CN110467624B - Adduct formed by combining flavane and stilbenes compound - Google Patents
Adduct formed by combining flavane and stilbenes compound Download PDFInfo
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- CN110467624B CN110467624B CN201810445439.3A CN201810445439A CN110467624B CN 110467624 B CN110467624 B CN 110467624B CN 201810445439 A CN201810445439 A CN 201810445439A CN 110467624 B CN110467624 B CN 110467624B
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- flavane
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- reaction
- furan
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- -1 stilbenes compound Chemical class 0.000 title abstract description 24
- 235000021286 stilbenes Nutrition 0.000 title abstract description 13
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 29
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 abstract description 28
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- Food Science & Technology (AREA)
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Abstract
本发明公开了一类黄烷与二苯乙烯类化合物通过环戊烷[c]呋喃骈合而成的加合物及其制备方法与抗糖尿病活性。本发明的化合物具有通式(Ⅰ)所示的结构，其制备方法包括以下步骤：(1)合成4位连接硫代基团的黄烷衍生物；(2)合成黄烷4位与二苯乙烯2位连接的中间体；(3)合成一类黄烷与二苯乙烯类化合物通过环戊烷[c]呋喃骈合而成的加合物。本发明的化合物制备方法简单并且具有显著的抗糖尿病作用。 The present invention discloses a kind of adduct of flavan and stilbene compound through cyclopentane[c]furan, a preparation method and antidiabetic activity thereof. The compound of the present invention has the structure represented by the general formula (I), and its preparation method comprises the following steps: (1) synthesizing a flavan derivative with a thio group at the 4-position; (2) synthesizing the 4-position of flavan and diphenyl An intermediate connected at the 2-position of ethylene; (3) Synthesis of a class of adducts of flavans and stilbene compounds through cyclopentane[c]furan. The compound of the present invention has a simple preparation method and has a remarkable antidiabetic effect. 
Description
Technical Field
The invention relates to a structure modification method of a natural product and anti-diabetic activity in the field of medicines.
Background
Alpha-glucosidase is widely distributed in organisms and plays a very important role in the metabolic processes of the organisms. The alpha-glucosidase participates in biosynthesis and catabolism of glycolipid and glycoprotein in vivo, carbohydrate in food is decomposed into oligosaccharide alpha-glucose and fructose under the action of saliva and pancreatic amylase, and then the oligosaccharide alpha-glucose and fructose are decomposed into monosaccharide at the brush border of mucous cell of small intestine by the glycosidase and absorbed into blood circulation by epithelial cell of upper section of small intestine. The alpha-glucosidase inhibitor can reduce the activity of the alpha-glucosidase in vivo, thereby effectively controlling the absorption of monosaccharide by organisms and reducing the blood sugar level.
Protein tyrosine phosphatase 1B (PTP1B), one of the major members of the Protein tyrosine phosphatase family, plays an important negative regulatory role in the insulin signal transduction pathway. Research proves that the PTP1B inhibitor applied in insulin-sensitive cells can increase the phosphorylation levels of insulin receptors and substrates thereof, and the PTP1B inhibitor plays the roles of insulin analogues and insulin sensitizers. By knocking out PTP1B gene or using antisense nucleotide (ASO) to inhibit the expression of PTP1B protein and mRNA in vivo, not only can the sensitivity of the tested mouse to insulin be obviously improved, but also the probability of patients with obesity can be obviously reduced. PTP1B is a novel target for the treatment of insulin resistance and related metabolic diseases.
The polyflavanostilbene A is separated from a traditional Chinese medicine giant knotweed rhizome in the early stage of the subject group, and is a compound with a novel framework structure. The structural feature is that the ring A is rearranged into ECG of alpha, beta-unsaturated cyclohexanone, which is processed by cyclohexane [ c ]]Polymers of furan ring fragments with polydatin. The connection mode between the polydatin and ECG is discovered for the first time, and in order to clarify the formation mechanism, the synthesis route is researched, wherein a polymer with 4-position flavan connected with 2-position polydatin is an important intermediate for forming polyflavanos-tilbene A, and the polymer is probably obtained by nucleophilic substitution reaction of 4-position flavan derivative and polydatin. Meanwhile, in vitro pharmacological experiments show that the polyflavanostilbene A has stronger inhibition effect on alpha-glucosidase and IC thereof5017.7. mu.M. The inhibition rate of the gene recombinant human PTP1B (protein tyrosine phosphatase 1B) is 95.3 percent, and IC is50At 5.05. mu.M.
Disclosure of Invention
The present invention aims at providing one kind of adduct of flavane and stilbenes through combining cyclopentane [ c ] furan.
Another object of the present invention is to provide a process for the preparation of such compounds.
Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of an adduct of a flavane and a stilbene compound by the synthesis of cyclopentane [ c ] furan and a pharmaceutically acceptable carrier and/or excipient.
The invention also aims to provide the application of the adduct formed by combining flavane and stilbenes compounds through cyclopentane [ c ] furan in the preparation of the medicine for treating and/or preventing diabetes.
The invention provides the following technical scheme:
the first aspect of the invention provides a dimer compound formed by combining flavane and stilbenes through cyclopentane [ c ] furan, which is characterized by having a structure shown in a general formula (I).
Wherein, (1) RAAnd RBIs 1, 2 and 3 optional substituents on a benzene ring,
the position of one substituent is:
the positions of the two substituents are as follows:
the three substituent positions are:
wherein R is1、R2、R3Each independently selected from: hydrogen, hydroxy, C1-5 alkoxy, amino, halogen;
(2) RC is selected from: hydrogen, hydroxy, or of the general formula (II) and (III)
Wherein R is 1, 2, 3 arbitrary substituents on a benzene ring,
the position of one substituent is:
the positions of the two substituents are as follows:
the three substituent positions are:
wherein R, R1, R2, R3 are each independently selected from: hydrogen, hydroxyl, C1-5 alkoxy, amino, halogen.
(3) RD is selected from: hydrogen, hydroxy, C1-5 alkoxy.
Most preferred compounds are selected from:
the second aspect of the invention provides a synthetic method of dimer compounds formed by combining flavane and stilbenes compounds through cyclopentane [ c ] furan, and the preparation method comprises the following steps: (1) synthesizing flavane derivatives with 4-position connecting sulfo group; (2) synthesizing an intermediate with flavan 4 and stilbene 2 connected; (3) synthesizing an adduct of flavane and stilbene compounds through the synthesis of cyclopentane [ c ] furan.
The preparation method further comprises the following steps:
the method comprises the steps of taking dried rhodiola crenulata roots as a crude drug, crushing, performing reflux extraction for 3 times by using 80% ethanol, combining extract, filtering, performing reduced pressure concentration to obtain extract, performing water precipitation treatment, filtering precipitate, performing reduced pressure concentration on filtrate, performing HP-20 macroporous adsorption resin separation, performing elution by using three gradients of pure water, 50% ethanol and 95% ethanol, performing reduced pressure concentration on eluent of 50% ethanol, and performing freeze drying to obtain a rhodiola crenulata flavan polymer part (see the detailed patent in China, CN 201010587820.7). The site was dissolved in anhydrous methanol and the corresponding thionating agent, and aqueous HBr was added and reacted at 60 ℃ for 4h to give intermediate 1. Dissolving intermediate 1 in DMF, sequentially adding resveratrol (or its derivative), AgOOCCF at-10 deg.C3The reaction was stirred to give intermediate 2. Taking the intermediate 2 to dissolve in methanol and adding FeCl3·6H2And (4) obtaining a target product after the reaction of the aqueous solution of O.
In a third aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to each of the aspects of formula (I) and a pharmaceutically acceptable carrier.
The invention also relates to pharmaceutical compositions containing a compound of the invention as active ingredient together with conventional pharmaceutical excipients or auxiliaries. Generally, the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the compound of the present invention. The compound of the invention is generally present in an amount of 0.1 to 100mg in a unit dosage form, with a preferred unit dosage form containing 4 to 50 mg.
Pharmaceutical compositions of the compounds of the invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants and brought into a suitable administration form or dosage form for use as human or veterinary medicine.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intramuscular, subcutaneous, nasal, oromucosal, dermal, peritoneal or rectal administration.
The route of administration of the compounds of the invention or the pharmaceutical compositions containing them may be by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.
The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.
For example, in order to form a unit dosage form into a tablet, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For example, to form the administration units into pills, various carriers well known in the art are widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.
For example, to encapsulate the administration unit, the active ingredient of the compounds of the present invention is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. The effective component of the compound can also be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application.
For example, the compounds of the present invention may be formulated as injectable preparations, such as solutions, suspensions, emulsions, lyophilized powders, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acid ester, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations and the therapeutic purpose, and thus the therapeutic dosage of the present invention can be widely varied. Generally, the dosage of the pharmaceutical ingredients of the present invention used is well known to those skilled in the art. The prophylactic or therapeutic objectives of the present invention can be accomplished by appropriate adjustment of the actual amount of drug contained in the final formulation of the compound composition of the present invention to achieve the desired therapeutically effective amount. Suitable daily dosage ranges for the compounds of the invention: the dosage of the compound of the invention is 0.001-100 mg/Kg of body weight, preferably 0.1-60 mg/Kg of body weight, more preferably 1-30 mg/Kg of body weight, and most preferably 2-15 mg/Kg of body weight. The compound of the invention is taken by an adult patient at 10-500 mg, preferably 20-100 mg, once or 2-3 times; the dosage of the composition for children is 5-30 mg/kg body weight, preferably 10-20 mg/kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen of the therapeutic means. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.
The fourth aspect of the invention relates to the application of dimer compound formed by combining flavane and stilbenes compound through cyclopentane [ c ] furan in the medicine for preventing and/or treating diabetes.
Experiments prove that the flavane and stilbenes compound of the invention passes through cyclopentane [ c ]]The adduct synthesized by furan shows obvious antidiabetic activity on a model for evaluating the curative effect of the antidiabetic medicament and an alpha-glucosidase inhibition activity model, and IC thereof50The value was lower than the positive control drug acarbose.
1. The compound of the invention has novel structure, is not reported in documents, and has the potential of further developing a new medicament for reducing blood sugar.
2. The compound of the invention has better reductionThe compounds have better pharmacological activity in the aspect of inhibiting activity of the sugar on alpha-glucosidase and IC of the compounds50All below 10 μ M, and IC of positive control drug50At 500. mu.M.
At present, no report on the inhibition activity of the compounds on alpha-glucosidase is found.
3. The compound has a mature synthetic route and is simple and easy to obtain.
The flavane and stilbenes compound of the invention pass through cyclopentane [ c ]]The inhibition rate of the adduct synthesized by furan on the gene recombination human PTP1B (protein tyrosine phosphatase 1B) is 95.3 percent, and IC50Is 5.05 mu M, which indicates that the compound has better pharmacological action of promoting the sugar metabolism of the organism, and can be clinically used for reducing the blood sugar level and treating diabetes and related metabolic diseases.
Effective technical effects
1. The adduct formed by combining the flavane and the stilbenes compound through cyclopentane [ c ] furan has a novel structure, is not reported in documents, and has the potential of further developing a new antidiabetic drug.
2. The preparation method of the adduct synthesized by combining the flavane and the stilbenes compound through cyclopentane [ c ] furan has novel route and simple separation.
3. The dimer compound formed by combining the flavane and the stilbenes compound through cyclopentane [ c ] furan has better anti-diabetic activity, can obviously inhibit the activities of alpha-glucosidase and PTP1B, thereby reducing the blood sugar level in an organism by blocking the sugar absorption of the organism and promoting the sugar metabolism of the organism. The anti-diabetic activity of the compounds is not reported at present.
Detailed Description
EXAMPLE 1 Synthesis of Compound S4
Compound S4 was prepared and tested as follows:
1. obtaining of rhodiola crenulata flavane polymer part
The method comprises the steps of taking dried rhodiola crenulata roots as a crude drug, crushing, performing reflux extraction for 3 times by using 80% ethanol, combining extract, filtering, performing reduced pressure concentration to obtain extract, performing water precipitation treatment, filtering precipitate, performing reduced pressure concentration on filtrate, performing HP-20 macroporous adsorption resin separation, performing elution by using three gradients of pure water, 50% ethanol and 95% ethanol, performing reduced pressure concentration on eluent of 50% ethanol, and performing freeze drying to obtain a rhodiola crenulata flavan polymer part (see the detailed patent in China, CN 201010587820.7).
2. Synthesis of intermediate compound S1
Dissolving a certain amount of rhodiola crenulata flavane polymer part in absolute methanol according to the mass ratio of 1:30, adding a corresponding thioreagent according to the mass ratio of 1:0.5 and 48% of HBr aqueous solution (mass ratio) according to the mass ratio of 1:0.5, reacting for 4 hours at 60 ℃, adding distilled water with the mass ratio of 3:1 to the reaction liquid into the reaction liquid for suspension, extracting for 3 times by using ethyl acetate, combining organic layers, drying the organic layers by using anhydrous sodium sulfate, concentrating under reduced pressure, and sequentially carrying out reverse phase silica gel column separation to efficiently prepare a liquid phase 65% (MeOH/H) of a liquid phase2O volume ratio) gave 4- (S) - (benzylthio) -epicatechin gallate (S1) as a white powder with a yield of 41.5%.
UVλmax(MeOH)nm:278,216；mp.135.6～138.1℃；ESI-MS:(m/z 563.1[M-H]-,599.0[M+Cl]-)；1H NMR(400MHz,DMSO-d6)δH:7.45(2H,m,2″′,6″′-H),7.33(2H,m,3″′,5″′-H),7.23(1H,m,4″′-H),6.83(1H,brs,2′-H),6.78(2H,s,2″,6″-H),6.67(2H,s,5′,6′-H),5.92(1H,d,J＝2.0Hz,8-H),5.82(1H,d,J＝2.0Hz,6-H),5.43(1H,brs,3-H),5.25(1H,brs,2-H),4.07(1H,d,J＝2.0Hz,4-H),4.05(1H,dd,J＝27.0,13.0Hz,S-C-H).
3. Synthesis of intermediate compound S2
Synthesis method 1
Weighing 564mg (1mmol) of 4-benzylthio epicatechin gallate (S1) in a 100mL eggplant-shaped bottle, adding 30mL of THF, stirring to dissolve, sequentially adding 630mg (5mmol) of resveratrol and 990mg (5mmol) of silver tetrafluoroborate at-10 ℃, stirring at 10 ℃ for reaction for 10h, and monitoring the reaction by HPLC. Filtering to remove precipitate, adding 50mL distilled water into the reaction solution to terminate the reaction, extracting with ethyl acetate (30mL × 3 times), combining organic layers, drying the organic layer with anhydrous sodium sulfate column, evaporating to dryness under reduced pressure, and preparing liquid phase under high pressure (MeOH/H)2O ═ 45%), yielding 54.7mg of product in 8.2% yield.
Synthesis method 2
Weighing 564mg (1mmol) of 4-benzylthio epicatechin gallate (S1) in a 100mL eggplant-shaped bottle, adding 30mL of DMF, stirring to dissolve, sequentially adding 630mg (5mmol) of resveratrol and 990mg (5mmol) of silver tetrafluoroborate at-10 ℃, stirring at 10 ℃ for reaction for 10h, and monitoring the reaction by HPLC. Filtering to remove precipitate, adding 50mL distilled water into the reaction solution to terminate the reaction, extracting with ethyl acetate (30mL × 3 times), combining organic layers, drying the organic layer with anhydrous sodium sulfate column, evaporating to dryness under reduced pressure, and preparing liquid phase under high pressure (MeOH/H)2O ═ 45%), yielding 362.7mg, 54.3% yield.
Synthesis method 3
Weighing 564mg (1mmol) of 4-benzylthio epicatechin gallate (S1) in a 100mL eggplant-shaped bottle, adding 30mL of DMF, stirring to dissolve, and sequentially adding 630mg (5mmol) of resveratrol and AgOOCCF at-10 deg.C31100mg (5mmol), stirring at-10 ℃ for 10h and monitoring by HPLC for completion of the reaction. Filtering to remove precipitate, adding 50mL distilled water into the reaction solution to terminate the reaction, extracting with ethyl acetate (30mL × 3 times), combining organic layers, drying the organic layer with anhydrous sodium sulfate column, evaporating to dryness under reduced pressure, and preparing liquid phase under high pressure (MeOH/H)2O ═ 45%), yielding 422.2mg, 63.2% yield.
HRESIMS(m/z669.1609[M+H]+,calcd,669.1603)；1、1H NMR(500MHz,acetone-d6)δH:5.68(1H,brs,2-H),5.55(1H,brs,3-H),4.57(1H,brs,4-H),5.95(1H,d,J＝2.0Hz,6-H),6.10(1H,d,J＝2.0Hz,8-H),7.02(1H,d,J＝2.0Hz,2′-H),6.67(1H,overlap,5′-H),6.73(1H,overlap,6′-H),7.15(2H,brs,2″,6″-H),6.27(1H,d,J＝2.5Hz,4″′-H),6.73(1H,overlap,6″′-H),7.97(1H,d,J＝16.0Hz,7″′-H),6.58(1H,d,J＝16.0Hz,8″′-H),7.08(2H,d,J＝8.5Hz,10″′,14″′-H),6.72(2H,d,J＝8.5Hz,11″′,13″′-H)；13C NMR(125MHz,acetone-d6)δC:76.1(C-2),75.2(C-3),38.7(C-4),158.6(C-5),96.8(C-6),158.5(C-7),96.1(C-8),158.1(C-9),102.5(C-10),132.4(C-1′),115.5(C-2′),146.0(C-3′),146.2(C-4′),116.4(C-5′),119.7(C-6′),122.3(C-1″),110.8(C-2″,6″),146.7(C-3″,5″),139.7(C-4″),167.0(C＝O),142.5(C-1″′),117.7(C-2″′),158.7(C-3″′),104.8(C-4″′),158.4(C-5″′),107.1(C-6″′),126.7(C-7″′),131.5(C-8″′),129.5(C-9″′),129.5(C-10″′,14″′),116.7(C-11″′,13″′),158.4(C-12″′).
4. Synthesis of Compound S4
Compound S2334 mg (0.5mmol) was weighed into a 100mL eggplant-shaped bottle, and 50mL of CH was added3OH, stirring to dissolve, and dropwise adding FeCl 3.6H2O in water, [67.5mg (0.25mmol) dissolved in 10mL H2In O]After stirring the reaction for 22 hours at normal temperature, the reaction was monitored by HPLC. Evaporation to dryness under reduced pressure and preparation of the liquid phase under high pressure (MeOH/H)2O53%), yielding 124.8mg of product in 36.5% yield.
HRESIMS(m/z685.1538[M+H]+,calcd,685.1552)；1H NMR(500MHz,DMSO-d6)δH:4.89(1H,brs,2-H),5.48(1H,brs,3-H),3.82(1H,brs,4-H),2.62(1H,d,J＝15.5Hz,6a-H),2.70(1H,d,J＝15.5Hz,6b-H),5.80(1H,brs,8-H),6.52(1H,d,J＝2.0Hz,12-H),6.54(1H,d,J＝8.5Hz,15-H),6.46(1H,dd,J＝8.5,2.0Hz,16-H),6.83(2H,s,19,23-H),6.10(1H,brs,12′-H),4.74(1H,d,J＝1.5Hz,14′-H),4.44(1H,d,J＝8.0Hz,8′-H),5.28(1H,d,J＝7.5Hz,7′-H),7.08(2H,d,J＝8.5Hz,2′,6′-H),6.63(2H,d,J＝8.5Hz,3′,5′-H)；13C NMR(125MHz,DMSO-d6)δC:76.8(C-2),72.5(C-3),48.6(C-4),103.8(C-5),47.4(C-6),194.2(C-7),104.5(C-8),175.0(C-9),61.4(C-10),128.9(C-11),113.9(C-12),145.1(C-13),144.9(C-14),115.2(C-15),117.3(C-16),164.1(C-17),118.2(C-18),108.7(C-19,23),145.5(C-20,22),143.3(C-21),143.3(C-9′),105.9(C-10′),153.5(C-11′),101.4(C-12′),157.5(C-13′),103.8(C-14′),61.4(C-8′),81.8(C-7′),128.8(C-1′),127.6(C-2′,6′),114.3(C-3′,5′),156.5(C-4′).
EXAMPLE 2 Synthesis of Compound S7
1. Synthesis of intermediate compound S5
Dissolving a certain amount of rhodiola kirilowii flavan polymer part in absolute methanol according to the mass ratio of 1:30, adding a corresponding thioreagent according to the mass ratio of 1:0.5 and 48% HBr aqueous solution (mass ratio) according to the mass ratio of 1:0.5, reacting for 4 hours at 60 ℃, adding distilled water with the mass ratio of 3:1 to the reaction liquid into the reaction liquid for suspension, extracting for 3 times by using ethyl acetate, combining organic layers, drying the organic layers by using anhydrous sodium sulfate, concentrating under reduced pressure, and sequentially carrying out reverse phase silica gel column separation to efficiently prepare a liquid phase (MeOH/H)2O65%) to give 4- (S) - (benzylthio) -epigallocatechin gallate (S5) as a white powder with a yield of 44.6%.
UVλmax(MeOH)nm:278,216；mp.146.3～147.4℃；ESI-MS:(m/z579.2[M-H]-,615.0[M+Cl]-)；1H NMR(400MHz,DMSO-d6)δ:7.44(2H,m,2″′,6″′-H),7.33(2H,m,3″′,5″′-H),7.24(1H,m,4″′-H),6.78(2H,s,2″,6″-H),6.38(2H,s,2′,6′-H),5.92(1H,d,J＝2.0Hz,8-H),5.82(1H,d,J＝2.0Hz,6-H),5.36(1H,brs,3-H),5.29(1H,brs,2-H),4.05(1H,dd,J＝27.0,13.0Hz,S-C-H),4.04(1H,d,J＝2.0Hz,4-H).
2. Synthesis of intermediate compound S6
Weighing 580mg (1mmol) of 4- (S) - (benzylthio) -epigallocatechin gallate (S5) in a 100mL eggplant-shaped bottle, adding 30mL of DMF, stirring for dissolving, and sequentially adding 1140mg (5mmol) of resveratrol and AgOOCCF at-10 deg.C31100mg (5mmol), stirring at-10 ℃ for 10h and monitoring by HPLC for completion of the reaction. Filtering to remove precipitate, adding 50mL distilled water into the reaction solution to terminate the reaction, extracting with ethyl acetate (30mL × 3 times), combining organic layers, drying the organic layer with anhydrous sodium sulfate column, evaporating to dryness under reduced pressure, and preparing liquid phase under high pressure (MeOH/H)2O ═ 45%) to give the product S6 in 65.4% yield.
HRESIMS(m/z685.1553[M+H]+,calcd,685.1552)；1、1H NMR(500MHz,acetone-d6)δH:5.60(1H,brs,2-H),5.53(1H,brs,3-H),4.54(1H,brs,4-H),5.93(1H,d,J＝2.5Hz,6-H),6.08(1H,d,J＝2.0Hz,8-H),6.54(1H,brs,2′,6′-H),7.12(2H,brs,2″,6″-H),6.25(1H,d,J＝2.5Hz,4″′-H),6.71(1H,overlap,6″′-H),7.96(1H,d,J＝16.0Hz,7″′-H),6.57(1H,d,J＝16.0Hz,8″′-H),7.06(2H,d,J＝8.5Hz,10″′,14″′-H),6.71(2H,d,J＝8.5Hz,11″′,13″′-H)；13C NMR(125MHz,acetone-d6)δC:76.0(C-2),75.1(C-3),38.7(C-4),158.6(C-5),96.8(C-6),158.5(C-7),96.2(C-8),158.1(C-9),102.6(C-10),131.7(C-1′),107.2(C-2′,6′),146.9(C-3′,5′),133.6(C-4′),122.4(C-1″),110.8(C-2″,6″),146.9(C-3″,5″),139.6(C-4″),167.1(C＝O),142.5(C-1″′),117.7(C-2″′),158.3(C-3″′),104.8(C-4″′),158.2(C-5″′),107.1(C-6″′),126.7(C-7″′),131.4(C-8″′),131.3(C-9″′),129.5(C-10″′,14″′),116.7(C-11″′,13″′),158.3(C-12″′).
3. Synthesis of Compound S7
Weighing compound S5342 mg (0.5mmol) in 100mL eggplant-shaped bottle, and adding 40mLCH3And (3) stirring to dissolve OH, dropwise adding 48.5mg (0.25mmol) of silver tetrafluoroborate, stirring at normal temperature for reaction for 10 hours, and monitoring the reaction completion by HPLC. Evaporation to dryness under reduced pressure and preparation of the liquid phase under high pressure (MeOH/H)2O ═ 48%) to give the product S7 in 6.3% yield.
HRESIMS(m/z701.1484[M+H]+,calcd,701.1501)；1H NMR(500MHz,DMSO-d6)δ:7.10(2H,d,J＝9.0,10″′,14″′-H),6.85(2H,s,2″,6″-H),6.64(2H,d,J＝9.0,11″′,13″′-H),6.11(3H,s,2′,6′,6″′-H),5.70(1H,s,8-H),5.50(1H,s,3-H),5.29(1H,d,J＝8.0,8″′-H),4.81(1H,s,2-H),4.77(1H,s,4″′-H),4.44(1H,d,J＝8.0,7″′-H),3.84(1H,s,4H),2.68(2H,m,6H)；13C NMR(125MHz,DMSO-d6)δ:194.1(C-7),175.0(C-9),164.0(O-C-O-),157.5(C-5″′),156.5(C-12″′),153.5(C-3″′),145.7(C-3′,5′),145.5(C-3″,5″),143.3(C-4″,1″′),132.6(C-1′,4′),128.9(C-9″′),128.8(C-10″′,14″′),118.2(C-1″),114.2(C-11″′,13″′),108.8(C-2″,6″),105.8(C-2″′),105.1(C-2′,6′),104.5(C-8),103.7(C-5,6″′),101.4(C-4″′),81.8(C-8″′),76.8(C-2),72.5(C-3),61.5(C-10,7″′),47.5(C-4),47.4(C-6).
Experimental example 1 in vitro screening model: protein tyrosine phosphatase 1B (PTP1B) inhibitory Activity screening
Insulin exerts its biological effects through the insulin signaling system. In the insulin signaling system, many important cytokines such as IRS-1 are activated by tyrosine phosphatase acidification and then inactivated by the loss of phosphorylation by protein tyrosine phosphatase 1B (PTP 1B). Thus, inhibitors of PTP1B may potentiate the effects of body insulin by prolonging the insulin signaling pathway. At present, PTP1B has become one of the important targets of insulin sensitizers.
1 materials and methods
1.1 materials
The cell culture medium and the glutamine are products of GIBCO company; fetal Calf Serum (FCS) is a product of japan Biofluids, Inc; glutamate Dehydrogenase (GDH) was purchased from Oriental Yeast co., LTD, japan; the gene recombinant human GFAT (hGFAT, EC2.6,1.16), various viruses and cells are friendly supplied by the university of Shiga medical science of Japan. The PTP1B specific antibody is a product of BioLabs company; the RL2 polyclonal antibody is Affinity Bioreagens, Inc; the gene recombinant PTP1B is a product of Biomol Research laboratories, Inc. The protein concentration was determined using a Bio-Red protein assay reagent, UV-265W spectrophotometer (Shimadzu). Extracting DNA by using a Bio-Red DNA purification kit; the DNA concentration was determined with an Ultrospec III Analyzer (Pharmacia, LKB); the DNA was labeled with the Bea BESTTM Labeling Kit (Takapa, Japan) to prepare a probe. Other reagents were purchased from Sigma.
1.2 methods
By adopting a molecular biological method, IPTG is used for inducing the hGST-PTP1B-BL21E.Coli engineering bacteria of gene recombination to over-express human PTP1B protein, and the hGST-PTP1B protease is obtained by purifying through a GST affinity chromatography column. Protein content was determined using Bio-Rad protein assay reagents. The influence of the drug on the activity of hGST-PTP1B protease is observed by using a method of in vitro enzymology and taking the polypeptide para-Nitrophenyl phospate as a substrate.
2 results
In vitro pharmacological experiments show that the inhibition rate of the compound S4 on the gene recombinant human PTP1B (protein tyrosine phosphatase 1B) is 95.3 percent, and the IC is50At 5.05. mu.M
Experimental example 2 in vitro screening model: screening of alpha-glucosidase inhibitory Activity
The alpha-glucosidase is positioned in the brush border of the small intestine and mainly plays a role in promoting the decomposition and absorption of amylodextrin, polysaccharide, sucrose and maltose by the intestinal tract and decomposing other oligosaccharides into dextroglucose, galactose, dextrofructose and the like. The alpha-glucosidase inhibitor can inhibit the brush border alpha-glucosidase (including amylase, maltase, sucrase, isomaltase, etc.) reversibly to delay the conversion of polysaccharide and disaccharide into absorbable monosaccharide, and reduce the increase of postprandial blood sugar. In addition, the lower small intestine normally has no food components, and after the alpha-glucosidase inhibitor is taken, chyme such as carbohydrate, fat, protein and the like in the intestine can enter the far end of the ileum, and the part is the position with the most abundant storage amount of the small intestine glucagon-like peptide-1 (GLP-1), so that GLP-1 secretion can be stimulated to increase, insulin release can be stimulated, and the postprandial blood glucose concentration can be reduced.
1 method
Respectively adding 50 mu L and 80 mu L of 0.1MPBS buffer solution into the experimental group and the blank group; adding 10 μ L of each sample, 30 μ L of alpha-glucosidase, reacting in 37 deg.C constant temperature water bath for 5min, centrifuging at 90rpm, adding 20 μ L of PNPG (1mM) each, reacting in 37 deg.C constant temperature water bath for 15min, centrifuging at 90rpm, and adding 0.4M Na2CO3The reaction was stopped with 50. mu.L. The OD value was measured at 400nm with a spectrophotometer.
2 results
In vitro pharmacological experiments show that the compound S4 has strong inhibition effect on alpha-glucosidase and IC thereof5017.7. mu.M.
Claims (4)
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| CN105085461A (en) * | 2014-05-21 | 2015-11-25 | 中国医学科学院药物研究所 | Flavane compound, preparation method thereof and hypoglycemic activity |
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