CN107163009B - The miscellaneous terpene compound of ganoderma lucidum, its Pharmaceutical composition and its application - Google Patents
The miscellaneous terpene compound of ganoderma lucidum, its Pharmaceutical composition and its application Download PDFInfo
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- CN107163009B CN107163009B CN201710286626.7A CN201710286626A CN107163009B CN 107163009 B CN107163009 B CN 107163009B CN 201710286626 A CN201710286626 A CN 201710286626A CN 107163009 B CN107163009 B CN 107163009B
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- ganoderma lucidum
- pharmaceutical composition
- methanol
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 3
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- 235000001637 Ganoderma lucidum Nutrition 0.000 title description 12
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L31/00—Edible extracts or preparations of fungi; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
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Abstract
The invention discloses a kind of miscellaneous terpene compound, Pharmaceutical composition and its application.The compound has structure shown in chemical formula (I), has the activity for inhibiting aldose reductase, has very wide application prospect.
Description
Technical field
The present invention relates to miscellaneous terpenoids, and in particular to the miscellaneous terpenoid that extracts from fungi and its as aldose
The purposes of reductase inhibitor.
Background technique
Ganoderma lucidum (Ganoderma lucidum (Leyss.ex Fr.) Karst.) is under the jurisdiction of Eumycota (Eumycota), load
Daughter bacteria subphylum (Basidiomycotina), Hymenomycetes (Hymenomycetes), Aphyllophorales (Aphyllophorales), spirit
Sesame section (Gamodermataceae), Ganoderma (Ganoderma)." its property is sweet for record in " China's book on Chinese herbal medicine "；Taste is flat；It is nontoxic；Return
Lung, the heart, spleen, kidney channel.Replenishing qi and blood；Tranquilizing mind；Strengthening the spleen and stomach.Cure mainly consumptive disease, palpitaition, insomnia, dizziness, spiritlessness and weakness, chronic cough asthma,
Coronary heart disease, silicosis, tumour." ganoderma lucidum is included by Chinese medicine in " Chinese Pharmacopoeia ", ganoderma lucidum polysaccharide therein, triterpene, nucleosides, life
The ingredients such as alkaloids, amino acid polypeptide, microelement are the main foundations of its effective substance, are wherein main living with triterpene and polysaccharide
Property ingredient.Modern pharmacological studies have shown that ganoderma lucidum triterpene compounds have liver protection, antitumor, AntiHIV1 RT activity -4 and HIV-4 protease
The effects of activity, antihistaminicum discharge, inhibit angiotensins, is anti-oxidant.Recent research indicate that there is one kind in ganoderma lucidum to hydroxyl
The farnesyl of base phenol replaces the miscellaneous terpenoid of species, has preferable effect in terms for the treatment of metabolic syndrome.
Metabolic syndrome is mainly shown as that insulin resistance, central obesity improve blood pressure and blood lipid, and have become the world
The disease of property.Although having the drug such as insulin, Statins and fibrates medicine of some clinical treatment metabolic syndromes at present
Object, but due to its side effect and therapeutic efficiency it is not ideal enough etc. be still that this kind of therapeutic agent faces many problems.Aldose
Reductase (aldose reductase, AR) is present in the histoorgans such as human nerve, red blood cell, crystalline lens, retina,
The glucose being catalyzed in blood in polyalcohol access generates sorbierite, is the key that polyalcohol access rate-limiting enzyme.Work as blood sugar concentration
When maintaining normal physiologic levels, it is not activated, lower to the affinity of glucose, and glucose is seldom converted into sorb at this time
Alcohol.Under hyperglycemic state (such as diabetes), hexokinase is saturated, at this moment aldose reduction enzyme activition, promotes intracorporal grape
Sugar is converted into sorbierite.However, the vigor of sorbitol dehydrogenase (sorbitol dehydrogenase, SDH) is not correspondingly
Proportional increase, the efficiency that sorbierite is converted into fructose do not improve.Sorbierite itself since polarity not easily passs through by force cell membrane,
It will form accumulation in the cell, permeability of cell membranes made to change, and make Na in cell+-K+Atpase activity decline, makes
It is lost at inositol, leads to the damage of cell metabolism and function.Since eyes and nerve cell etc. organize containing for interior aldose reductase
Amount is higher, and the environment of hyperglycemia makes this access be easy to be opened in diabetic body, causes the pathology to these tissues
Damage, such as cataract, neuropathy, renal lesions, retinopathy, atherosclerosis diabetic complication
(diabetes control and complications, DCC).Diabetic complication seriously threatens the life of diabetic
Quality is deposited, the drug for blocking or weakening aldose reductase activity can be used to prevent or postpone the generation of diabetic complication.
Since 1970, aldose reductase inhibitor research become treatment diabetes medicament research hot spot, have some types into
Enter clinical test or list marketing, but a lot of drugs due to clinical test problem with the presence of exiting.At present for facing
The aldose reductase inhibitor that uses of bed is still seldom in we study for a long period of time, from the fructification acetic acid second of Mount Emei's red sesame
The compound with aldose reductase inhibition activity is separated in ester crude extract.These compounds are shown with positive drug according to pa
His similar activity is taken charge of, provides lead compound for aldose reduction enzyme inhibitor pharmaceutical exploitation.
Summary of the invention
The present invention isolates and purifies its extract using ganoderma lucidum as research object, miscellaneous terpenoid is obtained, to this
A little compounds have carried out Structural Identification and bioactivity research, it is found that there is these compounds good aldose reductase to inhibit to live
Property, there is potential medical value.
For this purpose, the first aspect of the present invention, provides a kind of logical formula (I) compound represented or its pharmaceutical salts
In formula (I),
R1For-H, R2For-OH, R3For-OH, R4For-OH；
Or R1And R2At ehter bond, R3And R4At double bond；
Or R1For-H, R2For-OH, R3And R4At double bond.
Preferably, the logical formula (I) compound can be for such as following formula 1-3 compound represented
Specific embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
HPLC analyzer is Agilent1200 analytic type liquid chromatograph.The condition of HPLC is as follows: with chromatography methanol by sample
Product are formulated as the solution of 10mg/ml, and applied sample amount is each 15ul, and chromatographic column is prepared by 10 × 250mm of Kromasil C18 half
Column, column temperature are 25 DEG C, and 210nm wavelength carries out HPLC preparation.
The extract of the preparation ganoderma lucidum of embodiment 1
Ganoderma lucidum fruitbody is shredded, is weighed 2500 grams.With the aqueous solution refluxing extraction of 95% ethyl alcohol of 10L volumn concentration
3 times, every time 1 hour.Combined extract, reduced pressure are dried to obtain 170 grams of extracts.
Further extract distilled water 600ml is dissolved, three times with isometric n-hexane extraction, discards organic phase.
Again three times with isometric ethyl acetate aqueous phase extracted, water phase, combined ethyl acetate extract liquor are discarded.Second is evaporated with Rotary Evaporators
Acetoacetic ester obtains medicinal extract 49g, is denoted as GS.
The preparation of 2 compound of embodiment
Ganoderma lucidum crude extract ethyl acetate layer GS by silica gel column chromatography separate, with n-hexane: ethyl acetate system (just oneself
Alkane: the volume ratio of ethyl acetate is 1:0,50:1,30:1,20:1,15:1,10:1,4:1,2:1), methylene chloride: methanol system
(methylene chloride: the volume ratio of methanol is 1:0,100:1,50:1,30:1,10:1,5:1) successively carries out gradient elution, Mei Geti
Degree 4 retention volumes of washing, one fraction of each retention volume.It is analyzed according to thin-layer chromatography chromatographic behavior, merges similar flow point,
In n-hexane: ethyl acetate (volume ratio 1:0) system obtains fraction GS-1；In n-hexane: ethyl acetate (volume ratio 100:
1~30:1) in obtain fraction GS-2~5；In n-hexane: obtaining fraction GS-6, GS-7 in ethyl acetate (volume ratio 20:1)；
In n-hexane: obtaining fraction GS-8 in ethyl acetate (volume ratio 10:1)；In methylene chloride: in methanol (volume ratio 1:0)
Obtain fraction GS-9~10；In methylene chloride: obtaining fraction GS-11~13 in methanol (volume ratio 50:1)；In methylene chloride:
Fraction GS-14 is obtained in methanol (volume ratio 20:1) in methylene chloride: fraction GS- is obtained in methanol (volume ratio 30:1)
15；In methylene chloride: obtaining fraction GS-16 in methanol (volume ratio 20:1,10:1,1:0).16 fractions are obtained, it will be each
Fraction freeze-drying.
By thin-layer chromatographic analysis it has also been found that activity substance content is higher in GS-9, therefore ODS reverse phase silicon is utilized to GS-9
Rubber column gel column separation.It is 20%, 40%, 50%, 70% with volumn concentration, the aqueous solution of 90% methanol is successively eluted, often
A eluent system washes 1500ml.According to thin-layer chromatography chromatographic behavior, irradiates 254nm ultraviolet lamp and judge different fractions, in volume hundred
Fraction GS-9-1~3 are obtained in the methanol aqueous solution that point content is 20%；The methanol aqueous solution for being 40% in volumn concentration
Fraction GS-9-4~6 are obtained in system；Fraction GS-9-7 is obtained in the methanol aqueous solution system that volumn concentration is 50%
~8；Fraction GS-9-9~10 are obtained in the methanol aqueous solution system that volumn concentration is 70%；It is in volumn concentration
Fraction GS-9-11 is obtained in 90% methanol aqueous solution system.It obtains 11 sub- fractions and is freeze-dried.
Find that activity substance content is higher in GS-9-7 by thin-layer chromatographic analysis, to GS-9-7 further progress HPLC system
It is standby.Using the sour water of 52% acetonitrile of volumn concentration, (sour water herein is the water of 0.01% trifluoroacetic acid as volumn concentration
Solution) solution is that eluant, eluent carries out HPLC preparation, flow velocity 2ml/min collects the chromatographic peak of 23min, obtains compound 1；It receives
The chromatographic peak for collecting 30min, obtains compound 2；The chromatographic peak for collecting 33min obtains compound 3.
The confirmation of 3 compound 1-3 of embodiment
Nuclear magnetic resonance, infrared, Mass Spectrometer Method are carried out to 3 compounds being prepared respectively, determine the knot of each compound
Structure.
Wherein used Nuclear Magnetic Resonance is Varian Mercury-500 and -600 megahertzs, and infrared chromatograph is
Nicolet IS5FT-IR, mass spectrograph are Bruker APEX III 7.0T and APEX II FT-ICR.
Confirmed, compound 1 is new natural products, replaces the miscellaneous terpene compound of species to contain for the farnesyl of para hydroxybenzene phenol
Skeleton I.
Compound 1 (Ganomycin J)
The structural formula of compound 1 is as follows:
11-5- of (R, 2Z, 5E)-2- (2- (2,5- dihydroxy phenyl) ethylidene)-9,10- dihydroxy-6,10- dimethyl
Olefin(e) acid
(R,2Z,5E)-2-(2-(2,5-dihydroxyphenyl)ethylidene)-9,10-dihydroxy-6,10-
dimethylundec-5-enoic acid
The carbon spectrum and hydrogen spectrum confirmation data of the NMR of compound 1 is as shown in table 1
Table 11H(500MHz)and 13C(125MHz)NMR(DMSO-d6)
Compound 2 (Ganomycin B)
The structural formula of compound 2 is as follows:
11-5,9- dienoic acid of (2Z, 5E)-2- (2- (2,5- dihydroxy phenyl) ethylidene)-6,10- dimethyl
(2Z,5E)-2-(2-(2,5-dihydroxyphenyl)ethylidene)-6,10-dimethylundeca-5,
9-dienoic acid
Compound 3 (Ganomycin I)
The structural formula of compound 3 is as follows:
(R, E) -5- (2,5- dihydroxy phenyl) -3- (nine -3,7- diene -1- base of 4,8- dimethyl) furans -2 (5H)-alkane
(R,E)-5-(2,5-dihydroxyphenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)
furan-2(5H)-one
The physicochemical property of compound 1-3 is as follows:
Compound 1
Ganomycin J (1): yellow oily liquid, [α]25 D+67.99(c 0.1,MeOH)；UV(MeOH)λmax(logε)
216(3.14),308(1.06)nm；CD(c 1.35×10-3M,MeOH)λmax(Δε)249(+2.84),350(-0.29)nm；IR
(neat)νmax 3275,2975,1749,1638,1456,1202,789cm-1；Positive ion mode HRTOFMS m/z [M+H]+
379.2117 (calculated value C21H31O6,379.2121)。
Compound 2
Ganomycin B (2): yellow oily liquid；UV(MeOH)λmax(logε)214(4.30),297(3.53)nm；IR
(KBr)νmax 3272,2968,2855,2355,2341,1683,1630,1459,1380,1248,1200,961,813cm-1；
1HNMR(methanol-d4,500MHz)δH6.61 (d, J=2.8, H-3 '), 6.52 (dd, J=8.5,2.8, H-5 '), 6.64
(d, J=8.51, H-6 '), 3.69 (d, J=7.7, H-1), 5.98 (t, J=7.8, H-2), 2.33 (t, J=7.2 (br), H-
4), 2.19 (dt, J=7.2,7.3 (br), H-5), 5.1 (tq, J=7.3,0.9, H-6), 2 (t, J=7.8 (br), H-8),
2.05 (dd, J=7.1,7.8 (br), H-9), 5.39 (tq, J=7.1,1.0, H-10), 1.62 (s, H-12), 1.68 (s, H-
13), 1.61 (d, J=1.0, H-14)；13C NMR(methanol-d4,125MHz)δC 149.3(C-1′),128.04(C-
2′),117.76(C-3′),151.17(C-4′),114.78(C-5′),116.91(C-6′),31.75(C-1),140.52(C-
2),133.32(C-3),35.88(C-4),28.49(C-5),124.61(C-6),136.73(C-7),40.38(C-8),27.7
(C-9),125.5(C-10),132(C-11),17.8(C-12),25.9(C-13),16.15(C-14),172.32(C-15).Just
Ion mode HRTOFMS m/z [M+H]+345.2069 (calculated value C21H39O4,345.2066)。
Compound 3
Ganomycin I (3): pale yellow oily liquid, [α]25 D+36(c 0.1,MeOH)；UVλmax(logε)212
(3.50),297(3.65)nm；CDλmaxnm(Δε)(MeOH)212(-0.099),240(+0.028)；IR(KBr)νmax3425,
2923,1752,1501,1241,1136,1049cm-1,HRFABMS 343.18748(calcd for C21H26O4,
343.18311)；1HNMR(methanol-d4,400MHz)δH7.32 (1H, d, J=1.4Hz, H-2 '), 6.66 (1H, d, J=
8.4Hz, H-6), 6.58 (1H, dd, J=2.8,8.4Hz, H-5), 6.46 (1H, d, J=2.8Hz, H-3), 6.21 (1H, d, J=
1.4Hz,H-1′),5.10(1H,br t,H-10′),5.03(1H,br t,H-6′),2.30(2H,m,H-4′),2.27(2H,m,
H-5′),1.99(2H,m,H-9′),1.95(2H,m,H-8′),1.63(3H,s,H-12′),1.55(6H,s,H-13′,H-
15′)；13CNMR(CD3OD,125MHz)δC 176.7(C-14′),151.4(C-4),151.1(C-21),148.8(C-1),
137.7(C-7′),132.9(C-3′),132.1(C-11′),125.3(C-10′),123.9(C-6′),123.4(C-2),
117.14(C-6),117.11(C-3),113.1(C-5),79.8(C-1′),40.7(C-8′),27.6(C-9′),26.8(C-
4′),26.1(C-5′),25.8(C-12′),17.7(C-13′),16.2(C-15′)；Positive ion mode HRTOFMS m/z [M+H]
+ 343.1909 (calculated value C21H39O4,343.1920).
The external inhibition aldose reductase activity of compound shown in embodiment 4, formula 1-3 is tested
3 compounds shown in formula 1-3 prepared by embodiment 3 are accurately weighed, 20mM are configured to DMSO, for active testing
(after final concentration range is dissolved in a small amount of DMSO at 1-100 μM, preparation, it is diluted to respective concentration with distilled water, controls DMSO most
Final volume score < 0.1%)；As positive control, (final concentration is respectively 20 μM, 10 μM, 5 μM, 2 μM, 1 μM to Epalrestat, is prepared
When be dissolved in a small amount of DMSO after, be diluted to respective concentration with distilled water, control final volume score < 0.1% of DMSO).
Experimental procedure: sequentially adding following reagent in 96 orifice plates, and the other proportion of difference group is as follows:
Test group :+15 μ L of+25 μ l PBS buffer solution of NADPH solution of+25 μ L concentration (0.1mM) of 10 μ L compound solution
Aldose reduction enzyme dilution
Positive controls :+25 μ l PBS buffer solution of NADPH solution of+25 μ L concentration (0.1mM) of 10 μ L Epalrestat solution
+ 15 μ L aldose reduction enzyme dilutions
Blank group :+15 μ L aldose reduction enzyme dilution of+35 μ LPBS buffer of NADPH solution of 25 μ L concentration (0.1mM)
Background group :+15 μ L aldose reduction enzyme dilution of+60 μ L PBS buffer solution of NADPH solution of 25 μ L concentration (0.1mM)
React compound and enzyme sufficiently being placed at room temperature for 10min 96 orifice plates for adding reagent, later in addition to background group,
Other three groups are respectively added 25 μ L 10mM D, and L glycerol aldehyde solution reacts 30 minutes in 37 DEG C of insulating boxs as substrate, and measurement is each
Optical density of the hole in 340nm.
Experimental data is statisticallyd analyze, the IC of each test sample is calculated50The results are shown in Table 2 for value.As it can be seen that shown compound
There is certain aldose reductase enzyme inhibition activity, compound shown in formula 3 is suitable with positive drug Epalrestat intensity.
The aldose reductase inhibition activity testing result of 2 1-3 of table
Claims (4)
1. a kind of formula (1) compound represented or its pharmaceutical salts
2. compound or pharmaceutically acceptable salt thereof described in claim 1 is preparing the application in aldose reductase inhibitor.
3. compound or pharmaceutically acceptable salt thereof described in claim 1 is preparing the application in aldose reduction enzyme inhibitor pharmaceutical.
4. compound or pharmaceutically acceptable salt thereof described in claim 1 preparation prevention or the treatment drug of diabetic complication, food,
Application in health care product.
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| CN105213363A (en) * | 2015-04-30 | 2016-01-06 | 中国科学院微生物研究所 | The application of hydroquinone farnesyl compounds |
| CN106236745A (en) * | 2016-07-21 | 2016-12-21 | 中国科学院微生物研究所 | The purposes of aromatic series farnesyl compounds |
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| CN105213363A (en) * | 2015-04-30 | 2016-01-06 | 中国科学院微生物研究所 | The application of hydroquinone farnesyl compounds |
| CN107519160A (en) * | 2015-04-30 | 2017-12-29 | 中国科学院微生物研究所 | The application of hydroquinones farnesyl class compound |
| CN106236745A (en) * | 2016-07-21 | 2016-12-21 | 中国科学院微生物研究所 | The purposes of aromatic series farnesyl compounds |
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