CN112546035A - Use of compounds and compositions thereof for preventing and/or treating obesity - Google Patents
Use of compounds and compositions thereof for preventing and/or treating obesity Download PDFInfo
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- CN112546035A CN112546035A CN201911393617.3A CN201911393617A CN112546035A CN 112546035 A CN112546035 A CN 112546035A CN 201911393617 A CN201911393617 A CN 201911393617A CN 112546035 A CN112546035 A CN 112546035A
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Abstract
The invention relates to the field of new application of compounds, in particular to application of compounds and compositions thereof in preventing and/or treating obesity. The present invention provides the use of a composition comprising an effective concentration of a compound selected from the group consisting of: 4-hydroxy-3-methoxycinnamic acid can also be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, and any combination thereof, and a pharmaceutically acceptable carrier. The composition can effectively promote lipolysis, reduce cell fat content, and prevent and/or treat obesity.
Description
Technical Field
The invention relates to the field of new application of compounds, in particular to application of compounds and compositions thereof in preventing and/or treating obesity.
Background
The incidence of global obesity has increased gradually in recent years, and the World Health Organization (WHO) is more in the form of "infectious disease" and called "global obesity", which is estimated by the World Health Organization in 2014 to be about 39% overweight (about 19 million people) and more 13% obese (about 6 million people) worldwide. Obese individuals are at increased risk for a variety of health problems and may develop a variety of complications, including hypertension, hyperlipidemia, cardiovascular disease, sleep apnea, angina, degenerative arthritis, hyperuricemic osteoarthritis, type ii diabetes, and cancer; among them, when the body is hyperglycemic for a long time, the pancreas is fatigued to secrete more insulin to reduce blood sugar, and once the pancreas is overloaded, the second type diabetes develops. In addition, blood lipids refer to fats in blood, mainly including cholesterol and triglycerides, and are called hyperlipidemia when the concentration of cholesterol or triglycerides circulating in blood is higher than normal; when the cholesterol or triglyceride level is too high or the concentration of high density lipoprotein is too low, it is also called dyslipidemia. Hyperlipidemia is closely related to chronic diseases such as cerebral apoplexy, hypertension, diabetes, nephropathy, etc. besides heart diseases.
Thus, obesity reduces quality of life and may lead to premature death, and thus morbidly obese patients have a much shorter average life than normal weight. Although genes may be involved in the development of obesity, the obesity epidemic is mainly attributed to a high calorie diet and a sedentary lifestyle. Thus, lifestyle changes can prevent obesity and its complications.
While low calorie diets and regular exercise can be used to reduce weight and treat obesity, these approaches are difficult to implement and have limited efficacy, primarily due to adaptive physiological mechanisms that maintain energy storage in the body. In addition, some drugs have been approved for long-term obesity treatment (e.g., orlistat, phentermine, or topiramate), however, these drugs often cause serious side effects, thereby limiting treatment efficacy and patient compliance; furthermore, bariatric surgery can lead to significant weight loss, but such interventional surgery is not suitable for all overweight people; for these reasons, there is a real need to study safe and effective ways to reduce body weight and fat accumulation.
In view of the above, there is a need for a composition comprising effective ingredients that can effectively promote lipolysis, reduce fat formation and reduce the chance of obesity, based on the improvement of the living level of modern people and the improvement of health care concept, in response to obesity and the overall health problems caused by obesity due to changes in living and eating habits of modern people.
Disclosure of Invention
Accordingly, an object of the present invention is to provide a use of a composition for the preparation of a medicament for preventing and/or treating obesity, wherein the composition comprises an effective concentration of a compound selected from the group consisting of: 4-hydroxy-3-methoxycinnamic acid can also be called 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid) ((E) -3- (4-hydroxy-3-methoxy-phenyl) prop-2-enoic acid), 7- [ [2-O- (6-Deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one (7- [ [2-O- (6-Deoxy-alpha-L-mannopyranosyl) -beta-D-gluco-pyranosyl ] ] oxy ] -2, 3-Dihydroxy-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one), 5,7-Dihydroxy-2- (4-hydroxyphenyl) benzo-4-one (5,7-Dihydroxy-2- (4-hydroxyphenyl) chroman-4-one), any combination thereof, and a pharmaceutically acceptable carrier.
It is still another object of the present invention to provide a use of a composition for the preparation of a medicament for promoting lipolysis, wherein the composition comprises an effective concentration of a compound selected from the group consisting of: 4-hydroxy-3-methoxycinnamic acid also can be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, and any combination thereof, and a pharmaceutically acceptable carrier.
Another object of the present invention is to provide a use of 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one for the preparation of a medicament for the prevention and/or treatment of obesity.
In one embodiment of the invention, the effective concentration of the compound is at least 10 μ g/mL.
In yet another embodiment of the present invention, the pharmaceutical composition is for promoting decomposition of fat; and the pharmaceutical composition promotes the decomposition of fat in adipocytes.
In yet another embodiment of the present invention, the effective concentration of the 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one is at least 10 μ g/mL.
In another embodiment of the invention, the 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one is to promote decomposition of fats.
The compound 4-hydroxy-3-methoxycinnamic acid of the invention can also be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, 5-hydroxy-2- (3-hydroxy-4-methoxyphenyl) -4-oxo-3, 4-dihydro-2H-chromen-7-yl-2-O- (6-deoxyhexopyranosyl) hexopyranoside, and (S) -2,3-dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one, the 4-hydroxy-3-methoxycinnamic acid can also be called 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), the 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one and the 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one are effective in promoting lipolysis to reduce the fat content in cells. Thus, the 4-hydroxy-3-methoxycinnamic acid of the invention may also be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, and 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, are useful for the preparation of a composition for promoting lipolysis and/or reducing the fat content of cells, and are a pharmaceutical, a process for the preparation of a composition for the treatment of lipolysis and/or for the treatment of obesity, A cosmetic or a food can be administered to an individual by oral administration, smearing, etc.
The following description of the present invention is provided in connection with the accompanying drawings, which are included to illustrate and not to limit the scope of the present invention, and it will be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope of the invention, and it is intended to cover all modifications and equivalents as may fall within the true spirit and scope of the invention.
Drawings
FIG. 1 is an HPLC fingerprint analysis of a seville orange flower extract according to an embodiment of the present invention;
FIG. 2 is a hydrogen spectrum of compound TCI-CA-01 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 3 is a mass spectrum of compound TCI-CA-01 purified from a Citrus aurantium Linn extract according to an embodiment of the present invention;
FIG. 4 is a hydrogen spectrum of compound TCI-CA-02 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 5 is a mass spectrum of compound TCI-CA-02 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 6 is a hydrogen spectrum of compound TCI-CA-03 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 7 is a mass spectrum of compound TCI-CA-03 purified from a Citrus aurantium extract according to an embodiment of the present invention;
FIG. 8 is a hydrogen spectrum of compound TCI-CA-04 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 9 is a mass spectrum of compound TCI-CA-04 purified from the seville orange flower extract according to an embodiment of the present invention;
FIG. 10 is a hydrogen spectrum of compound TCI-CA-05 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 11 is a mass spectrum of compound TCI-CA-05 purified from a seville orange flower extract according to an embodiment of the present invention;
FIG. 12 is a bar graph showing the efficacy of compounds TCI-CA-01, TCI-CA-02, TCI-CA-03, TCI-CA-04, and TCI-CA-05 in promoting lipolysis, which were purified from a Citrus aurantium extract according to an embodiment of the present invention; p < 0.001.
Detailed Description
As used herein, the numerical values are approximations and all numerical data are reported to be within the 20 percent range, preferably within the 10 percent range, and most preferably within the 5 percent range.
Statistical analysis was performed using Excel software. Data are presented as mean ± Standard Deviation (SD) and differences between groups were analyzed by student's t-test (student's t-test).
In accordance with the present invention, the pharmaceutical may be manufactured in a dosage form (dosage form) suitable for parenteral (parenteral) or oral (oral) administration using techniques well known to those skilled in the art, including, but not limited to: injections (injections) [ for example, sterile aqueous solution (sterile aqueous solution) or dispersion (dispersion) ], sterile powder (sterile powder), troche (tablet), tablet (troche), buccal tablet (dosage), pill (pill), capsule (capsule), dispersible powder (dispersible powder) or granule (granule), solution, suspension (suspension), emulsion (emulsion), syrup (syrup), elixir (elixir), syrup (syrup), and the like.
The medicament according to the invention may be administered by a parenteral route (parenteral routes) selected from the group consisting of: intraperitoneal injection (intraperitoneal injection), subcutaneous injection (subcutaneous injection), intramuscular injection (intramuscular injection), and intravenous injection (intravenous injection).
The pharmaceutical according to the present invention may comprise a pharmaceutically acceptable carrier which is widely used in pharmaceutical manufacturing technology. For example, the pharmaceutically acceptable carrier may comprise one or more agents selected from the group consisting of: solvents (solvents), emulsifiers (emulsifiers), suspending agents (suspending agents), disintegrating agents (disintegrants), binding agents (binders), excipients (excipients), stabilizing agents (stabilizing agents), chelating agents (chelating agents), diluents (diluents), gelling agents (gelling agents), preservatives (preserving), lubricants (lubricants), absorption delaying agents (absorbing agents), liposomes (lipids), and the like. The selection and amounts of such agents are within the skill and routine skill of those skilled in the art.
According to the present invention, the pharmaceutically acceptable carrier comprises a solvent selected from the group consisting of: water, normal saline (normal saline), Phosphate Buffered Saline (PBS), aqueous alcohol-containing solutions (aqueous solution linking alcohol), and combinations thereof.
According to the invention, the medicament may be administered by a parenteral route (parenteral routes) selected from the group consisting of: subcutaneous injection (subecanal injection), intradermal injection (intraepithelial injection), and intralesional injection (intralesion).
According to the present invention, the food product may be used as a food additive (food additive) to be added during the preparation of the raw material or during the preparation of the food by conventional methods, and formulated with any edible material into a food product for ingestion by humans and non-human animals.
According to the present invention, the types of food products include, but are not limited to: beverages (leafages), fermented foods (fermented foods), bakery products (bakery products), health foods (health foods) and dietary supplements (dietary supplements).
According to the present invention, five compounds purified from the ethyl acetate layer extract of the substitutional flower extract of the present invention were obtained by Column chromatography (Column chromatography) and Thin Layer Chromatography (TLC): 4-hydroxy-3-methoxycinnamic acid also known as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid) ((E) -3- (4-hydroxy-3-methoxy-phenyl) prop-2-enoic acid), herein designated TCI-CA-01; 7- [ [2-O- (6-Deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one (7- [ [2-O- (6-Deoxy- α -L-mannopyranosyl) - β -D-glucopyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxypyranyl) -4H-1-benzopyran-4-one), herein designated TCI-CA-02; 5,7-Dihydroxy-2- (4-hydroxyphenyl) benzo-4-one (5,7-Dihydroxy-2- (4-hydroxyphenyl) chroman-4-one), herein designated as TCI-CA-03; 5-hydroxy-2- (3-hydroxy-4-methoxyphenyl) -4-oxo-3,4-dihydro-2 h-chromen-7-yl-2-o- (6-deoxyhexopyranosyl) hexapyranoside (5-hydroxy-2- (3-hydroxy-4-methoxy-phenyl) -4-oxo-3,4-dihydro-2h-chromen-7-yl2-o- (6-deoxyhexoxy-phenyl) hexopyranoside), herein designated TCI-CA-04; and (S) -2,3-Dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one ((S) -2,3-Dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one), herein designated TCI-CA-05.
The procedures and parameters for chemical separation and chemical structure analysis of mixtures according to the present invention are within the skill of those skilled in the art.
The invention provides a use of a composition for preparing 4-hydroxy-3-methoxycinnamic acid, also known as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, and/or 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, for promoting lipolysis and/or reducing the fat content of cells, can effectively promote lipolysis to reduce the content of fat in cells.
Also, the composition for promoting lipolysis and/or reducing the fat content of cells of the present invention may further comprise an effective concentration of a compound selected from the group consisting of: 4-hydroxy-3-methoxycinnamic acid can also be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-Dihydroxy-2- (4-hydroxyphenyl) benzo-4-one (5,7-Dihydroxy-2- (4-hydroxy-phenyl) chroman-4-one), and any combination thereof, and a pharmaceutically acceptable carrier, and the composition is a medicine, a health product, a food.
As will be described in detail below, the 4-hydroxy-3-methoxycinnamic acid of the present invention can also be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-. alpha. -L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, 5-hydroxy-2- (3-hydroxy-4-methoxyphenyl) -4-oxo-3, detailed extraction and purification methods of 4-dihydro-2H-chromium-7-yl-2-o- (6-deoxyhexopyranosyl) hexopyranoside and (S) -2,3-dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one; and test experiments of the five compounds in promoting lipolysis in adipocytes, respectively.
Chemical analysis material
N-hexane (n-hexane), ethyl acetate (ethyl acetate), acetone (acetone), methanol (methanol), ethanol (ethanol), n-butanol (n-butanol), acetonitrile (acetonitrile), chloroform-d 1 (deuterization degree 99.5%), methanol-d 6 (deuterization degree 99.5%), heavy water (deuterium oxide, deuterization degree greater than 99.8%), and dimethyl sulfoxide-d6(dimethyl sulfoxide-d6Degree of deuteration>99.9%) was purchased from merck, taiwan, china.
Chemical analysis instrument
The compounds were isolated by Column chromatography (Column chromatography) and Thin layer chromatography (Thin layer chromatography). Specifically, the tubing for column chromatography was selected from Sephadex LH-20 (from Amersham BioSciences, UK), Diaion HP-20 (from Mitsubishi Chemical Co., Japan), Merck Kieselgel 60(40-63 μm, from Mummer)Gram, Germany, number Art.9385), Merck
RP-18(40-63um, available from Merck, Germany under the number Art.0250). High Performance Liquid Chromatography (HPLC) system equipped with Hitachi L-2310 series pump, Hitachi L-2420UV-VIS detector (detection wavelength 200nm to 380nm), and D-2000Elite data processing software; the tubular column being of the selected self-analytical grade
HS C18 (250X 4.6mm,5 μm; SUPELCO) column and Mightysil RP-18GP 250 (250X 4.6mm,5 μm; Kanto Chemical) column, as well as semi-preparative grades
HS C18 (250X 10.0mm,5 μm; SUPELCO) column and preparative scale
HS C18 (250X 21.0mm,5 μm; SUPELCO) column. The chromatography system was equipped with UV lamp UVP UVGL-25 (wavelength 254nm and 365 nm). The thin layer chromatography sheet is coated with silica gel 60F254(0.25 mm; from Merck, Germany) or RP-18F254SAluminum flakes (0.25 mm; available from merck, germany).
The chemical structure of the compound was analyzed by Mass Spectrometry (MS) and Nuclear magnetic resonance spectrometry (NMR). Specifically, measurements were performed using a two-dimensional ion trap tandem Fourier transform mass spectrometry, electrospray ionization tandem mass spectrometry (ESI-MS/MS), and Bruker amaZon SL system, in m/z; and one-dimensional and two-dimensional NMR spectra were taken using 400MHz Varian 400FT-NMR, with Chemical shifts (Chemical shift) expressed in δ, in ppm; tetramethylsilane (TMS) was used as an internal standard; coupling constants (J) are in Hz and are in s window peak (Singlet), d Doublet (Doublet), t Triplet (Triplet), q Quartet (Quartet), p quintet, m Multiplet (Multiplet), and brs broad.
Example 1 isolation and purification of the compounds TCI-CA-01, TCI-CA-02, TCI-CA-03, TCI-CA-04, and TCI-CA-05 of the present invention
The compound purified in this example was obtained from Citrus aurantium (Citrus), a evergreen shrub plant of the Citrus genus (Citrus) of the family Rutaceae (Rutaceae), also known as neroli, green orange, bitter orange. From the Mediterranean sea, in the ancient Hirrayas era, it has been used by ancient Hirrayas as an aromatherapy bactericide, and as a phytotherapeutic sedative. The seville orange flower prefers warm humid climate and is not cold-resistant, and the seville orange flower is white or purplish red. The seville orange flower has the effects of regulating qi, resolving depression, relieving abdominal distension and pain, vomiting, promoting blood circulation, breaking qi, promoting phlegm and the like, and can be used for calming mood and relieving tension and uneasiness because the seville orange flower has strong fragrance and smells like the seville orange flower.
Firstly, preparing a seville orange flower extract, mixing a seville orange flower dry material and an extraction solvent of water, alcohol or an alcohol-water mixture at a liquid-solid ratio of 5-20:1-5, wherein the extraction solvent is preferably water, and extracting for 0.5-3 hours at 50-100 ℃ in the solvent after homogenizing. After extraction, the mixture was cooled to room temperature, and the crude extract was filtered through a 400-mesh sieve to obtain a filtrate. Finally, the filtrate is concentrated under reduced pressure at 45-70 ℃ to obtain the seville orange flower extract of the invention, and the fingerprint of High Performance Liquid Chromatography (HPLC) is shown in figure 1.
Then, 10 liters of the substitutional flower extract is separated and purified, ethyl acetate and water are mixed according to the ratio of 1:1, the substitutional flower extract is extracted for three times in a liquid phase distribution extraction mode, the extract liquor of the ethyl acetate layer is combined and is concentrated and dried under reduced pressure, and 4.4g of the ethyl acetate layer extract of the substitutional flower extract is obtained.
Next, the active ingredients in the ethyl acetate layer extract of the seville orange flower extract of the present invention were traced according to the Bioassay guided fractionation method (Bioassay guided fractionation). Firstly, 4.4g of ethyl acetate layer extract is separated and purified by a column chromatography method, wherein a silica gel molecular sieve tube is used as a chromatography material, methanol is used as an elution liquid, and the extraction liquid is subjected to column chromatographyPerforming column chromatography, and separating to obtain 7 divided layers (F1-F7); subsequently, the fraction F1 was subjected to further separation and purification by a medium-pressure column chromatography, in which Merck was packed
RP-18 is a chromatographic material, a mixed solution of water and methanol is used as an extracting solution, the polarity of the extracting solution is gradually reduced, after separation and purification by tube column chromatography, spot-taking is carried out by a thin layer chromatography, and then merging is carried out, and finally 5 sub-divided layers (F1-1-F1-7) are obtained.
And separating and purifying the sub-layer F1-3 by HPLC, wherein a mixed solvent system of water and acetonitrile mixed in a ratio of 4:1 is used as a mobile phase, and 6.9mg of compound TCI-CA-01, 8.0mg of compound TCI-CA-02 and 12.7mg of compound TCI-CA-03 are obtained after separation and purification.
And separating and purifying the sub-division layer F1-5 by HPLC, wherein a mixed solvent system of water and acetonitrile mixed in a ratio of 3:1 is used as a mobile phase, and 5.6mg of compound TCI-CA-04 and 9.2mg of compound TCI-CA-05 are obtained after separation and purification.
Comparing the compounds TCI-CA-01, TCI-CA-02, TCI-CA-03, TCI-CA-04 and TCI-CA-05 analyzed by a nuclear magnetic resonance spectrometer and a mass spectrometer, determining the names and chemical structural formulas of the five compounds as shown in the following table 1, wherein the hydrogen spectrum data of TCI-CA-01 is shown in figure 2, and the mass spectrum data of TCI-CA-01 is shown in figure 3; the hydrogen spectrum data of TCI-CA-02 is shown in FIG. 4, and the mass spectrum data of TCI-CA-02 is shown in FIG. 5; the hydrogen spectrum data of TCI-CA-03 is shown in FIG. 6, and the mass spectrum data of TCI-CA-03 is shown in FIG. 7; the hydrogen spectrum data of TCI-CA-04 is shown in FIG. 8, and the mass spectrum data of TCI-CA-04 is shown in FIG. 9; the hydrogen spectrum data of TCI-CA-05 is shown in FIG. 10, and the mass spectrum data of TCI-CA-05 is shown in FIG. 11; wherein, the compound TCI-CA-01 is 4-hydroxy-3-methoxycinnamic acid, also called 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid) ((E) -3- (4-hydroxy-3-methoxy-phenyl) prop-2-enoic acid), the compound is commonly called Ferulic acid (Ferulic acid) and the structural formula thereof is the compound of the formula (I); the compound TCI-CA-02 is 7- [ [2-O- (6-Deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one (7- [ [2-O- (6-Deoxy-alpha-L-mannopyranosyl) -beta-D-glucopyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran an-4-one), commonly known as Naringin (Naringin) and the structural formula thereof is the compound of formula (II); the compound TCI-CA-03 is 5,7-Dihydroxy-2- (4-hydroxyphenyl) benzo-4-one (5,7-Dihydroxy-2- (4-hydroxyphenyl) chroman-4-one), commonly known as Naringenin (Naringenin), and the structural formula of the compound is a compound shown as a formula (III); the compound TCI-CA-04 is 5-hydroxy-2- (3-hydroxy-4-methoxyphenyl) -4-oxo-3,4-dihydro-2 h-chromium-7-yl-2-o- (6-deoxyhexopyranosyl) hexopyranoside (5-hydroxy-2- (3-hydroxy-4-methoxyphenyl) -4-oxo-3,4-dihydro-2h-chromen-7-yl2-o- (6-deoxyhexoxyphenyl) hexopyranoside), commonly known as Neohesperidin (Neohesperidin) and the structural formula of which is the compound shown in formula (IV); and the compound TCI-CA-05 is (S) -2,3-Dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one ((S) -2,3-Dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one), commonly known as Hesperetin (Hesperetin), and the structural formula of the compound is the compound shown as the formula (V).
TABLE 1 chemical name and structural formula for compound TCI-CA-01, compound TCI-CA-02, compound TCI-CA-03, compound TCI-CA-04, and compound TCI-CA-05.
Example 3 efficacy of the active ingredient of the seville orange flower extract of the present invention in promoting lipolysis
This example was conducted using mouse Bone marrow stromal cells (Bone marrow stromal cells) to test the efficacy of compounds TCI-CA-01, TCI-CA-02, TCI-CA-03, TCI-CA-04, and TCI-CA-05) of the present invention in promoting lipolysis. Wherein the mouse bone marrow stromal cells are purchased from American type culture Collection (American type culture Collection)
) Number CRL-2749TM. The cells were cultured in preadipocyte Expansion Medium (Pre-adipocyte Expansion Medium) containing 90% Alpha-MEM (Minimum Essential Medium Eagle-Alpha Modification, ex Gibco, USA) cell culture, 10% Fetal Bovine Serum (Total Bovine Serum, ex Gibco, USA), and 1.0% Penicillin/streptomycin (penicilimin-streptomycin, ex Gibco, USA) added before differentiation; and mouse bone marrow stromal cells were differentiated using a Differentiation Medium comprising 90% α -MEM cell culture, 20% fetal bovine serum, and 1.0% penicillin/streptomycin.
To confirm that the compound TCI-CA-01, the compound TCI-CA-02, the compound TCI-CA-03, the compound TCI-CA-04, and the compound TCI-CA-05 had the effect of promoting lipolysis, bone marrow stromal cells of mice were first differentiated into adipocytes, and 8X10 was added4Mouse bone marrow stromal cells were cultured in 24-well plates containing 0.5mL of the above-mentioned preadipocyte expansion medium at 37 ℃ for 7 days while replacing the above-mentioned differentiation medium with fresh one every 3 days, and after 7 days, the formation of lipid droplets was observed microscopically to ensure that the cells had been completely differentiated, followed by dividing the cells into the following seven groups: (1) control groups (Mock) containing only cell culture fluid, (2) an experimental group to which 10. mu.g/mL of the compound TCI-CA-01 of the present invention was added, (3) an experimental group to which 10. mu.g/mL of the compound TCI-CA-02 of the present invention was added, (4) an experimental group to which 10. mu.g/mL of the compound TCI-CA-03 of the present invention was added, (5) an experimental group to which 10. mu.g/mL of the compound TCI-CA-04 of the present invention was added, (6) an experimental group to which 10. mu.g/mL of the compound TCI-CA-05 of the present invention was added, and (7) an experimental group to which 10. mu.g/mL of the compound TCI-CA-02 of the present invention was added and 10. mu.g/mL of the compound TCI-CA-03 of the present, and cultured at 37 ℃ for 7-10 days, and also replaced with fresh differentiation medium every 3 days.
Then, the extracellular glycerol values were measured using a glycerol assay kit (available from Cayman Chemical, U.S.A.), in which triglyceride stored in cells is decomposed to generate free glycerol andthe amount of fatty acids, and therefore the amount of lipolysis in the cells, can be inferred by measuring the extracellular glycerol content. The kit quantifies the value of extracellular glycerol by measuring the product content of a coupled enzyme reaction system which can generate bright purple products, and establishes a standard curve by using a standard product to calculate the value of extracellular glycerol of a sample. Wherein cell culture supernatant was collected from each well, 25. mu.L of the cell culture supernatant was transferred to a new 96-well culture plate, 100. mu.L of reconstituted Free Glycerol Assay Reagent (Free Glycerol Assay) was added to each well and reacted for 15 minutes at room temperature, followed by reading OD540nmThe numerical value of (c). And student t-test was performed using Excel software to determine if there was a statistically significant difference between the two sample populations (. p value)<0.05; p value<0.01; p value<0.001)。
The results of the test for promoting lipolysis by the compound TCI-CA-01, the compound TCI-CA-02, the compound TCI-CA-03, the compound TCI-CA-04, and the compound TCI-CA-05 of the present invention are shown in FIG. 12. As can be seen from FIG. 12, the compound TCI-CA-01 of the present invention was effective in promoting the decomposition of fat as compared with the control group; after the compound TCI-CA-02 and the compound TCI-CA-03 have the effects, the lipolysis can be respectively and obviously promoted by 8 percent and 15 percent compared with a control group; the effects of the compound TCI-CA-04 of the invention and the compound TCI-CA-05 are similar to those of the control group. The results show that the active ingredients of the seville orange flower extract, namely the compound TCI-CA-01, the compound TCI-CA-02 and the compound TCI-CA-03 can effectively promote lipolysis so as to reduce the content of fat in cells. However, the results of the mixing of TCI-CA-02 and TCI-CA-03 having excellent lipolytic activity with adipocytes acting on them were similar to those of the control group, and showed that it was not possible to effectively add the lipolytic activity to the lipolytic activity by combining any of the lipolytic-accelerating compounds.
In summary, the compound 4-hydroxy-3-methoxycinnamic acid of the present invention can also be called 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, 5-hydroxy-2- (3-hydroxy-4-methoxyphenyl) -4-oxo-3, 4-dihydro-2H-chromen-7-yl-2-O- (6-deoxyhexopyranosyl) hexopyranoside, and (S) -2,3-dihydro-5,7-dihydroxy-2- (3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one, the 4-hydroxy-3-methoxycinnamic acid can also be called 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), the 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one and the 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one are effective in promoting lipolysis to reduce the fat content in cells. Thus, the 4-hydroxy-3-methoxycinnamic acid of the invention may also be referred to as 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, and 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, are useful for the preparation of a composition for promoting lipolysis and/or reducing the fat content of cells, and are a pharmaceutical, a process for the preparation of a composition for the treatment of lipolysis and/or for the treatment of obesity, A cosmetic or a food can be administered to an individual by oral administration, smearing, etc.
Claims (10)
1. Use of a composition for the manufacture of a medicament for the prevention and/or treatment of obesity, wherein the composition comprises an effective concentration of a compound selected from the group consisting of: 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, and any combination thereof, and a pharmaceutically acceptable carrier.
2. The use according to claim 1, wherein the effective concentration of the compound is at least 10 μ g/mL.
3. Use according to claim 1, characterized in that the composition is intended to promote the breakdown of fats.
4. Use according to claim 3, wherein the composition is for promoting the breakdown of fat in adipocytes.
5. Use of a composition comprising an effective concentration of a compound selected from the group consisting of: 3- (4-hydroxy-3-methoxyphenyl) -2-propenoic acid), 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one, 5,7-dihydroxy-2- (4-hydroxyphenyl) benzo-4-one, and any combination thereof, and a pharmaceutically acceptable carrier.
6. Use according to claim 5, wherein the effective concentration of the compound is at least 10 μ g/mL.
7. Use according to claim 5, wherein the composition is for promoting the breakdown of fat in adipocytes.
8. The application of 7- [ [2-O- (6-deoxy-alpha-L-mannopyranosyl) -beta-D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one in preparing medicine for preventing and/or treating obesity.
9. The use according to claim 8, characterized in that the effective concentration of 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one is at least 10 μ g/mL.
10. Use according to claim 8, characterized in that the 7- [ [2-O- (6-deoxy- α -L-mannopyranosyl) - β -D-pyranosyl ] ] oxy ] -2,3-dihydro-5-hydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one is promoting decomposition of fat.
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