Fast, reproducible, selective, and effective HPLC method was developed for analyses of ketone and caffeine in pharmaceutical preparation. The columns used were Sunniest PhE (phenyl) (250 × 4.6 mm, 5.0 µm) and Sunshell PFP (100 × 4.6 mm, 2.6 µm) of Chromanik Japan. The mobile phase used was water–acetonitrile (60:40, v/v, at different pH values) at 1.0 mL/min flow rate. The detection was at 280 nm with 27 ± 1°C as working temperature. The ranges of capacity (k), separation (α), and resolution (Rs) factors at different pH values on both columns were 2.60–5.10, 1.32–1.60, and 3.22–4.28, respectively. The values of limit of detection (LOD) and limit of quantitation (LOQ) of raspberry ketone and caffeine on both columns ranged from 5.0 to 20.0 and 7.0 to 25.0, respectively. The developed mechanistic aspect is useful for designing separation strategies of other molecules on these phenyl columns. The reported method may be used for quality control in industries and government organizations. Besides, fast analyses may be carried out in various food products.

Raspberry ketone in food supplements – High intake, few toxicity data – A cause for safety concern?

Raspberry ketone (4-(4-hydroxyphenyl)-2-butanone) is marketed on the Internet as a food supplement. The recommended intake is between 100 and 1400 mg per day. The substance is naturally occurring in raspberries (up to 4.3 mg/kg) and is used as a flavouring substance. Toxicological studies on raspberry ketone are limited to acute and subchronic studies in rats. When the lowest recommended daily dose of raspberry ketone (100 mg) as a food supplement is consumed, it is 56 times the established threshold of toxicological concern (TTC) of 1800 μg/day for Class 1 substances. The margin of safety (MOS) based on a NOAEL of 280 mg/kg bw/day for lower weight gain in rats is 165 at 100 mg and 12 at 1400 mg. The recommended doses are a concern taking into account the TTC and MOS. Investigations of raspberry ketone in quantitative structure-activity relationship (QSAR) models indicated potential cardiotoxic effects and potential effects on reproduction/development. Taking into account the high intake via supplements, the compound's toxic potential should be clarified with further experimental studies. In UK the pure compound is regarded as novel food requiring authorisation prior to marketing but raspberry ketone is not withdrawn from Internet sites from this country.

Weathering and Chemical Degradation of Methyl Eugenol and Raspberry Ketone Solid Dispensers for Detection, Monitoring, and Male Annihilation of Bactrocera dorsalis and Bactrocera cucurbitae (Diptera: Tephritidae) in Hawaii.

Solid male lure dispensers containing methyl eugenol (ME) and raspberry ketone (RK), or mixtures of the lures (ME + RK), and dimethyl dichloro-vinyl phosphate (DDVP) were evaluated in area-wide pest management bucket or Jackson traps in commercial papaya (Carica papaya L.) orchards where both oriental fruit fly, Bactrocera dorsalis (Hendel), and melon fly, Bactrocera cucurbitae (Coquillett), are pests. Captures of B. dorsalis with fresh wafers in Jackson and bucket traps were significantly higher on the basis of ME concentration (Mallet ME [56%] > Mallet MR [31.2%] > Mallet MC [23.1%]). Captures of B. cucurbitae with fresh wafers in Jackson and bucket traps were not different regardless of concentration of RK (Mallet BR [20.1%] = Mallet MR [18.3%] = Mallet MC [15.9%]). Captures of B. dorsalis with fresh wafers, compared with weathered wafers, were significantly different after week 12; captures of B. cucurbitae were not significantly different after 16 wk. Chemical analyses revealed presence of RK in dispensers in constant amounts throughout the 16-wk trial. Degradation of both ME and DDVP over time was predicted with a high level of confidence by nonlinear asymptotic exponential decay curves. Results provide supportive data to deploy solid ME and RK wafers (with DDVP) in fruit fly traps for detection programs, as is the current practice with solid TML dispensers placed in Jackson traps. Wafers with ME and RK might be used in place of two separate traps for detection of both ME and RK responding fruit flies and could potentially reduce cost of materials and labor by 50%.

Preparation of a raspberry ketone precursor in the presence of rare earth oxide catalysts

The raspberry precursor 4-(4-hydroxyphenyl)-but-3-ene-2-one which afterwards undergoes a catalytic hydrogenation to produce raspberry ketone was synthesized by aldol condensation of acetone and 4-hydroxybenzaldehyde over rare earth oxides as basic catalysts and supported rare earth oxides as acid–base bifunctional catalysts. Thereby, several rare earth metal oxides were tested in their neat form as well as supported on carriers with high surface areas such as alumina, titania, tetragonal zirconia and charcoal. The catalysts were characterized by XRD, BET, NH3/CO2-TPD and pyridine-FTIR. All experiments were carried out batch wise in 75ml autoclaves adjusting molar ratios of acetone and 4-hydroxybenz-aldehyde from 12:1 to 4:1, temperature range from 80 to 200°C and autogeneous pressures from 1 to 25bar. It could also be realized, that titania and alumina are no inert materials, but also highly active catalysts for this reaction. An experimental design program was used to optimize the reaction conditions as well as the conversion and selectivity. In addition the reaction was carried out in a fixed bed plug flow reactor to determine stability and robustness of the catalyst. The quality/contaminations of the starting material have a strong influence on the catalytic performance.

Responses of fruit flies (Tephritidae:Dacinae) to novel male attractants in northQueensland,Australia, and improved lures for some pest species

AbstractMale fruit fly attractants, cue‐lure and methyl eugenol (ME), have been successfully used for the last 50 years in the monitoring and control ofDacini fruit flies (BactroceraandDacusspecies). However, over 50% ofDacini are non‐responsive to either lure, including some pest species. A new lure, zingerone, has been found to weakly attract cue‐ andME‐responsive species inMalaysia. InAustralia it attracted a weakly cue‐responsive minor pestBactrocera jarvisi(Tryon) and three ‘non‐responsive’ species. Similar compounds were tested inQueensland and attracted cue‐ andME‐responsive species and two ‘non‐responsive’ species. In this study, 14 novel compounds, including raspberry ketone formate (RKF) (Melolure) and zingerone, were field tested in comparison with cue‐lure andMEat 17 sites in northQueensland. The most attractive novel lures were isoeugenol, methyl‐isoeugenol, dihydroeugenol and zingerone. Several ‘non‐responsive’ species responded to the new lures:Bactrocera halfordiae(Tryon), a species of some market access concern, was most attracted to isoeugenol;B. barringtoniae(Tryon),B. bidentata(May) andB. murrayi(Perkins) responded to isoeugenol, methyl‐isoeugenol and dihydroeugenol; two new species ofDacusresponded to zingerone.Bactrocera kraussi(Hardy), a cue‐responsive minor pest in northQueensland, was significantly more attracted to isoeugenol than cue‐lure. The cue‐responsiveD. absonifacies(May) andD. secamoneae Drew were significantly more attracted to zingerone than cue‐lure.Bactrocera yorkensis Drew &Hancock, aME‐responsive species was significantly more attracted to isoeugenol, methyl‐isoeugenol and dihydroeugenol thanME. The preferential response toRKFor cue‐lure was species specific. Six species were significantly more attracted toRKF, including the pestsB. tryoni(Froggatt),B. frauenfeldi(Schiner) and minor pestB. bryoniae(Tryon); eight species were significantly more attracted to cue‐lure including the pestB. neohumeralis(Hardy). These findings have significance in the search for optimal male lures for pest species elsewhere in the world.

The mechanism of melanocytes-specific cytotoxicity induced by phenol compounds having a prooxidant effect, relating to the appearance of leukoderma.

Specific phenol compounds including rhododendrol (RD), a skin-brightening ingredient in cosmetics, are reported to induce leukoderma, inducing a social problem, and the elucidation of mechanism of leukoderma is strongly demanded. This study investigated the relationship among the cytotoxicities of six phenol compounds on B16F10 melanoma cells and HaCaT keratinocytes and generated reactive oxygen species (ROS). As a result, the cytotoxicity of RD on B16F10 cells was higher than that on HaCaT cells, and RD significantly increased intracellular ROS and hydrogen peroxide (H2O2) levels in B16F10 cells. Furthermore, although raspberry ketone (RK), RD derivative, also increased intracellular ROS in B16F10 cells, increase in ROS was suppressed by disodium dihydrogen ethylenediaminetetraacetate dehydrate (EDTA). The amounts of increased ROS with RK in HaCaT cells without melanocyte were further increased by tyrosinase. Therefore, tyrosinase, a metalloprotein having copper, was speculated to be one of causative agents allowing phenol compounds to work as a prooxidant. Hydroxyl radical was generated by adding a mixture of tyrosinase and H2O2 to RD, and the amount of the radical was further increased by UVB, indicating that RD cytotoxicity was caused by intracellularly increased ROS, which possibly related to phenol induced prooxidants.

Crystal structure of (E)-2-[4-(4-hy-droxy-phen-yl)butan-2-yl-idene]hydrazine-1-carbo-thio-amide.

The title compound, C11H15N3OS, is a thio­semicarbazone derivative of the raspberry ketone rheosmin [systematic name: 4-(4-hy­droxy­phen­yl)butane-2-one]. The mol­ecule deviates from planarity, with the bridging C—C—C=N torsion angle equal to −101.3 (2)°. The maximum deviation from the mean plane of the non-H atoms of the thio­semicarbazone fragment [C=N—N—C(= S)—N] is 0.085 (5) Å for the Schiff base N atom, and the dihedral angle between this mean plane and the aromatic ring is 50.31 (8)°. In the crystal, mol­ecules are linked by N—H⋯O, N—H⋯S and O—H⋯S hydrogen bonds, forming a three-dimensional structure, with the mol­ecules stacked along [011].

Mushroom flavour

Mushrooms and fungi not only present a fascinating world of shapes, both macro- and microscopic, but they are also an interesting source of flavours, fragrances and odours, e.g. garlic, coconut, flour-like, cucumber or fruit-like, as well as the most characteristic for this kingdom of living organisms mushroom-like flavour and aroma. Fungi can possess many different and interesting flavours and fragrances – starting from nice anise-like, fruit-like, cucumber, garlic, to cheese-garlic, and ending with potato or flour-like smells. Some mushrooms emit carbide or distinctly faecal-like odour. The taste of mushrooms is frequently correlated with their aroma. What components does the core of a mushroom flavour consist of? Chemical analysis of specimens reveals compounds responsible for characteristic flavour and odour. It was found that the most characteristic flavour compound is defined mainly by C8 volatiles. Between all C8 compounds the most important for mushroom flavour are oct-1-en-3-ol, octan-3-ol, octan-3-on and oct-1-en-3-on. Fungi and mushrooms can enable biotechnological production of some flavour components, for instance the Nidula niveotomentosa produces a characteristic raspberries compound – raspberry ketone in submerged cultures; the biotechnological production can also provide rare and tasty forest mushroom biomass e.g. edible boletus.

Raspberry ketone, a naturally occurring phenolic compound, inhibits adipogenic and lipogenic gene expression in 3T3-L1 adipocytes

Context: Raspberry ketone (RK) is a natural phenolic compound of red raspberry. The dietary intake of RK has been reported to exert anti-obese actions and alter the lipid metabolism in vivo and human studies.Objective: To elucidate a possible mechanism for anti-obese actions of RK, the effects of RK on the adipogenic and lipogenic gene expression in 3T3-L1 adipocytes were investigated.Materials and methods: 3T3-L1 maturing pre-adipocytes were treated from day 2 to day 8 of differentiation and mature adipocytes for 24 h on day 12 with 1, 10, 20, and 50 μM of RK. Triacylglycerols were assessed by spectrophotometry and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR).Results: Treatment of adipocytes with RK suppressed adipocyte differentiation and fat accumulation in a concentration-dependent manner. RK suppressed the expression of major genes involved in the adipogenesis pathway including peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT enhancer binding protein-α (C/EBPα), which led to further down-regulation of adipocyte fatty acid-binding protein-2 (aP2). In addition, treatment with 10 μM of RK also reduced mRNA levels of lipogenic genes such as acetyl-CoA carboxylase-1 (ACC1), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1). In mature adipocytes, RK increased the transcriptional activities of genes involved in lipolysis and the oxidative pathways including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), and carnitine palmitoyl transferase-1B (CPT1B).Discussion and conclusion: These findings suggest that RK holds great promise for an herbal medicine with the biological activities altering the lipid metabolism in 3T3-L1 adipocytes.

Synthesis of fragrant 1,3-diazaadamantan-6-ones

5-Benzyl-1,3-diazaadamantan-6-one and its derivatives at the benzene ring were synthesized by the condensation of hexamethylenetetramine with 4-phenylbutan-2-one (jasmarol) and its derivatives, viz., 4-(4-hydroxyphenyl)butan-2-one (raspberry ketone), 4-(4-methoxyphenyl)butan-2-one (anisylacetone), and 4-(4-hydroxy-3-methoxyphenyl)butan-2-one (vanillylacetone, zingerone).

Sexual selection in true fruit flies (Diptera: Tephritidae): transcriptome and experimental evidences for phytochemicals increasing male competitive ability.

In male tephritid fruit flies of the genus Bactrocera, feeding on secondary plant compounds (sensu lato male lures=methyl eugenol, raspberry ketone and zingerone) increases male mating success. Ingested male lures alter the male pheromonal blend, normally making it more attractive to females and this is considered the primary mechanism for the enhanced mating success. However, the male lures raspberry ketone and zingerone are known, across a diverse range of other organisms, to be involved in increasing energy metabolism. If this also occurs in Bactrocera, then this may represent an additional benefit to males as courtship is metabolically expensive and lure feeding may increase a fly's short-term energy. We tested this hypothesis by performing comparative RNA-seq analysis between zingerone-fed and unfed males of Bactrocera tryoni. We also carried out behavioural assays with zingerone- and cuelure-fed males to test whether they became more active. RNA-seq analysis revealed, in zingerone-fed flies, up-regulation of 3183 genes with homologues transcripts to those known to regulate intermale aggression, pheromone synthesis, mating and accessory gland proteins, along with significant enrichment of several energy metabolic pathways and gene ontology terms. Behavioural assays show significant increases in locomotor activity, weight reduction and successful mating after mounting; all direct/indirect measures of increased activity. These results suggest that feeding on lures leads to complex physiological changes, which result in more competitive males. These results do not negate the pheromone effect, but do strongly suggest that the phytochemical-induced sexual selection is governed by both female preference and male competitive mechanisms.

Potential adverse effects of raspberry ketone sold as food supplement

Potential adverse effects of raspberry ketone sold as food supplement