ITCS20080019A1 - NATURAL MOLECULE EXTRACTED FROM A CITRUS, EXTRACTION PROCESS AND PHARMACEUTICAL USE - Google Patents
NATURAL MOLECULE EXTRACTED FROM A CITRUS, EXTRACTION PROCESS AND PHARMACEUTICAL USE Download PDFInfo
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- ITCS20080019A1 ITCS20080019A1 IT000019A ITCS20080019A ITCS20080019A1 IT CS20080019 A1 ITCS20080019 A1 IT CS20080019A1 IT 000019 A IT000019 A IT 000019A IT CS20080019 A ITCS20080019 A IT CS20080019A IT CS20080019 A1 ITCS20080019 A1 IT CS20080019A1
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- Italy
- Prior art keywords
- citrus fruit
- natural molecule
- flavonoid
- fruit according
- cancer
- Prior art date
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- 235000020971 citrus fruits Nutrition 0.000 title claims description 15
- 238000000605 extraction Methods 0.000 title claims description 5
- 241000207199 Citrus Species 0.000 title description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- 229930003935 flavonoid Natural products 0.000 claims description 14
- 150000002215 flavonoids Chemical class 0.000 claims description 14
- 235000017173 flavonoids Nutrition 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 235000013399 edible fruits Nutrition 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 235000010672 Monarda didyma Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- -1 3-hydroxy-3-methyl glutaryl Chemical group 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 claims description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 claims description 2
- 230000003627 anti-cholesterol Effects 0.000 claims description 2
- 229930019673 naringin Natural products 0.000 claims description 2
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 claims description 2
- 229940052490 naringin Drugs 0.000 claims description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 claims description 2
- 244000003027 Bergamotto Species 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 238000002953 preparative HPLC Methods 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 235000012000 cholesterol Nutrition 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004896 high resolution mass spectrometry Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 244000179970 Monarda didyma Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 235000009917 Crataegus X brevipes Nutrition 0.000 description 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 description 1
- 235000009685 Crataegus X maligna Nutrition 0.000 description 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 description 1
- 235000009486 Crataegus bullatus Nutrition 0.000 description 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 description 1
- 235000009682 Crataegus limnophila Nutrition 0.000 description 1
- 235000004423 Crataegus monogyna Nutrition 0.000 description 1
- 240000000171 Crataegus monogyna Species 0.000 description 1
- 235000002313 Crataegus paludosa Nutrition 0.000 description 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 description 1
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 1
- 150000002216 flavonol derivatives Chemical class 0.000 description 1
- 235000011957 flavonols Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- ARGKVCXINMKCAZ-UZRWAPQLSA-N neohesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UZRWAPQLSA-N 0.000 description 1
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/752—Citrus, e.g. lime, orange or lemon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Cardiology (AREA)
- Genetics & Genomics (AREA)
- Vascular Medicine (AREA)
- Alternative & Traditional Medicine (AREA)
- Botany (AREA)
- Heart & Thoracic Surgery (AREA)
- Mycology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Description
Molecola naturale estratta da un agrume, processo di estrazione e uso farmaceutico Campo della tecnica dell’invenzione. Natural molecule extracted from a citrus fruit, extraction process and pharmaceutical use Field of the inventive technique.
La presente invenzione riguarda una nuova molecola estratta da un agrume, in particolare dal bergamotto, il processo di estrazione e il suo uso come farmaco anti-colesterolemico. The present invention relates to a new molecule extracted from a citrus fruit, in particular from bergamot, the extraction process and its use as an anti-cholesterol drug.
Stato dell’arte State of the art
I flavonoidi sono presenti in maniera massiccia nelle specie vegetali, e possiedono doti nutrizionali e farmaceutiche notevoli; nel secolo scorso, studi epidemiologici hanno dimostrato che il consumo a lungo termine di vegetali e frutta offre una notevole protezione nei confronti di malattie croniche, come ad esempio il cancro.<1-7>Poichè la produzione incontrollata di radicali liberi è implicata nell’insorgenza del cancro,<8-11>si è focalizzata l’attenzione sul possibile ruolo dei nutrienti di questo tipo di dieta come soppressori e/o spazzini di radicali.<12-15>Flavonoids are massively present in plant species, and possess remarkable nutritional and pharmaceutical qualities; in the last century, epidemiological studies have shown that the long-term consumption of vegetables and fruit offers considerable protection against chronic diseases, such as cancer. <1-7> As the uncontrolled production of free radicals is implicated in onset of cancer, <8-11> attention was focused on the possible role of nutrients in this type of diet as suppressors and / or scavengers of radicals. <12-15>
Studi più recenti suggeriscono che l’assunzione di flavonoli e flavoni, o altri flavonoidi ha un effetto protettivo contro malattie vascolari o alcuni tipi di cancro.<16-26>More recent studies suggest that the intake of flavonols and flavones, or other flavonoids, has a protective effect against vascular diseases or some types of cancer. <16-26>
Nel documento US2008031861 è descritto un integratore che per abbassare il colesterolo in una persona utilizza un integratore contenente un flavonoide ed un enzima. Document US2008031861 describes a supplement that uses a supplement containing a flavonoid and an enzyme to lower cholesterol in a person.
CN101073610 descrive un processo per ottenere dal biancospino sali organici acidi di calcio contenenti flavonoidi che possono essere usati per abbassare il colesterolo. CN101073610 describes a process for obtaining organic acidic calcium salts containing flavonoids from hawthorn which can be used to lower cholesterol.
In US2006182823 viene descritto un metodo per estrarre componenti flavonoidi ed alcaloidi da foglie di loto. In US2006182823 a method for extracting flavonoid and alkaloid components from lotus leaves is described.
Sommario della presente invenzione Summary of the present invention
La presente invenzione riguarda l’isolamento e la determinazione strutturale di alcuni composti presenti negli agrumi e particolarmente nel frutto della specie Bergamia appartenente al genere Citrus (Bergamotto). Essi sono presenti in quantità rilevanti (ca. 300-500 mg/kg) nelle diverse parti del frutto e appartengono alla classe dei flavonoidi. La caratteristica principale di questi nuovi composti è la presenza nella molecola del gruppo 3-idrossi-3-metil glutarile (HMG) sotto forma di estere sulla porzione zuccherina della molecola (schema 1). The present invention relates to the isolation and structural determination of some compounds present in citrus fruits and particularly in the fruit of the Bergamia species belonging to the genus Citrus (Bergamot). They are present in significant quantities (approx. 300-500 mg / kg) in the different parts of the fruit and belong to the class of flavonoids. The main characteristic of these new compounds is the presence in the molecule of the 3-hydroxy-3-methyl glutaryl (HMG) group in the form of ester on the sugar portion of the molecule (scheme 1).
Schema 1 Scheme 1
Il gruppo HMG, presente nelle nuove molecole individuate, ha un ruolo fondamentale nella biosintesi del colesterolo, infatti esso, in vivo, viene biosintetizzato attraverso una serie di reazioni enzimatiche. Uno di questi passaggi chiave prevede la trasformazione (riduzione) dell’acido 3-idrossi-3-metil glutarico coniugato al coenzima-A (HMG-CoA) ad acido mevalonico. Normalmente per bloccare la biosintesi del colesterolo, si utilizzano farmaci denominati “statine”; questi hanno una struttura simile all’HMG-CoA e riescono a bloccare l’enzima HMG reduttasi responsabile della trasformazione (riduzione) descritta sopra. Le nuove molecole, trovate nel succo di bergamotto sono anche esse coniugate dell’HMG (Schema) e possono, quindi, inibire l’enzima reduttasi. Le prove in vitro descritte in fondo a questo abstract danno credito a questa ipotesi. The HMG group, present in the new molecules identified, plays a fundamental role in the biosynthesis of cholesterol, in fact it is biosynthesized in vivo through a series of enzymatic reactions. One of these key steps involves the transformation (reduction) of 3-hydroxy-3-methyl glutaric acid conjugated to coenzyme-A (HMG-CoA) to mevalonic acid. Normally, to block the biosynthesis of cholesterol, drugs called "statins" are used; these have a similar structure to HMG-CoA and are able to block the HMG reductase enzyme responsible for the transformation (reduction) described above. The new molecules found in bergamot juice are also conjugated to HMG (Scheme) and can, therefore, inhibit the reductase enzyme. The in vitro tests described at the bottom of this abstract give credence to this hypothesis.
I composti sono stati isolati attraverso un procedimento estrattivo ed una separazione cromatografia. Il procedimento estrattivo consiste nell’aggiunta di una miscela di solventi (metanolo etanolo e cloroformio in rapporto volumetrico 65:30:5 (v/v/v)),ovvero gli stessi solventi puri od in diverse proporzioni, al frutto precedentemente sminuzzato in tutte le sue parti. Il preparato viene posto sotto agitazione per 2 ore. Alla fine il solvente viene filtrato e ridotto in volume fino a consistenza sciropposa. Il residuo, solubilizzato con acqua, viene sottoposto a estrazione in fase solida attraverso una cartuccia a fase inversa. La cartuccia viene prima attivata con metanolo ed acqua, poi il residuo viene versato sulla cartuccia ed eluito dapprima con acqua per rimuovere gli zuccheri e poi con metanolo o etanolo. Il residuo metanolico che contiene perlopiù flavonoidi viene evaporato a secchezza e sottoposto a separazione cromatografia. Il sistema cromatografico è un HPLC semipreparativo utilizzante una colonna in fase inversa ed un detector UV/MS oppure un sistema MPLC a fase inversa utilizzante gli stessi solventi di eluizione. Per isolare il composto si utilizza una corsa cromatografia con fase mobile acqua e metanolo o etanolo o acetonitrile. Le frazioni corrispondenti agli estratti ionici m/z 755 (composto 1) e m/z 725 (composto 2) vengono raccolte e separate dal solvente per evaporazione per ottenere i composti puri. Il composto 1 è stato caratterizzato attraverso esperimenti di spettrometria di massa ad alta risoluzione (HRMS) e risonanza magnetica ad alta risoluzione (NMR). Lo spettro HRMS in sorgente di 1 genera il picco pseudomolecolare [M+H]<+>con valore 755.2387 che corrisponde alla formula elementare C34H43O19con uno scarto di -0.80 ppm sul valore teorico. Lo spettro HRMSMS della specie [M+H]<+>genera una serie di picchi interpretabili attraverso lo schema 2. The compounds were isolated through an extractive process and a chromatographic separation. The extraction process consists in adding a mixture of solvents (methanol, ethanol and chloroform in a volumetric ratio 65: 30: 5 (v / v / v)), or the same pure solvents or in different proportions, to the fruit previously chopped in all its parts. The preparation is stirred for 2 hours. Finally the solvent is filtered and reduced in volume to a syrupy consistency. The residue, solubilized with water, is subjected to solid phase extraction through a reverse phase cartridge. The cartridge is first activated with methanol and water, then the residue is poured onto the cartridge and eluted first with water to remove the sugars and then with methanol or ethanol. The methanol residue, which mostly contains flavonoids, is evaporated to dryness and subjected to chromatographic separation. The chromatographic system is a semipreparative HPLC using a reversed phase column and a UV / MS detector or a reversed phase MPLC system using the same elution solvents. A water and methanol or ethanol or acetonitrile mobile phase chromatography run is used to isolate the compound. The fractions corresponding to the ionic extracts m / z 755 (compound 1) and m / z 725 (compound 2) are collected and separated from the solvent by evaporation to obtain the pure compounds. Compound 1 was characterized through high resolution mass spectrometry (HRMS) and high resolution magnetic resonance (NMR) experiments. The HRMS spectrum in source of 1 generates the pseudomolecular peak [M + H] <+> with value 755.2387 which corresponds to the elementary formula C34H43O19 with a deviation of -0.80 ppm on the theoretical value. The HRMSMS spectrum of the [M + H] <+> species generates a series of peaks that can be interpreted through scheme 2.
3′′′ 3.59 (dd) 3.59 (dd) 3 ′ ′ ′ 3.59 (dd) 3.59 (dd)
4′′′ 3.62 (dd) 3.66 (dd) 4 ′ ′ ′ 3.62 (dd) 3.66 (dd)
5′′′ 3.90 (m) 3.90 (dd) 5 ′ ′ ′ 3.90 (m) 3.90 (dd)
6′′′ 1.31 (d) 1.31 (d) 6 ′ ′ ′ 1.31 (d) 1.31 (d)
2′′′′ 2.65-2.52 (m) 2.65-2.52 (m) 2 ′ ′ ′ ′ 2.65-2.52 (m) 2.65-2.52 (m)
4′′′′ 2.65-2.52 (m) 2.65-2.52 (m) 4 ′ ′ ′ ′ 2.65-2.52 (m) 2.65-2.52 (m)
6′′′′ 1.26 (s) 1.26 (s) 6 ′ ′ ′ ′ 1.26 (s) 1.26 (s)
La molecola è stata sottoposta a reazione di idrolisi basica per verificare l’esistenza di legami esterei. Dopo 4 ore di reazione con carbonato di sodio, si forma una specie avente ione molecolare a m/z 611. I tempi di ritenzione cromatografici del prodotto di reazione e dello standard neoesperidina, sono uguali per cui si arriva alla conclusione che il prodotto di reazione è proprio neoesperidina. La corsa mostra anche la formazione di un prodotto avente ione molecolare m/z 163, che corrisponde all’acido eliminato dalla reazione di idrolisi. Quest’ultimo prodotto viene separato tramite cromatografia preparativa e sottoposto ad esperimenti HRMS ed NMR (tabella 2), che indicano che esso corrisponde all’HMG. The molecule was subjected to a basic hydrolysis reaction to verify the existence of ester bonds. After 4 hours of reaction with sodium carbonate, a species is formed having a molecular ion at m / z 611. The chromatographic retention times of the reaction product and of the neohesperidin standard are the same so that it is concluded that the reaction product is just neoesperidina. The run also shows the formation of a product having a molecular ion m / z 163, which corresponds to the acid eliminated by the hydrolysis reaction. The latter product is separated by preparative chromatography and subjected to HRMS and NMR experiments (table 2), which indicate that it corresponds to HMG.
Tabella 2. Dati NMR per l’acido 3-metil-3-idrossil glutarico (HMG) ottenuto dopo idrolisi basica. Table 2. NMR data for 3-methyl-3-hydroxyl glutaric acid (HMG) obtained after basic hydrolysis.
<set>dati<1>H-NMR (δ (m)) dati<13>C-NMR (δ (m)) <set> data <1> H-NMR (δ (m)) data <13> C-NMR (δ (m))
3-CH31.22 (s) 28 (q) 3-CH31.22 (s) 28 (q)
2,4-CH32.46 (m) 46.5 (t) 2,4-CH32.46 (m) 46.5 (t)
1,5-COOH 8.21 (s) 173 (s) 1,5-COOH 8.21 (s) 173 (s)
3-OH -- 69 (s) 3-OH - 69 (s)
Il risultato è che la molecola incognita 1 è una molecola di neosperidina coniugata attraverso un legame estereo in posizione 6 del glucosio all’HMG. La posizione del legame estereo è confermata dai dati NMR in tabella 1. The result is that the unknown molecule 1 is a molecule of neosperidin conjugated through an ester bond in position 6 of glucose to HMG. The position of the ester bond is confirmed by the NMR data in Table 1.
L’intera procedura viene ripetuta per il composto 2 che come risultato finale fornisce la struttura della naringina coniugata attraverso un legame estereo in posizione 6 del glucosio all’HMG. The entire procedure is repeated for compound 2 which as a final result provides the structure of the conjugated naringin through an ester bond in position 6 of the glucose to HMG.
Una volta isolate, le molecole 1 e 2 sono state sottoposte ad esperimenti in vitro per verificare il loro potenziale inibitorio del processo biosintetico di produzione del colesterolo. E’ stato utilizzato un kit enzimatico reperibile in commercio; Il kit risulta composto da: 10 ml di tampone 5x; 25 mg di NADPH, 2 ml di substrato (HMG-CoA); 200µl di HMGR (dominio catalitico) 0,55-0,65 mg/ml, 200µl di soluzione dell’inibitore Pravastatina. Il kit è progettato in modo da seguire la diminuzione di assorbanza alla lunghezza d’onda di 340 nm, che rappresenta l'ossidazione del NADPH ad opera della porzione catalitica di HMGR in presenza del substrato HMG-CoA ed eventualmente di un inibitore. Once isolated, molecules 1 and 2 were subjected to in vitro experiments to verify their inhibitory potential of the biosynthetic process of cholesterol production. A commercially available enzymatic kit was used; The kit consists of: 10 ml of 5x buffer; 25 mg of NADPH, 2 ml of substrate (HMG-CoA); 200µl of HMGR (catalytic domain) 0.55-0.65 mg / ml, 200µl of Pravastatin inhibitor solution. The kit is designed to follow the decrease in absorbance at a wavelength of 340 nm, which represents the oxidation of NADPH by the catalytic portion of HMGR in the presence of the HMG-CoA substrate and possibly an inhibitor.
Il composto 1 già a concentrazioni di circa 300 µmol/L mostra un’inibizione dell’80% dopo 8 minuti (grafico 1) Compound 1 already at concentrations of about 300 µmol / L shows an inhibition of 80% after 8 minutes (graph 1)
Grafico 1 Graph 1
Il composto 2 nelle stesse condizioni mostra un inibizione del 75% dopo 8 minuti (grafico 2): Compound 2 under the same conditions shows 75% inhibition after 8 minutes (graph 2):
Grafico 2 Graph 2
I risultati mostrano che tutte e due le molecole derivate dell’HMG hanno una attività inibitoria simile, sebbene a concentrazioni molto maggiori, a quella delle statine utilizzate per combattere il colesterolo. The results show that both HMG-derived molecules have similar inhibitory activity, albeit at much higher concentrations, to that of the statins used to fight cholesterol.
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Also Published As
| Publication number | Publication date |
|---|---|
| EP2424545A1 (en) | 2012-03-07 |
| WO2010041290A1 (en) | 2010-04-15 |
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