CN118047788A - Isopentenyl phenolic compound, and preparation method and application thereof - Google Patents
Isopentenyl phenolic compound, and preparation method and application thereof Download PDFInfo
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- CN118047788A CN118047788A CN202211407242.3A CN202211407242A CN118047788A CN 118047788 A CN118047788 A CN 118047788A CN 202211407242 A CN202211407242 A CN 202211407242A CN 118047788 A CN118047788 A CN 118047788A
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- ethanol
- hplc
- isopentenyl
- phenolic compound
- water
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Abstract
The invention discloses an isopentenyl phenolic compound, a preparation method and application thereof. The invention provides an isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof. The isopentenyl phenolic compound I has stronger affinity to PPARgamma, can obviously reduce the glucose content in insulin resistance model cell fluid, raise the level of adiponectin, has no obvious effect of promoting adipocyte differentiation, and has small side effect.
Description
Technical Field
The invention relates to an isopentenyl phenolic compound, a preparation method and application thereof.
Background
Along with the improvement of the social life level and the change of the mode, the type 2 diabetics are increased continuously, and the healthy life of people is seriously influenced. Among them, insulin resistance (Insulin resistance, IR) is one of the main causes of the onset of type 2 diabetes. It is mainly manifested in that the sensitivity of peripheral tissues such as liver, adipose tissue and the like to insulin is reduced, so that the organism competitively generates more insulin to maintain blood sugar level, hyperinsulinemia is generated, and further glycolipid metabolic disorder is caused, and metabolic diseases such as type 2 diabetes and the like are caused. Rosiglitazone as a drug for the treatment of diabetes improves IR resistance and increases insulin sensitivity but also brings about a number of adverse effects such as weight gain, sodium retention in water, osteoporosis, tumors and cardiovascular risk. The discovery of efficient, safe insulin sensitizers is therefore of great value.
Peroxisome proliferator-activated receptor gamma (pparγ), a ligand-activated nuclear receptor transcription factor, is expressed mainly in adipose tissue and plays a key role in the link of adipocyte differentiation and glycolipid metabolism balance. PPARgamma binds to the ligand, activates PPARgamma receptor gene transcription, and further improves the expression of fat synthesis related factors (C/EBPalpha, aP2, FAS and the like), thereby promoting the differentiation of fat cells; by up-regulating the expression of insulin sensitization factor adiponectin, the transfer of peripheral tissues to glucose is increased, so that insulin resistance is improved, and the blood glucose reducing effect is exerted. Pparγ is an important target for the current discovery of insulin sensitizers. Meanwhile, PPARgamma is also closely related to diseases such as obesity, hypertension, atherosclerosis and tumor, and PPARgamma ligands have been shown to have beneficial effects on the above diseases (research progress of PPARgamma function and disease relationship. Chinese pharmacology report, 2012, 28 (5): 601-4).
Black mulberry (Morus nigra L.) is Morus (Moraceae) plant of Moraceae, and has effects of lowering blood sugar, blood lipid, blood pressure, and resisting virus, and the like, and the related researches report that black mulberry leaf and stem contain abundant active substances such as phenols, including flavonoids, stilbenes, DA adducts, etc.; alkaloid component, coumarin component, etc. Wherein the water-soluble and phenolic components have the function of reducing blood sugar, and the water-soluble alkaloid components are developed into mulberry twig total alkaloids tablets to be marketed at present.
Disclosure of Invention
The invention aims to solve the technical problem that the existing medicines for reducing insulin resistance are few in variety, and therefore, the invention provides an isopentenyl phenolic compound I or pharmaceutically acceptable salt thereof. The isopentenyl phenolic compound has stronger affinity to PPARgamma, can obviously reduce the glucose content in insulin resistance model cell sap and increase the level of adiponectin; meanwhile, the compound has weaker agonistic activity to PPARgamma, has no obvious effect of promoting the differentiation of fat cells and has small side effect.
The technical problems are solved by the following technical scheme.
The invention provides an isopentenyl phenol compound I or a pharmaceutically acceptable salt thereof,
In one embodiment of the present invention, the prenylphenol compound I may be:
in one embodiment of the present invention, the prenylphenol compound I may have a retention time of 23.7min under the following HPLC conditions:
chromatographic column model: AGILENT ECLIPSE XDB-C 18, (250X 10mm,5 μm),
Mobile phase and volume ratio: acetonitrile in water=63:37,
Sample injection amount: 200. Mu.L of the gel was used,
Column temperature: at room temperature, the temperature of the mixture is higher,
Detection wavelength: at a wavelength of 210nm,
Flow rate: 3mL/min.
In one embodiment of the present invention, the prenylphenol compound I may have a retention time of 23.7min under the following HPLC conditions:
chromatographic column model: AGILENT ECLIPSE XDB-C 18, (250X 10mm,5 μm),
Mobile phase and volume ratio: acetonitrile in water=63:37,
Sample injection amount: 200. Mu.L of the gel was used,
Column temperature: at room temperature, the temperature of the mixture is higher,
Detection wavelength: at a wavelength of 210nm,
Flow rate: 3mL/min of the total weight of the product,
Preparing a liquid phase: LC 3050N-type high performance liquid chromatograph.
The invention also provides a preparation method of the isopentenyl phenolic compound I, which comprises the following steps:
① Suspending the black mulberry stem and branch ethanol extract with water, performing AB-8 macroporous resin column chromatography, eluting with water, 40% ethanol and 95% ethanol respectively, concentrating and drying the eluate obtained by eluting with 95% ethanol to obtain mixture 1;
② Subjecting the mixture 1 to silica gel column chromatography, performing gradient elution by using a mixed solution of petroleum ether and ethyl acetate, sequentially performing volume ratio of petroleum ether to ethyl acetate of 10:1,7:1,5:1,2:1,1:1 and 2:3, collecting eluent with volume ratio of dichloromethane to methanol of 12:1 and Rf value of 0.40, and concentrating and drying to obtain a mixture 2;
③ Performing gel column chromatography on the mixture 2, eluting with dichloromethane and methanol in a volume ratio of 1:1, collecting eluent with a volume ratio of dichloromethane to methanol of 12:1 and an Rf value of 0.40, and concentrating and drying to obtain a mixture 3;
④ Subjecting the mixture 3 to reverse phase silica gel column chromatography, gradient eluting with methanol and water, wherein the volume ratio of methanol to water is 40:60, 50:50, 60:40, 70:30, 80:20, 90:10 in sequence, collecting eluent with Rf value of 0.40 when the volume ratio of dichloromethane to methanol is 12:1 and detecting by silica gel thin layer chromatography, and concentrating to obtain crude product of isopentenyl phenolic compound I;
⑤ Purifying the crude product of the isopentenyl phenolic compound I by HPLC, wherein a chromatographic column stationary phase of the HPLC is C18 bonded silica gel, and a mobile phase is a mixed solution of acetonitrile and water; the volume ratio of acetonitrile to water is 63:37.
The preparation method can further comprise the following steps;
Extracting the black mulberry stem and branch coarse powder with ethanol, filtering and concentrating the extracting solution to obtain the black mulberry stem and branch ethanol extract.
In one embodiment of the invention, the ethanol is 85% -95% ethanol, for example 90% ethanol, in the process of extracting the black mulberry stem and branch coarse powder with ethanol.
In one embodiment of the present invention, the extraction temperature of the black mulberry stem and branch coarse powder is 75-90 ℃, for example 80 ℃.
In one embodiment of the invention, the volume-mass ratio of the ethanol to the black mulberry stem coarse powder is 5-10L/kg, for example 8L/kg, in the process of extracting the black mulberry stem coarse powder with ethanol.
In one embodiment of the present invention, the number of times of extraction of the black mulberry stem and branch coarse powder with ethanol is 1 to 3, for example, 2.
In one embodiment of the present invention, the extraction time of the black mulberry stem and branch coarse powder is 0.5 to 2 hours, for example, 1 hour, during the extraction with ethanol.
In one embodiment of the present invention, in step ①, the weight ratio of the ethanol extract to the water is 1:5-15, e.g., 1:10, when the ethanol extract is suspended with water.
In one embodiment of the present invention, in step ①, the volumes of water, 40% ethanol and 95% ethanol are 5 times the column volumes, respectively, when performing AB-8 macroporous resin column chromatography.
In one embodiment of the present invention, in step ②, the petroleum ether and ethyl acetate mixed solution is used in an amount of 3 column volumes per gradient.
In one embodiment of the present invention, in step ③, the packing material of the gel column is hydroxypropyl sephadex, preferably, hydroxypropyl sephadex is LH-20.
In one embodiment of the present invention, in step ④, the packing material for reverse phase silicse:Sup>A gel column chromatography is preferably ODS-C18, more preferably ODS-A-HG.
In one embodiment of the present invention, in step ④, the amount of mixed solvent used for each gradient is 3 column volumes when the gradient elution is performed with methanol and water.
In one embodiment of the invention, in step ⑤, the packing particle size of the HPLC column is 5-10 μm, for example 5 μm.
In one embodiment of the present invention, in step ⑤, the length of the HPLC column is 100-250 mm, such as 250mm.
In one embodiment of the invention, in step ⑤, the HPLC column has an inner diameter of 9.4-30 mm, e.g., 10mm.
In one embodiment of the present invention, in step ⑤, the HPLC column is AGILENT ECLIPSE XDB-C 18, 250X 10mm,5 μm.
In one embodiment of the present invention, in step ⑤, the column temperature of the HPLC column is 20-50deg.C, such as room temperature.
In one embodiment of the present invention, in step ⑤, the detection wavelength of the HPLC is 200 to 400nm, for example 210nm.
In one embodiment of the present invention, in step ⑤, the flow rate of the mobile phase of the HPLC is 1-15 mL/min, such as 3mL/min.
In one embodiment of the present invention, in step ⑤, the sample volume of the HPLC is 10 to 1000. Mu.L, for example 200. Mu.L.
The invention also provides a pharmaceutical composition which comprises the isopentenyl phenolic compound I or pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient.
In the pharmaceutical composition, the isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof may be the only active ingredient.
In the pharmaceutical composition, the pharmaceutical excipients are pharmaceutical excipients which are conventionally applicable in the field, preferably sucrose, gelatin, glycerol, pregelatinized starch, microcrystalline cellulose, lactose or inorganic calcium salts.
In the pharmaceutical composition, the pharmaceutical dosage form of the pharmaceutical composition can be tablets, capsules, granules, powder or liquid preparations.
The pharmaceutical composition may be administered to the subject by any suitable route, preferably orally, intravenously or topically, more preferably orally.
The pharmaceutical compositions may be prepared using methods known to those skilled in the art.
The invention also provides an application of the isopentenyl phenolic compound I or the pharmaceutically acceptable salt thereof in preparing an insulin sensitizer.
The invention also provides an application of the isopentenyl phenolic compound I or the pharmaceutically acceptable salt thereof in preparing PPAR gamma partial agonists.
The invention also provides application of the isopentenyl phenol compound I or pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating insulin resistance or metabolic diseases caused by the insulin resistance.
The invention also provides application of the isopentenyl phenol compound I and pharmaceutically acceptable salts thereof in preparing medicines for preventing or treating type 2 diabetes, obesity, hypertension, hyperlipidemia, atherosclerosis or tumors.
As used herein, "room temperature" refers to 10-30deg.C.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a prototype of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. When relatively basic functional groups are present in the compounds of the present invention, the acid addition salts may be obtained by contacting a prototype of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic or organic acids, which can be converted to base addition salts or acid addition salts when the compounds of the present invention contain relatively acidic and relatively basic functionalities. See specifically Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977), or 、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002).
The term "treatment" refers to therapeutic therapy. Treatment, where a particular disorder is involved, refers to (1) alleviation of a disease or one or more biological manifestations of a disorder, (2) interference with (a) one or more points in a biological cascade leading to or causing a disorder or (b) one or more biological manifestations of a disorder, (3) amelioration of one or more symptoms, effects or side effects associated with a disorder, or one or more symptoms, effects or side effects associated with a disorder or treatment thereof, or (4) alleviation of progression of a disorder or one or more biological manifestations of a disorder.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effect that the isopentenyl phenolic compound shown in the formula I is discovered, has strong affinity to PPARgamma, can obviously reduce the glucose content in insulin resistance model cell fluid, raise the level of adiponectin, has no obvious effect of promoting adipocyte differentiation, and has small side effect.
Drawings
FIG. 1 is the HSQC spectrum (acetone-d 6,600 MHz) of isopentenyl phenolic compound I obtained in example 1.
FIG. 2 is a HMBC spectrum (acetone-d 6,600 MHz) of the isopentenyl phenol compound I obtained in example 1.
FIG. 3 is an ECD spectrum (JASCO Corp., J-810. Solvent used: chromatographic grade acetonitrile; test concentration: 0.02 mg/mL) of the isopentenyl phenolic compound I obtained in example 1.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE 1 preparation of Isopentenylphenol Compound I
1. Extracting by heating and reflux extracting dried coarse powder of ramulus Mori (Morus nigra L.) with 90% ethanol, wherein the amount of 90% ethanol is 8 (v/m, L/kg) times of the amount of the medicinal materials, and extracting twice for 1 hr each time. Filtering the extractive solutions, mixing, and concentrating to obtain extract.
2. Column chromatography, namely suspending the extract with 10 times of water, carrying out AB-8 macroporous resin column chromatography, eluting with water, 40% ethanol and 95% ethanol respectively, wherein the dosage of each eluent is 5 times of column volume. Concentrating and drying eluent obtained by eluting with 95% ethanol, performing silica gel column chromatography, performing gradient elution with petroleum ether and ethyl acetate (10:1, 7:1,5:1,2:1,1:1, 2:3) mixed solution, wherein the amount of the mixed solvent used in each gradient is 3 times of column volume, identifying by a silica gel thin layer plate, and combining with the same Rf value to obtain 23 components.
Collecting the 10 th component (namely eluent collected when the using amount of the eluent is 10 times of column volume, namely eluent collected when the using amount of the mixed solvent (petroleum ether: ethyl acetate=2:1) is 1 times of column volume), detecting by silica gel thin layer chromatography, wherein when the developing agent is dichloromethane, the methanol=12:1, the Rf value=0.40; concentrating under reduced pressure, subjecting to gel column (Sephadex LH-20, GE HEALTHCARE Bio-Sciences AB, uppsala, sweden) chromatography, eluting with dichloromethane: methanol at 1:1, sequentially collecting with 15mL test tube, identifying with silica gel thin layer plate, combining with Rf value to obtain 7 components, and collecting 6 th component (silica gel thin layer chromatography detection, developing solvent is dichloromethane: methanol=12:1, rf value is 0.40); concentrating and drying, subjecting to reverse phase silicse:Sup>A gel ODS-C18 (ODS-A-HG, YMC Co., td., japan) chromatography, respectively eluting with methanol and water (40:60, 50:50, 60:40, 70:30, 80:20, 90:10) in se:Sup>A gradient, collecting each component sequentially with the amount of mixed solvent of 2 times of column volume, identifying by silicse:Sup>A gel thin layer plate, combining with Rf value to obtain 15 components, collecting the 9 th component (i.e. eluent collected when the amount of mixed solvent (methanol: water=80:20) is 10 times of column volume), detecting by silicse:Sup>A gel thin layer chromatography, and concentrating and drying to obtain crude product of isopentenyl phenolic compound I when Rf=0.40 when the amount of developing solvent is dichloromethane: methanol=12:1.
HPLC preparation, namely, preparing and purifying the crude product of the isopentenyl phenolic compound I by HPLC to obtain the isopentenyl phenolic compound I: (5 ar,10 as) -1,3,8,10 a-tetrahydroxy-4- (2-hydroxy-3-methyl-3-buten-1-yl) -5a- (3-methyl-2-buten-1-yl) -5a,10 a-dihydro-11H-benzofuran [3,2-b ] chroman-11-one with a retention time of 23.7min.
The chromatographic conditions for HPLC were as follows:
chromatographic column model: AGILENT ECLIPSE XDB-C 18, (250X 10mm,5 μm),
Sample injection amount: 200. Mu.L of the gel was used,
Column temperature: at room temperature, the temperature of the mixture is higher,
Stationary phase: a C18-bonded silica gel, wherein,
Mobile phase and volume ratio: acetonitrile in water=63:37,
Detection wavelength: at a wavelength of 210nm,
Flow rate: 3mL/min of the total weight of the product,
Preparing a liquid phase: LC 3050N-type high performance liquid chromatograph.
EXAMPLE 2 structural identification of Isopentenylphenol Compound I
Compound I, yellow oily (methanol); (c 1.06, meoh); the HR-ESI-MS m/z 453.1557[ M-H ] – (calculated 453.1549,C25H25O8);UV(MeOH)λmax(logε)309(2.96);CD(MeOH)λmax(Δε)217(+7.45),238(-1.26),250(+1.53),274(-1.61),293(+2.37),331(+1.34)nm;IR(KBr)νmax(cm-1):3359,2927,1635,1649,1343,1262,1199,1148,1096;1H-NMR(600MHz,(CD3)2CO) and 13C-NMR(150MHz,(CD3)2 CO) data are shown in Table 1.
The molecular formula of the compound is deduced to be C 25H26O8 and the unsaturation degree is deduced to be 13 through an excimer ion peak [ M-H ] – and M/z 453.1557 given by HRESIMS spectrum; the IR spectrum shows the presence of absorption at 3359,2927,1635,1459,1148cm -1, indicating the presence of benzene rings, carbonyl groups and double bonds in the compound; the UV spectrum has maximum ultraviolet absorption at 309nm, suggesting that the compound is Morgandone type flavone.
1 H-NMR spectrum gives signals of a characteristic C-5 hydrogen bond hydroxyl signal delta H 11.70.70 (1H, br s, OH-5) of the flavonoid component; a set of ABX system aromatic proton signals δ H 7.35.35 (1 h, d, j=8.0 hz, h-6 '), 6.50 (1 h, dd, j=8.0, 2.0hz, h-5 ') and 6.37 (1 h, d, j=2.0 hz, h-3 '); a unimodal aromatic proton signal δ H 5.92.92 (1 h, s, h-6); a set of 3-methyl-2-butenyl signals δH5.35(1H,br t,J＝6.4Hz,H-10),3.10(1H,br dd,J＝14.4,8.0Hz,H-9a),2.76(1H,br dd,J＝14.4,7.6Hz,H-9b),1.60(3H,br s,H-13) and 1.59 (3H, br s, H-12); a set of 2-hydroxy-3-methyl-3-butenyl signals δH 4.84(1H,br s,H-17a),4.64(1H,br s,H-17b),4.30(1H,br dd,J＝7.6,3.6Hz,H-15),2.90(1H,br dd,J＝14.4,3.6Hz,H-14a),2.80(1H,br dd,J＝14.4,7.6Hz,H-14b) and 1.64 (3H, br s, H-18).
13 C-NMR spectra showed 25 carbon signals, including 15 flavone backbone carbon signals, with delta C 91.5.5 (C-2) and delta C 102.8 (C-3) further confirming that the compound is a sanggenon flavonoid component; 5 carbon signals for 3-methyl-2-butenyl, delta C136.5(C-11),δC 118.6(C-10),δC 32.1(C-9),δC 25.9.9 (C-12) and 18.1 (C-13), and 5 carbon signals for 3-hydroxy-2-methylbutenyl, delta C 148.3(C-16),δC 110.3(C-17),δC 76.1(C-15),δC 29.3 (C-14) and 18.2 (C-18).
The HSQC spectrum was used to determine the carbon signal of the attached hydrogen (FIG. 1). In the HMBC spectra (FIG. 2), H 2 -9a is associated with C-2, C-10 and C-11, H-9a is associated with C-3, and it is determined that 3-methyl-2-butenyl is attached at the C-2 position; h 2 -17 is associated with C-15, C-16 and C-18, H 2 -14 is associated with C-15 and C-16, the manner of attachment of the 2-hydroxy-3-methyl-3-butenyl group is confirmed, H 2 -14 is associated with C-8, C-8a and C-7, and it is determined that the group is attached at the C-8 position. Further, the chemical shift attribution of all carbon and hydrogen atoms is determined by the correlation of H-6 with C-7 and C-5, the correlation of H-6' with C-2' and C-4' and the correlation of H-3' with C-1' in the HMBC spectrum. The planar structure of the compound is determined.
In the ECD spectra of the compounds (FIG. 3), positive Cotton effect was exhibited at 217, 250, 293, 333nm, and negative Cotton effect was exhibited at 238 and 276 nm. According to the circular dichroism of the sanggenon flavone, and through literature comparison (Hu X,Wu J W,Zhang X D,et al.Isoprenylated flavonoids and adipogenesis-promoting constituents from Morus nigra[J].Journal of Natural Products,2011,74(4):816-824;Shi Y Q,Fukai T,Ochiai M.Absolute structures of 3-hydroxy-2-prenylflavanones with an ether linkage between the 2′-and 3-positions from moraceous plants[J].Heterocycles,2001,55(1):13-20),, the absolute configuration of the C-2 position and the C-3 position of the compound is respectively 2R,3S. Thus, compound I was identified as (5 ar,10 as) -1,3,8,10 a-tetrahydroxy-4- (2-hydroxy-3-methyl-3-buten-1-yl) -5a- (3-methyl-2-buten-1-yl) -5a,10 a-dihydro-11H-benzofuran [3,2-b ] chroman-11-one.
TABLE 1 Hydrogen and carbon Spectrum data for Compound I
EXAMPLE 3 insulin sensitization Studies of Isopentenylphenol Compound I
3.1 Instruments
The enzyme label instrument is BioTek and EPOCH; CO 2 incubator (Thermo 3111), microscope (Olympic CX 23), ultra clean bench (Su Xin YJ-840/YJ-1340), pipettor (Eppendorf).
3.2 Materials
3T3-L1 cells, which are mouse preadipocytes and are derived from a cell bank of the department of Chinese sciences; DMEM (Gibco, C11995500 CP); inducing culture solution of fetal bovine serum (Gibco,2110875CP);Antibiotic-Antimycotic(Lifetechnologies,15240-112);PBS,pH7.4(Gibco,10010-500BT);Trypsin-EDTA(0.25％)(Gibco,25200-056);IBMX(Sigma,I7018);Dexamethasone(Sigma,D4902);Insulin(Lifetechnologies,12585-014); is 1X conventional culture solution; 0.5mM IBMX;1 mu M Dexamethasone;2 μg/mL Insulin; preserving at 4 ℃ for standby. Dexamethasone stock.25 mg of DEX were dissolved in 1mL of absolute ethanol (M.W = 392.46 g/mol) and stored at 4℃for further use as 64. Mu.M stock solution. IBMX stock 110mg IBMX was dissolved in 1mL DMSO (M.W =222.2 g/mol) and stored at-20 ℃ after packaging for later use. Mouse Adiponectin ELISA Kit Biyun, PA002. Cell culture dish, coning 430167; cell culture flask Corning 430639; cell culture plates Costar,3596, 3599; glucose test box is built in Nanjing, F006-1-1.
SGF(Sanggenol F，) For laboratory homemade, the preparation method refers to literature Xu Liangjin. Research on chemical components and biological activities of two ethnic medicinal plants [ D ]. Shanghai: china medical industry research institute, 2018.
3.3 Experimental procedure
3.3.1 Cell culture
Mouse preadipocytes 3T3-L1 were routinely cultured in DMEM medium (containing 1X antibiotics) with 10% FBS.
3.3.2 Induction of differentiation
Day0, conventional culture medium was changed to induction medium (containing DEME, 0.5mM IBMX, 1. Mu.M dexamethasone, 2. Mu.g/mL insulin and 10% FBS), and cultured for 48h;
day 2. The cells were collected and the induction culture medium was changed to insulin-containing medium (DMEM containing 10. Mu.g/mL insulin and 10% FBS) and cultured for 48 hours;
day4, DMEM medium containing 10% FBS was changed once every 48 hours.
Day8-10 more than 90% of the cells can mature within 8-10 days.
3.3.3 Preliminary cytotoxicity investigation of Compounds
Mice 3T3-L1 cells, which were induced to differentiate and mature, were counted and inoculated onto 96-well plates at 10000 cells/100. Mu.l/well, and 90. Mu.l of culture medium (serum-containing) was added to each well for overnight culture, followed by 10. Mu.l of compound solution. After 48h of incubation, 100 μl of CTG was added to each well, and the mixture was allowed to stand at room temperature for 10min, and the chemiluminescent values of each well were measured on a microplate reader, thereby calculating the cell viability at the corresponding concentrations of each compound.
3.3.4 Construction of insulin resistant adipocytes and Experimental groupings
The induced differentiation maturation of the 3T3-L1 adipocytes of mice were randomly divided into a Control group (Control), an insulin resistance group (Model) and a drug treatment group, the Control group was cultured in 10% FBS-containing high glucose DMEM medium (1% antibiotics), the Model group was cultured in 1. Mu.M dexamethasone-containing high glucose DMEM medium (10% FBS and 1% antibiotics), the culture was continued for 96 hours, the drug treatment group was further added with each of the different concentrations of the drugs on the basis of the Model treatment, and the culture was continued for 48 hours, and all the above groups were further divided into insulin-free treatment and insulin-1 nmol/L-added insulin treatment. Glucose and adiponectin levels were measured after 48 hours. Using rosiglitazone as a positive control drug, and detecting the glucose content in the supernatant by adopting a glucose oxidase-peroxidase method (GOD-POD) according to the instruction of a kit; ELISA method to determine the adiponectin content in the cells.
3.3.5 Statistical analysis:
The GRAPHPAD PRISM 5.0.0 software was chosen for statistical analysis and the results were expressed as mean ± standard deviation (x±s), the comparison of the mean between the two groups was chosen for t-test, the test level α=0.05.
3.3.6 Activity results
Compound I was not significantly toxic to cells at 30 μm and cell viability was approximately 85%, so both concentrations of 30 μm and 10 μm were chosen for investigation. As shown in tables 2 and 3, when the 3T3-L1 adipocytes develop insulin resistance, the glucose content in the model group cell fluid is significantly increased, regardless of the basal state or the insulin stimulated state; the adiponectin content is obviously reduced. The positive medicine rosiglitazone can obviously promote the uptake of insulin resistance model cells to glucose and promote the secretion of adiponectin at the concentration of 1.0 and 10.0 mu M. The compound I can obviously reduce the content of glucose in the cell fluid at the concentration of 10.0 and 30.0 mu M; at high concentration (30 mu M), the content of adiponectin in the cell fluid is obviously improved, which is superior to SGF.
Table 2. Effect of compounds on glucose uptake in insulin resistant 3T3-L1 adipocytes (n=3,)
Rosiglitazone was used as a positive control. The ratio of # to the control group, P < 0.01; * P < 0.05 compared with insulin resistant group; * P < 0.01 compared to insulin resistant group
Table 3. Effect of compound I on adiponectin content in insulin resistant adipocytes (n=3,)
The ratio of # to the control group is less than 0.01; * P < 0.05 compared with insulin resistant group; * P < 0.01 compared to insulin resistant group.
EXAMPLE 4 examination of the adipogenic differentiation of Isopentenyl phenolic Compound I
4.1 Instruments
Inverted phase contrast microscope Olympus
Other conventional instruments such as a CO 2 incubator, an ultra-clean bench, a centrifuge, an Eppendorf pipettor and the like.
4.2 Materials and reagents
3T3-L1, mouse preadipocytes, derived from a cell bank of the national academy of sciences; conventional culture solution, DMEM;10% fbs (Lifetechnologies, 10099); 1X Antibiotic-Antimycotic; preserving at 4 ℃ for standby.
Induction culture solution, 1X conventional culture solution; 0.5mM IBMX;1uM Dexamethasone;2ug/mL instrument; preserving at 4 ℃ for standby.
Dexamethasone stock.25 mg of DEX are dissolved in 1mL of absolute ethanol (M.W = 392.46 g/mol) and stored at 64uM stock solution,4 ℃for further use.
IBMX stock 110mg IBMX was dissolved in 1mL DMSO (M.W =222.2 g/mol) and stored at-20 ℃ after packaging for later use.
5G of oil red O dye stock solution is dissolved in 100mL of isopropanol, heated and dissolved for 30min at 60 ℃ in a dark place, and filtered by filter paper, thus obtaining 5g/L of oil red O dye solution.
And (3) when the oil red O stain working solution is used, uniformly mixing the oil red O stain storage solution and distilled water according to the ratio of 6:4 (V/V), covering and standing for 30min, carefully sucking the supernatant, and filtering qualitative filter paper again.
Other :DMEM(Lifetechnologies,31966);FBS(Lifetechnologies,10099);Antibiotic-Antimycotic(Lifetechnologies,15240-112);IBMX(Sigma,I7018);Dexamethasone(Sigma,D4902);Insulin(Lifetechnologies,12585-014);PBS,pH7.4(Lifetechnologies,10010-049); oil red O (Sigma, O9755); 4% paraformaldehyde fixed liquid (Boster, AR 1068)
4.3 Experimental procedures
4.3.1 3T3-L1 preadipocyte differentiation
4.3.1.1 Cell culture mouse preadipocytes 3T3-L1 were routinely cultured in DMEM medium (containing 1X antibiotics) containing 10% FBS.
4.3.1.2 Induced differentiation after 3T3-L1 is cultured until fusion, induction is performed according to the following induced differentiation scheme, and the specific process is as follows:
4.3.1.2.1Day0, the conventional culture solution is changed into an induction culture solution, and the culture is carried out for 48 hours;
4.3.1.2.2Day2, collecting cells, changing the induction culture solution into insulin-containing culture solution, and culturing for 48h;
4.3.1.2.3 Day4A DMEM medium containing 10% FBS was changed once every 48 hours.
Adding compound with different concentrations and positive control rosiglitazone during induction, and inducing to day 7 for oil red blood cell staining and lipid droplet aggregation
4.3.2 Oil red O fat staining:
4.3.2.1 a part of culture solution in the culture dish is discarded, and PBS is used for washing 3 times;
4.3.2.2 fixing with 4% paraformaldehyde for 20min, and washing with PBS 3 times;
Incubating 4.3.2.3 the fixed cells with an oil red O diluent at room temperature for 1h, rinsing the cells with distilled water for 3 times, and observing and photographing by a microscope;
Part 4.3.2.4 is dissolved by isopropanol and then detected by an enzyme-labeled instrument to have OD490nm;
4.4 experimental results As shown in Table 4, compound I showed no significant adipocyte differentiation at a concentration of 10. Mu.M, and an adipocyte differentiation promoting rate of 3.72% at a concentration of 30. Mu.M, which was far weaker than SGF and rosiglitazone (1. Mu.M).
TABLE 4 promotion of adipocyte differentiation by Compound I
EXAMPLE 5 PPARgamma affinity assay of Isopentenylphenol Compound I
5.1 Laboratory apparatus
PERKINELMER EPOCH enzyme-labeled instrument, pipettor (Eppendorf), liquid handling system: echo 555 (Labcyte), etc
5.2 Experimental materials
LANTHASCREEN TM TR-FRET PPARgamma competitive binding assay kit (Invitrogen-PV 4894); DTT (Invitrogen-P2325)
5.3 Experimental procedures
Experiments were performed according to LANTHASCREEN TM TR-FRET PPARgamma competitive binding assay kit instructions.
① 200NL of compound and control GW1929 were transferred to the Echo plate using Echo, while 200nL of DMSO was transferred as a High Control (HC) and 200nL of GW1929 at 1000nM was transferred as a low control. Centrifuge for 1min, add 20. Mu.L buffer and centrifuge for 1min.
② To each well was added 10. Mu.L of 4 XPPARgamma-LBD/Tb-anti-GST Ab (containing 0.6nM PPARgamma-LBD, 0.21nM Tb-anti-GST Ab, and incubated in dark at 4℃for 60 min), centrifuged for 1min and incubated at room temperature for 30min.
③ Mu.L of 4 XFluormene TM Pan-PPAR GREEN was added, centrifuged for 1min and incubated for 1h at room temperature.
The TR-FRET signal was detected using an EnVision plate reader, the fluorescence intensity in each well was detected (donor fluorescence 495nm, acceptor fluorescence 520 nm), and the TR-FRET ratio was calculated (Value, 520nm fluorescence/495 nm fluorescence). Inhibition rates for compounds at different concentrations were obtained according to the following formula and IC 50 values were calculated using GRAPHPAD PRISM 5.0.0 software to plot a dose response curve.
Inhibition (%) = [1- (Value Compounds of formula (I) -Value Low control )/(Value High control -Value Low control ) ]
The binding constant K i value was calculated as follows:
Wherein [ tracer ] is the donor concentration corresponding to the maximum TR-FRET value in the detection reaction, which is set to 3nM in this experiment, kd is the binding constant of donor fluorescence, and Kd value in this experiment is 2.8+ -0.8 nM; IC 50 is the concentration of the test compound corresponding to half the maximum TR-FRET value.
5.4 Experimental results
As shown in Table 5, compound I showed a good affinity for PPARgamma receptor with an IC 50 value of 5.10. Mu.M and a binding constant (K i) of 2.46. Mu.M; the positive control rosiglitazone had an IC 50 value and Ki of 104.8nM and 50.6nM, respectively; the pparγ receptor affinity of compound I was better than that of SGF (IC 50 values and Ki were 18.39 μm and 8.87 μm, respectively).
Table 5. Affinity test of compounds for pparγ receptor (n=3)
Note that: ki=ic 50/(1+ [ tracer ]/Kd), [ tracer ] =3nm, kd=2.8 nm
EXAMPLE 6 PPARgamma agonistic Activity of Isopentenylphenol Compound I
6.1 Laboratory apparatus
PERKINELMER EPOCH enzyme-labeled instrument, pipettor (Eppendorf), liquid handling system: echo 555 (Labcyte), etc.
6.2 Experimental materials
HEK293 cells (AMERICAN TYPE Culture Collection, manassas, USA), plasmid vector pcDNA3.1, transfection reagent (Invitrogen); luciferase reporter plasmids, GAL4 DNA binding region (Gal 4 DB) expression plasmids, and the like.
6.3 Experimental procedure
Pparγ agonistic activity was evaluated using a double luciferase assay with HEK293 cells as test cells and rosiglitazone as positive control. HEK293 cells were first incubated at 37℃for 24 hours with 5% CO2/air, then 50ng of a mixture of pBIND-PPARgamma and pG5Luc were transfected into the cells by FuGENE HP transfection reagent, after 24 hours incubation, samples of different concentrations were added to each well, after 8 hours, the firefly signal and renilla signal from each well were read with a multifunctional microplate reader. Pparγ agonistic activity is expressed as the ratio of the luminous intensity of the sample system to the luminous intensity of the blank, and luminous intensity is expressed as the ratio of firefly signal intensity to renilla signal.
6.4 Experimental results: as shown by the results in Table 6, compounds I and SGF have no significant agonistic activity at 1. Mu.M and some PPARgamma agonistic activity at 10. Mu.M, but the percentages of rosiglitazone compared to the full agonist are 8.52% and 7.34%, respectively, suggesting that compounds I and SGF are partial agonists as well.
Table 6. Compounds PPARgamma agonistic Activity (n=3)
Note that: * p <0.05vs. dmso, n=3, corresponding to rosiglitazone percentage (%) = (fold Sample of -fold DMSO)/(fold Rosiglitazone -fold DMSO) ×100%
In conclusion, the isopentenyl phenolic compound I has obvious insulin sensitization activity and no obvious adipogenic differentiation effect, and is superior to the activity of the similar compound Sanggenol F in terms of activity and side effect. And at the concentration of 30 mu M, the insulin sensitization activity is equivalent to that of the positive drug rosiglitazone 1 mu M, but the side effect is obviously lower than that of the rosiglitazone, which indicates that the compound has potential development value.
Claims (10)
1. An isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof,
2. The isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the isopentenyl phenolic compound I is:
3. The isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the holding time of the isopentenyl phenolic compound I under any one of the following HPLC conditions is 23.7min:
HPLC condition 1: chromatographic column model: AGILENT ECLIPSE XDB-C 18, parameters of 250X 10mm,5 μm; mobile phase and volume ratio: acetonitrile water=63:37; sample injection amount: 200. Mu.L; column temperature: room temperature; detection wavelength: 210nm; flow rate: 3mL/min;
HPLC condition 2: chromatographic column model: AGILENT ECLIPSE XDB-C 18, parameters of 250X 10mm,5 μm; mobile phase and volume ratio: acetonitrile water=63:37; sample injection amount: 200. Mu.L; column temperature: room temperature; detection wavelength: 210nm; flow rate: 3mL/min; preparing a liquid phase: LC 3050N-type high performance liquid chromatograph.
4. A process for the preparation of the isopentenyl phenolic compound I according to any one of claims 1 to 3, characterized in that it comprises the following steps:
① Suspending the black mulberry stem and branch ethanol extract with water, performing AB-8 macroporous resin column chromatography, eluting with water, 40% ethanol and 95% ethanol respectively, concentrating and drying the eluate obtained by eluting with 95% ethanol to obtain mixture 1;
② Subjecting the mixture 1 to silica gel column chromatography, performing gradient elution by using a mixed solution of petroleum ether and ethyl acetate, sequentially performing volume ratio of petroleum ether to ethyl acetate of 10:1,7:1,5:1,2:1,1:1 and 2:3, collecting eluent with volume ratio of dichloromethane to methanol of 12:1 and Rf value of 0.40, and concentrating and drying to obtain a mixture 2;
③ Performing gel column chromatography on the mixture 2, eluting with dichloromethane and methanol in a volume ratio of 1:1, collecting eluent with a volume ratio of dichloromethane to methanol of 12:1 and an Rf value of 0.40, and concentrating and drying to obtain a mixture 3;
④ Subjecting the mixture 3 to reverse phase silica gel column chromatography, gradient eluting with methanol and water, wherein the volume ratio of methanol to water is 40:60, 50:50, 60:40, 70:30, 80:20 and 90:10 in sequence, collecting eluate detected by silica gel thin layer chromatography, and concentrating eluent with Rf value of 0.40 when the volume ratio of dichloromethane to methanol is 12:1 to obtain crude product of the isopentenyl phenolic compound I;
⑤ Purifying the crude product of the isopentenyl phenolic compound I by HPLC, wherein the stationary phase of an HPLC chromatographic column is C18 bonded silica gel, and the mobile phase is a mixed solution of acetonitrile and water; the volume ratio of acetonitrile to water is 63:37.
5. The method of claim 4, wherein the method of preparation satisfies one or more of the following conditions:
(1) Extracting the black mulberry stem and branch coarse powder with ethanol, filtering and concentrating the extracting solution to obtain the black mulberry stem and branch ethanol extract;
(2) In step ①, when the black mulberry twig ethanol extract is suspended by water, the weight ratio of the black mulberry twig ethanol extract to the water is 1:5-15;
(3) In the step ①, the dosage of the water, the 40% ethanol and the 95% ethanol is 5 times of the column volume when the AB-8 macroporous resin column chromatography is carried out;
(4) In the step ②, the gradient dosage of the petroleum ether and ethyl acetate mixed solution is 3 times of the column volume;
(5) In the step ③, the filler of the gel column is hydroxypropyl sephadex LH-20;
(6) In the step ④, the packing material of the reverse phase silica gel column chromatography is ODS-C18;
(7) In step ④, when methanol and water are used for gradient elution, the amount of the mixed solvent used for each gradient is 3 times of the column volume;
(8) In the step ⑤, the filler granularity of the HPLC chromatographic column is 5-10 μm;
(9) In the step ⑤, the length of the chromatographic column of the HPLC is 100-250 mm;
(10) In the step ⑤, the inner diameter of the chromatographic column of the HPLC is 9.4-30 mm;
(11) In the step ⑤, the column temperature of the HPLC chromatographic column is 20-50 ℃;
(12) In the step ⑤, the detection wavelength of the HPLC is 200-400 nm;
(13) In the step ⑤, the flow rate of the mobile phase of the HPLC is 1-15 mL/min;
(14) In step ⑤, the sample injection volume of the HPLC is 10-1000 mu L.
6. The method of claim 5, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the process of extracting the black mulberry stem and branch coarse powder with ethanol, the ethanol is 90 percent ethanol;
(2) In the process of extracting the black mulberry stem and branch coarse powder by ethanol, the extraction temperature is 80 ℃;
(3) In the process of extracting the black mulberry stem and branch coarse powder by ethanol, the volume-mass ratio of the ethanol to the black mulberry stem and branch coarse powder is 8L/kg;
(4) In the process of extracting the black mulberry stem and branch coarse powder by ethanol, the extraction times are 2 times;
(5) In the process of extracting the black mulberry stem and branch coarse powder by ethanol, the extraction time is 1 hour;
(6) In step ①, when the black mulberry twig ethanol extract is suspended with water, the weight ratio of the black mulberry twig ethanol extract to the water is 1:10;
(7) In the step ④, the packing material of the reverse phase silicse:Sup>A gel column chromatography is ODS-A-HG;
(8) In step ⑤, the HPLC column is AGILENT ECLIPSE XDB-C18, 250X 10mm,5 μm;
(9) In step ⑤, the column temperature of the HPLC column is room temperature;
(10) In step ⑤, the detection wavelength of the HPLC is 210nm;
(11) In step ⑤, the flow rate of the mobile phase of the HPLC is 3mL/min;
(12) In step ⑤, the sample volume of the HPLC is 200. Mu.L.
7. A pharmaceutical composition, comprising:
(1) An isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, and
(2) At least one pharmaceutical excipient.
8. Use of an isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 for the preparation of an insulin sensitizer or pparγ partial agonist.
9. Use of an isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the prevention or treatment of insulin resistance or metabolic diseases caused by it.
10. Use of an isopentenyl phenolic compound I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the prevention or treatment of type 2 diabetes, obesity, hypertension, hyperlipidemia, atherosclerosis or tumors.
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