WO2010003238A1 - Alcamides induisant des protéines de phase 2 - Google Patents

Alcamides induisant des protéines de phase 2 Download PDF

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Publication number
WO2010003238A1
WO2010003238A1 PCT/CA2009/000945 CA2009000945W WO2010003238A1 WO 2010003238 A1 WO2010003238 A1 WO 2010003238A1 CA 2009000945 W CA2009000945 W CA 2009000945W WO 2010003238 A1 WO2010003238 A1 WO 2010003238A1
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phase
alkamide
use according
protein
alkamides
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PCT/CA2009/000945
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English (en)
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Jonathan E. Page
Yuping Lu
David J. F. Konkin
James B. Johnston
Alena Corcoran
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National Research Council Of Canada
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton

Definitions

  • the present invention is related to compounds with biochemical activity, in particular to alkamide compounds that are inducers of phase 2 proteins.
  • phytochemicals plant natural products
  • Many phytochemicals with health-promoting activities often termed nutraceuticals, exert their effects through the induction of an "indirect antioxidant” response mediated through phase 2 proteins (Talalay 2000; Wu et al. 2004).
  • phase 2 proteins act to metabolize oxidative radicals, thereby attenuating inflammation, and to detoxify carcinogens.
  • Phase 2 protein inducers may prove useful in preventing chronic diseases such as cancer, neurodegeneration and cardiovascular disease. Examples of phytochemicals with phase 2 protein inducing activity that have been isolated from food or spice plants are shown in Table 1.
  • Nrf2 transcription factor 2
  • AREs antioxidant response elements
  • Echinacea is a genus of nine species of herbaceous plants in the family Asteraceae. All species are native to eastern and central North America. The plants have large, showy heads of composite flowers, blooming from early to late summer.
  • Echinacea America and has been used as a traditional medicine by First Nations people. Members of the genus Echinacea including E. angustifolia are widely used as immune stimulants and to prevent viral infections such as the common cold, although the effectiveness of such treatments is controversial (Linde et al. 2006).
  • the major class of lipophilic phytochemicals in Echinacea roots are the fatty acid amides or alkamides (also termed alkylamides or fatty acid N-alkylamides), which appear to be the constituents responsible for the immunemodulatory activity of Echinacea extracts (Woelkart and Bauer, 2007).
  • Other compounds known from the genus Echinacea include the phenolic constituents cichoric acid, echinacoside, caftaric acid and cynarin (Binns et al. 2002).
  • phase 2 proteins may provide drugs that can be used to prevent chronic diseases. Furthermore, knowledge about plant-derived phase 2 protein inducers may be useful in informing consumers about foods and dietary supplements useful for chemoprevention. There remains a need for new phase 2 protein inducers for the development of treatments for conditions that may be ameliorated by induction of phase 2 proteins.
  • phase 2 protein inducing effective amount of an alkamide or a pharmacologically acceptable salt thereof for inducing phase 2 proteins in an animal in need of phase 2 protein induction.
  • phase 2 protein induction comprising administering a phase 2 protein inducing effective amount of an alkamide or a pharmacologically acceptable salt thereof to the animal in need of phase 2 protein induction.
  • Preferred alkamides useful as phase 2 protein inducers have one or more carbonyl groups or hydroxy! groups on a side chain attached to the amide moiety. More preferably, where a carbonyl group is present on a side chain, the side chain is unsaturated and the carbonyl group is adjacent a carbon-carbon double bond.
  • alkamides have general formula (I):
  • R1 is H 3 C-O-C or a C 8 -Cg unsaturated carbon chain unsubstituted or substituted by one or more carbonyl or hydroxyl groups.
  • Compounds of the general formula (I) preferably have one or more carbonyl or hydroxyl groups on the carbon chain. Where a carbonyl group is on the carbon chain, the carbonyl group is preferably adjacent a double bond in the carbon chain.
  • Alkamides 1 , 3 and 4 are novel compounds.
  • Alkamides may be obtained from natural sources, for example, plants or plant parts.
  • alkamides are a family of more than 300 secondary metabolites found in distinct plant species and relatively well-characterized in the plant families: Aristolochiaceae, Asteraceae, Brassicaceae, Convolvulaceae, Euphorbiaceae, Menispermaceae, Piperaceae, Poaceae, Rutaceae, and Solanaceae.
  • alkamides Several plant genera containing high levels (>0.5%) of alkamides are found in the Asteraceae (e.g., Echinacea spp., Chrysanthemum spp., Anacyclus pyrethrum L, and Spilanthes oleracea L), Piperaceae ⁇ Piper spp.), and Rutaceae (Zanthoxylum spp.).
  • Asteraceae e.g., Echinacea spp., Chrysanthemum spp., Anacyclus pyrethrum L, and Spilanthes oleracea L
  • Piperaceae ⁇ Piper spp. Piperaceae ⁇ Piper spp.
  • Rutaceae Zanthoxylum spp.
  • plants from the genus Echinacea are an important source of alkamides (Binns et al. (2002)).
  • Species of Echinacea include Echinacea angustifolia
  • Echinacea laevigata Smooth Coneflower, Smooth Purple Coneflower
  • Echinacea pallida Echinacea pallida
  • Echinacea angustifolia is a preferred source of alkamides.
  • Alkamides from natural sources may be obtained through a variety of techniques. For example, whole plants or plant parts may be used as gathered, plants or plant parts may be dried and optionally ground into a powder, alkamides may be extracted from plants or plant parts with one or more solvents (e.g. organic solvents such as methanol, chloroform, etc.) and isolated from the solvent by further liquid/liquid partitioning and/or crystallization from and/or evaporation of the solvent. If required, chromatography may be used to help isolate the compounds from the natural source. Such techniques are generally well known in the art.
  • solvents e.g. organic solvents such as methanol, chloroform, etc.
  • chromatography may be used to help isolate the compounds from the natural source. Such techniques are generally well known in the art.
  • Alkamides may be used to induce phase 2 proteins in animals, for example mammals, (e.g. humans, rats, rabbits, monkeys, horses, cows, dogs, cats). Alkamides may be used in pure form (e.g. purified compound), in semi-pure form (e.g. an extract of natural source) or in raw form (e.g. ground plant material). To use alkamides, they may be administered to the animal by any suitable means, for example, as described below. Preferably, the animal is one which has been identified as needing phase 2 protein induction.
  • mammals e.g. humans, rats, rabbits, monkeys, horses, cows, dogs, cats.
  • Alkamides may be used in pure form (e.g. purified compound), in semi-pure form (e.g. an extract of natural source) or in raw form (e.g. ground plant material).
  • the animal is one which has been identified as needing phase 2 protein induction.
  • alkamides may be used as nutraceuticals or dietary supplements by administering them directly in pure form or as part of a pharmacologically acceptable composition.
  • the composition may comprise raw natural material (e.g. raw plant material), an extract (e.g. a plant extract) and/or may be formulated with other pharmacologically acceptable ingredients, for example, carriers, excipients, diluents or other active principles. Carriers, excipients or diluents as well as the methods of formulating the compositions are well known to those skilled in the art.
  • Cellulose, maltodextrin and water are preferred carriers, excipients or diluents.
  • compositions thereof are generally formulated in a dosage form.
  • Dosage forms include powders, tablets, capsules, solutions, suspensions, emulsions and other forms that are readily appreciated by one skilled in the art. Administration may be orally, parenterally, intravenously or by any other convenient method. Powders, capsules and tablets for oral administration are preferred.
  • Alkamides or compositions thereof may also be admixed with a food or beverage and taken orally in such a manner.
  • Foods or beverages may help mask undesirable flavours and are more palatable for consumption by humans or other animals.
  • Fortified foods and beverages may be made by adding alkamides or compositions thereof during the manufacturing of the food or beverage. Alternatively, the consumer may add the alkamides or composition thereof to the food or beverage near the time of consumption. Each ingredient of the composition may be added to the food or beverage together with the other ingredients or separately from the other ingredients. Examples of foods and beverages are cereals, snack bars, dairy products, fruit juices, powdered food and dry powder beverage mixes.
  • Effective daily dosages of alkamides may be readily determined by one skilled in the art. Generally, daily doses may be 5 mg/kg or greater based on body weight of the subject. Daily doses of 10 mg/kg or greater may be more efficacious. A daily dose of from 20 mg/kg to 500 mg/kg is of general therapeutic usefulness. Daily dosage may be given all at once in a single dose or can be given incrementally in several smaller dosages. Thus, the dosage forms of the present invention can be formulated such that the recommended daily dose is achieved by the administration of a single dose or by the administration of several smaller doses.
  • alkamides or compositions thereof may be included in commercial packages together with instructions for use in inducing phase 2 proteins.
  • packages may be in the form of sachets, bottles or blisterpacks but are not limited to such.
  • Instructions are normally in the form of a written material but are not limited to such.
  • alkamides are useful in treating or preventing a number of therapeutic indications related to oxidative stress, for example, cancer chemoprevention, neuroprotection (e.g. anti-ischemia), anti-inflammation (anti- hypertension and anti-atherosclerosis), cardiovascular protection and treatment, and treatment of dermatological damage and inflammation (e.g. sunburn).
  • cancer chemoprevention e.g. anti-ischemia
  • anti-inflammation anti- hypertension and anti-atherosclerosis
  • cardiovascular protection and treatment e.g. sunburn
  • Fig. 1 depicts structures of alkamides from Echinacea angustifolia roots that induce phase 2 gene expression as measured using the ARE-luciferase cell-based bioassay.
  • a diastereomer of Alkamide 5 also induces phase 2 gene expression.
  • Fig. 2 depicts a graph showing ARE-luciferase induction in U373 human astrocytoma cells by alkamides.
  • the isothiocyanate sulforaphane was used as a positive control for ARE regulated gene expression. All values are expressed relative to equivalent concentrations of DMSO vehicle such that no change in viability would be indicated by a fold change value of 1.
  • Fig. 3 depicts a graph showing toxicity of alkamides in U373 human astrocytoma cells. The toxicity of the isothiocyanate sulforaphane is shown for comparison. All values are expressed relative to equivalent concentrations of DMSO vehicle such that no change in viability would be indicated by a fold change value of 1.
  • Fig. 4 depicts a graph showing induction of NQO1 activity in mouse hepatoma cells (Hepa 1 c1c7) by alkamide 4.
  • the isothiocyanate sulforaphane was used as a positive control for phase 2 protein induction. All values are expressed relative to equivalent concentrations of DMSO vehicle such that no change in viability would be indicated by a fold change value of 1.
  • Fig. 5 depicts a graph showing XRE-luciferase induction in U373-XRE human astrocytoma cells by alkamides. All values are expressed relative to equivalent concentrations of DMSO vehicle such that no change in viability would be indicated by a fold change value of 1.
  • Extracts were tested for their ability to induce the phase 2 protein quinone reductase in mouse hepatoma (Hepa1c1c7) cells and their ability to induce the expression of an ARE promoter linked to a luciferase promoter.
  • alkamides were isolated using a combination of solvent-solvent partitioning and chromatographic separations. All compounds were identified using mass spectrometry and NMR. Of the 12 alkamides tested, seven showed activity in the ARE- luciferase bioassay and were found to exhibit limited toxicity in this cell line. One of these, alkamide 4, was tested in the murine NQO1 assay and found to induce the expression of this phase 2 protein.
  • Example 1 Extraction and Purification of Alkamides from Echinacea angustifolia DC
  • the ARE assay described below was used to guide the fractionation of E. angustifolia root extract. Extraction of the roots with methanol gave a methanol extract with moderate activity in the ARE bioassay. Separation into hexane, chloroform and water soluble metabolites showed the ARE activity to be associated with the lipophilic fractions, with the majority of the activity being chloroform soluble. Liquid-liquid partitioning localized the activity in the fraction of medium polarity which contained alkamides. The subsequent chromatographic separation led to the isolation of 12 alkamides.
  • the dried chloroform soluble (12 g) was applied to a silica gel open column (100-200 mesh, 4.2 * 30 cm), eluted with gradient hexane with EtOAc, followed by EtOAc with MeOH to yield 4 fractions: 30-40% EtOAc/Hexane (Fr. 3), 60% EtOAc/Hexane (Fr. 4), 100% EtOAc (Fr. 5), and 10% MeOH/EtOAc (Fr. 6). These fractions were subsequently separated by a combination of silica gel chromatography, reversed phase C-18 SPE cartridges and reversed-phase semi-preparative HPLC to yield pure alkamides in milligram amounts.
  • Alkamide 1 corresponds to formula (A) where R' is CH 3 , R" is CH 3 and there is a keto group at the 4-position.
  • Alkamide 2 corresponds to formula (A) where R' is H, R" is CH 3 and there is a double bond at the 4-position to provide an E configuration.
  • Alkamide 3 corresponds to formula (A) where R' is H, R" is CH 3 , there is a double bond at the 2- position to provide a Z configuration and there is a hydroxyl group at the 5-position.
  • Alkamide 4 corresponds to formula (B) with a keto group in the 6-position.
  • Alkamide 5 corresponds to formula (B) with a double bond at the 8-position to provide a Z configuration and hydroxyl groups at the 10- and 1 1 -positions.
  • Alkamide 6 is as shown above.
  • Alkamide 7 is a diastereomer of Alkamide 5.
  • Alkamide 8 corresponds to formula (A) where R' is CH 3 , R" is C 2 H 5 .
  • Alkamide 9 corresponds to formula (A) where R' is CH 3 , R" is CH 3 .
  • Alkamide 10 corresponds to formula (A) where R' is H, R" is CH 3 .
  • Alkamide 1 1 corresponds to formula (B) as shown.
  • Alkamide 12 corresponds to formula (B) with a double bond at the 8-position to provide a Z configuration.
  • Alkamides 1 , 3 and 4 have been identified as novel natural compounds and some physical properties are provided below.
  • Alkamide 1 Dodeca-4-keto-2E-ene-8,10-diynoic acid isobutylamide. A colorless powder; UV (LC-PDA 1 acetonitrile/H 2 O) ⁇ max (nm) 227.4; HR TOF-MS m/z [M+H] + 260.1644 (calcd. for Ci 6 H 22 NO 2 260.1651 ); ESI-MS m/z (rel.
  • Alkamide 4 Dodeca-6-keto-2E,4E-dienoic acid isobutylamide. A colorless crystal (5.9 mg); UV (LC-PDA, ACN/H 2 O) ⁇ max (nm) 276.9; HR TOF-MS m/z [M+H] + 266.2121 (calcd. for C 16 H 28 NO 2 266.2120); ESI-MS m/z (rel. int., %): [M+1] + 266 (100), 193 (28), 165 (15), 154 (9), 123 (8), 1 13 (37), 95 (5), 85 (13), 74 (8), 57 (7); for 1 H, 13 C NMR, and HMBC see Tables 1 and 2.
  • phase 2 protein inducing activity of phytochemical extracts, fractions and pure compounds was evaluated using the ARE-induction assay.
  • This assay is predicated on the hypothesis that activation of ARE-mediated gene expression correlates with the induction of protective phase 2 proteins.
  • a monoclonal human astrocytoma cell line, termed U373-ARE that stably expresses a firefly luciferase cassette under the transcriptional control of the antioxidant response element was generated.
  • triplicate wells of reporter and control cell lines (1X10 5 cells, 24-well culture plates) were incubated with the indicated concentrations of the test sample for 24 h at 37 0 C.
  • Alkamides 1-7 are considered active while Alkamides 8-12 are not
  • the results for Alkamides 1-6 are shown in Fig 2 alongside the results for sulforaphane, a known phase 2 protein inducer, for comparison
  • active Alkamide 2 does not have additional carbonyl or hydroxyl groups
  • active Alkamides 1-3 and 5-7 do
  • inactive Alkamides 8-12 do not, therefore, it is thought that the presence of additional carbonyl and/or hydroxyl groups on the side chain contribute to phase 2 protein induction, especially when the carbonyl is adjacent a carbon-carbon double bond in the side chain
  • Alkamide 1 showed toxicity at concentrations higher than 10 ⁇ g/mol and Alkamide 4 showed toxicity at concentrations higher than 50 ⁇ g/mol Alkamides 2, 3, 5 and 6 were relatively non-toxic at concentration up to 250 ⁇ g/mol
  • sulforaphane shows toxicity at concentrations approaching 100 ⁇ g/mol
  • Hepa-1c1c7 cells were plated in 96 well plates at approximately 5000 cells per well in 200 ⁇ l_ of the normal cell culture medium After 24 h the medium was replaced with medium supplemented with 100 U/ml penicillin G, 100 ⁇ g/ml streptomycin, and 10% charcoal treated FBS. Dilutions of test compounds or extracts dissolved in DMSO were prepared in this medium and added to a final DMSO concentration of 0.1 % (v/v). Each concentration was tested in triplicate and two independent experiments were conducted. After 48 h, medium was decanted and cell viability determined using CalceinTM AM reagent (Invitrogen, Carlsbad, CA).
  • Alkamide 4 The results for Alkamide 4 are shown in Fig. 4 alongside sulforaphane for comparison. Alkamide 4 was found to be an inducer of NQO1 activity at concentrations above 10 ⁇ M.
  • the ARE is a transcriptional element that regulates the expression of phase 2 proteins involved in the defense against oxidative stressors and toxins. Compounds which activate the ARE have strong potential for use as antioxidants by increasing the endogenous level of beneficial proteins within cells and tissues. However, many compounds that activate the ARE also activate the closely related xenobiotic response element (XRE), a detrimental response due to the potential for XRE activation to be associated with the pro-oncogenic activation of CYP1 family members. Thus, it is preferable to separate beneficial monofunctional ARE inducers from less desirable bifunctional inducers.
  • XRE closely related xenobiotic response element
  • a monoclonal human astrocytoma cell line termed U373-XRE that stably expresses a firefly luciferase cassette under the transcriptional control of the XRE was generated as a counter-screen to the ARE induction assay.
  • U373-XRE a monoclonal human astrocytoma cell line
  • stably expresses a firefly luciferase cassette under the transcriptional control of the XRE was generated as a counter-screen to the ARE induction assay.
  • triplicate wells of reporter and control cell lines (1X105 cells, 24-well culture plates) were incubated with the indicated concentrations of the test sample for 24 h at 37 0 C. Cells incubated with an equivalent concentration (v/v) of DMSO vehicle served as controls. After incubation, cells were harvested, washed with PBS and lysed on ice in 100 ⁇ l of lysis buffer.
  • Luciferase activity was immediately determined using 70 ⁇ l of the lysates with a commercial detection kit (Promega, Madison, Wl). Those samples found to induce luciferase expression that was at least as two-fold greater than vehicle controls are considered to be positive XRE inducers.
  • Binns SE Livesey JF, Arnason JT, Baum BR (2002) Phytochemical Variation in Echinacea from Roots and Flowerheads of Wild and Cultivated Populations. J. Agric. Food Chem. 50: 3673-3687.
  • Pawlus AD Su BN, Keller WJ, Kinghorn AD (2005) An anthraquinone with potent quinone reductase-inducing activity and other constituents of the fruits of Morinda itrifolia (Noni) J Nat Prod 68 1720-1722

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Abstract

On a découvert que les alcamides ou l’un de leurs sels pharmacologiquement acceptables possèdent une activité d’induction des protéines de phase 2 et sont donc utiles pour le traitement d’affections qui répondent à l’induction des protéines de phase 2, par exemple, des affections associées à un stress oxydatif, une inflammation, une maladie cardiovasculaire et une lésion dermatologique. Nouveaux alcamides isolés d’Echinacées avec les formules.
PCT/CA2009/000945 2008-07-11 2009-07-08 Alcamides induisant des protéines de phase 2 WO2010003238A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102249943A (zh) * 2010-05-12 2011-11-23 国际香料和香精公司 提高风味的酰胺化合物
US20120231096A1 (en) * 2010-06-22 2012-09-13 Golio Dominick I Composition and method of treating lipid encapsulated virus infections
US11274320B2 (en) 2019-02-25 2022-03-15 Ginkgo Bioworks, Inc. Biosynthesis of cannabinoids and cannabinoid precursors

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CA2307614A1 (fr) * 1997-10-23 1999-04-29 Elliot P. Friedman Echinacee de qualite pharmaceutique
WO2006002493A1 (fr) * 2004-07-07 2006-01-12 Mediherb Holdings Ltd Formulation déchinacée

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WO2006002493A1 (fr) * 2004-07-07 2006-01-12 Mediherb Holdings Ltd Formulation déchinacée

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GERTSCH. J. ET AL.: "Echinacea alkylamides modulate TNF-a gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways", FEBS LETTERS, vol. 577, 2004, pages 563 - 569 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102249943A (zh) * 2010-05-12 2011-11-23 国际香料和香精公司 提高风味的酰胺化合物
EP2386212A3 (fr) * 2010-05-12 2015-10-07 International Flavors & Fragrances Inc. Composés d'amide à amélioration de la saveur
CN102249943B (zh) * 2010-05-12 2016-01-20 国际香料和香精公司 提高风味的酰胺化合物
US20120231096A1 (en) * 2010-06-22 2012-09-13 Golio Dominick I Composition and method of treating lipid encapsulated virus infections
US8609160B2 (en) * 2010-06-22 2013-12-17 Dominick Golio Composition and method of treating lipid encapsulated virus infections
US11274320B2 (en) 2019-02-25 2022-03-15 Ginkgo Bioworks, Inc. Biosynthesis of cannabinoids and cannabinoid precursors

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