CN101513426B - Cinnamate compound and application thereof in the preparation of leukotriene A4 hydrolytic enzyme functional regulating medicine - Google Patents
Cinnamate compound and application thereof in the preparation of leukotriene A4 hydrolytic enzyme functional regulating medicine Download PDFInfo
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- CN101513426B CN101513426B CN2009100471884A CN200910047188A CN101513426B CN 101513426 B CN101513426 B CN 101513426B CN 2009100471884 A CN2009100471884 A CN 2009100471884A CN 200910047188 A CN200910047188 A CN 200910047188A CN 101513426 B CN101513426 B CN 101513426B
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Abstract
The invention discloses cinnamylate lipoid substance and the application thereof in the preparation of leukotriene A4 hydrolytic enzyme functional regulating medicine. The general structural formula of the cinnamylate lipoid substance is that experiment proves that the cinnamylate lipoid substance has obvious function of leukotriene A4 hydrolytic enzyme functional regulator and mainly prevents LTA4 being hydrolyzed into LTB4 by leukotriene A4 hydrolytic enzyme LTA4H. Therefore, the cinnamylate lipoid substance can be used for preparing medicine for treating asthma, systemic lupus erythematosus, inflammation, miocardial infarction, non-small cell lung cancer, acute myelaid leukemia and solid tumor.
Description
Technical field
The present invention relates to medicine, be specifically related to a kind of Flos Caryophylli Radix Incarvilleae Delavayi ester first (+) 2-(1-hydroxyl-4-oxo cyclohexyl) caffeic acetate's chemical compound and in the application of preparation in triolefin A4 hydrolytic enzyme functional regulating medicine.
Background technology
Leukotriene (leukotriene) is the arachidonic acid metabolite of (5,8,11, the 14-eicosatetraenoic acid is called for short AA).In the correlational study of diseases associated with inflammation such as asthma, inflammatory bowel, chronic obstructive pulmonary disease, arthritis and atherosclerosis, all made triolefin clear and had important physical, pathology function.The synthetic of leukotriene at first is that arachidonic acid is converted into unsettled epoxide leukotriene A (LTA4) beginning, and this conversion is under the effect of lipoxygenase, to carry out.Lipoxygenase mainly is present in the myeloid cell, especially in neutrophilic granulocyte, eosinophilic granulocyte, mononuclear cell, macrophage and mastocyte.LTA4 can combine with glutathion under the effect of LTC4 (leukotriene C) synzyme, generates the cysteinyl leukotriene, i.e. LTC4; LTA4 also can be hydrolyzed to two pure and mild LTB4 (leukotriene B4).LTC4 and his metabolite (LTD4 (leukotriene D), LTE4 (leukotriene E4)) can make smooth muscle contraction, trachea contraction, vascular permeability strengthen, and LTB4 is a kind of chemical attractant and agonist of potential neutrophilic granulocyte.
LTA4 is under the effect of leukotriene A hydrolytic enzyme (LTA4H), to accomplish to this specific hydrolysis of LTB4.LTA4H is a kind of zinciferous solute enzyme, and it distributes extensively, expresses moderate expression in leukocyte especially neutrophilic granulocyte at intestinal epithelial cell, lung and aorta height.
LTB4 is a kind of lipid medium of short scorching reaction, is derived through 5-LO (5-lipoxygenase) path by arachidonic acid.Known LTB4 is a kind of chemotactic factor and the agonist of leukocyte (especially neutrophilic granulocyte and T cell), in several kinds of allergy and inflammatory reaction, works.LTB4 can convene inflammatory cells such as neutrophilic granulocyte, eosinophilic granulocyte, also can activate neutrophilic granulocyte.The short scorching reaction of LTB4 mediation is through combining completion with G protein receptor (BLT1 (leukotriene B42 receptor hypotype BLT1) and BLT2 (leukotriene B42 receptor hypotype BLT2)).BLT1 mainly is expressed in peripheral white blood cells, especially at neutrophilic granulocyte, eosinophilic granulocyte, macrophage and monokaryon granulocyte.The receptor of muroid is also expressed on effector T cell, in animal model in asthma, find recently, it also mediate effector CD8+T cell transfer, TH1 and TH2 cell chemotaxis that LTB4 relies on and with the convening of endotheliocyte adhesion, CD4+T and CD8+T cell.It and BLT1 have 42% amino acid identity, but expression is more extensive, in tissue and the leukocyte expression are arranged all around spleen, the ovary regulating liver-QI etc.Compare with BLT1, BLT2 is lower with the bonded affinity of LTB4, mediation chemotaxis when LTB4 concentration is higher, and BLT1 is also different to the affinity of antagonist with BLT2.The LTB4 receptor antagonist also maybe be different to the affinity of BLT1 and BLT2, with the generation of LTA4H inhibitor blocking-up LTB4, will suppress the downstream events of BLT1 and BLT2 mediation simultaneously.
Research shows, in normal structure, introduces exogenous LTB4 and can bring out inflammatory symptom.At a lot of inflammation diseases, for example all observed the raising of LTB4 level in the diseases such as inflammatory bowel, chronic obstructive pulmonary disease, psoriasis, rheumatic arthritis, cystic fibrosis, asthma.Therefore, thus may have potential therapeutical effect through the LTA4H inhibitor to a lot of diseases to the level that the active inhibition of LTA4H reduces LTB4.
This has obtained confirmation in the mice study to the LTA4H defective.And on one's body the otitis disease and the inductive peritonitis mouse model of zymosan of arachidonic acid-induction, neutrophilic granulocyte stream significantly reduces.Experiment has confirmed that the LTA4H inhibitor is effective anti-inflammatory drug before clinical.For example, in vitro tests of mice blood and rat peritoneum in vivo test, oral LTA4H inhibitor SC57461 can cause the LTB4 of ionophore mediation to generate minimizing.Use the enteritis symptom that significantly to improve cotton hat wicked Adeps seu carnis Rhiopithecus roxellanae (Cotton Top Tamarin) same 8 weeks of inhibitor component for treating.The idiopathic colitis that these animals are taken place is closely similar with human inflammatory bowel, and therefore, these results suggest LTA4H inhibitor will have therapeutical effect to this or other inflammatory states of the mankind.
Normally immune system acute reaction that biopathogen invasion, chemistry or physical damnification are taken place of inflammation.But sometimes, inflammatory reaction also can develop into chronic states, becomes the reason of inflammatory diseases.The such chronic inflammatory disease of treatment control is the needs of medical treatment.Cause inflammatory reaction to comprise the generation of short scorching reaction medium LTB4.The generation of the short scorching reaction medium LTB4 of LTA4H catalysis, and the generation of LTA4H inhibitor blocking-up LTB4, therefore the disease for leukotriene mediations such as prevention or treatment inflammation provides probability.
Report (list of references N is arranged
IAMHE K
IERAN, P
AOLAM
ADERNA, C
ATHERINEG
ODSON.Lipoxins:Potential anti-inflammatory; Proresolution; And antifibrotic mediators inrenal disease.Kidney International.2004; Edema, neutrophil infiltration and cutaneous permeability that the lipoxin analog that 65:1145-1154) topical application is stable can suppress the mice inflammatory model strengthen, and therefore, increase or the generation of keeping lipoxin A 4 (LXA4) possibly have the good curing effect to inflammation.The possible drawback of 5-LO inhibitor is, it has blocked the upstream passages of LTA4, and this just not only blocks the synthetic of LTA4, LTB4 and cysteinyl leukotriene, also blocked the synthetic of LXA4.
According to leukotriene biosynthesis path, the inventor thinks that LTA4H inhibitor specific inhibition LTA4 is converted into LTB4, does not but influence the process that LTA4 is converted into lipoxin.Lipoxin (for example LXA4) has become the research focus, is a kind of natural anti-inflammatory composition, is the important medium in the course of reaction of diminishing inflammation, and has the important physiological effect.And, all found endogenic LXA4 in a lot of diseases associated with inflammation, for example, the patient compares with moderate asthma, and the LXA4 level is lower in the severe asthma patient body.The hypothesis that these data and LXA4 play a significant role in the control acute inflammatory reaction is consistent.Different with the LTA4 inhibitor, the upstream path of 5-LO inhibitor blocking-up LTA4.This just not only blocks the synthetic of LTA4, LTB4 and cysteinyl leukotriene, also influences the synthetic of LXA4.Simultaneously, also there is a kind of possibility, is exactly that the LTA4H inhibitor can cause LTA4 to increase, and goes into to urge scorching cysteinyl leukotriene, although also there is not this possibility of evidence proof at present through by-pass shunt.
The Bignoniaceae Herba Incarvilleae sinensis platymiscium Incarvillea L. whole world has 15 kinds, in state-owned 11 kinds, be distributed in the southwest more, also there is distribution in areas such as northeast, North China, northwest in addition, 5 kinds of hyoscines wherein are in the diseases such as treatment hepatitis, bacillary dysentery that are mainly used among the people.Its chemical constituent mainly contains monoterpene alkaloid, macro ring spermine Alkaloid, iridoid glycosides, flavonoid, ceramide type, sterols and triterpenes etc. and becomes to grade.Wherein the chemical constituent and the pharmacology activity research of Herba Incarvilleae sinensis and Westerner grass are more, other all rare reports.
Herba Incarvilleae sinensis platymiscium Herba Incarvilleae sinensis Incarvillea sinensis is used as " Herba speranskiae tuberculatae " in the China north and the Northeast, and appellation " Cornu Caprae seu Ovis Herba speranskiae tuberculatae " has the effect of reducing swelling and alleviating pain, is mainly used in diseases such as treatment traumatic injury and rheumatic arthritis.Herba Incarvilleae sinensis platymiscium Flos Caryophylli Radix Incarvilleae Delavayi Incarvillea mairei var.grandiflora (Wehrhahn) Grierson has another name called river, Yunnan Herba Incarvilleae sinensis, mainly is distributed in Yunnan (middle pasture, Lijing), Sichuan, Qinghai.Be born in high mountain grass slope, height above sea level 2500-3650 meter band.Root, leaf are used as medicine, and property is sweet, light, temperature.Be used for treating newborn lacking in puerperal, prolonged illness is weak, dizzy, anemia.Can from the Herba Incarvilleae sinensis platymiscium, extract the cinnamate compounds.
Summary of the invention
Particular problem to be solved by this invention is the application of research design cinnamate compounds in preparation leukotriene A hydrolytic enzyme functional regulating medicine.
The invention provides the application of a kind of cinnamate compounds in preparation leukotriene A hydrolytic enzyme functional regulating medicine, it is characterized in that this cinnamate compounds has following general structure (A), (B), (C) or (D) a kind of: preferred chemical compound is horned artemisia ester alkali C, 1-O-coffee acyl glycerol, 4-hydroxycinnamic acid, Flos Caryophylli Radix Incarvilleae Delavayi ester first, acteoside, different acteoside, ferulic acid, caffeic acetate, red pineapple flower ester first, Eutigoside A, Fuhsioside, Osmanthuside B6, Isomartynoside, Isocrenatoside, 3 ' " O-methylisocrenatoside, Calceolariosdie A, Plantamajoside
R in the formula
1Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
2Be selected from hydrogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, nitro, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, phenyl, benzyl, aromatic radical Ar, 5-7 membered aromatic heterocycle (contain 1-3 hetero atom that is selected from oxygen, sulfur, nitrogen; Can and close by phenyl and aromatic heterocycle; Or by one or more halogens that are selected from, C
1-C
6The straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl, sulfydryl, C
1-C
4Acyl group, the group of aromatic radical Ar replaces), 1～5 unitary glycosidic bond;
R in the formula
1Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
2, R
3Be selected from hydrogen, hydroxyl, the alkyl of 1～4 carbon, acetyl group, isovaleryl independently of one another;
R in the formula
4Be selected from hydrogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, nitro, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, phenyl, benzyl, aromatic radical Ar, 5-7 membered aromatic heterocycle (contain 1-3 hetero atom that is selected from oxygen, sulfur, nitrogen; Can and close by phenyl and aromatic heterocycle; Or by one or more halogens that are selected from, C
1-C
6The straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl, sulfydryl, C
1-C
4Acyl group, the group of aromatic radical Ar replaces), 1～5 unitary glycosidic bond;
R in the formula
1Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
2, R
3, R
4Be selected from hydrogen, hydroxyl, alkoxyl, C independently of one another
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
5Be selected from alkyl, alkoxyl, acetyl group, the isovaleryl of hydrogen, hydroxyl, 1～4 carbon, 1～5 unitary glycosidic bond, nitro, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy;
R in the formula
6Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
1Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
2, R
3, R
4Be selected from hydrogen, hydroxyl, alkoxyl, C independently of one another
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
5Be selected from alkyl, alkoxyl, acetyl group, isovaleryl, nitro, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, 1～5 unitary glycosidic bond of hydrogen, hydroxyl, 1～4 carbon;
R in the formula
6Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
1Be selected from hydrogen, hydroxyl, alkoxyl, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond;
R in the formula
2, R
3Be selected from alkyl, acetyl group, isovaleryl, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond of hydrogen, 1～4 carbon independently of one another;
R in the formula
4Be selected from alkyl, acetyl group, isovaleryl, halogen, cyanic acid, trifluoromethyl, trifluoromethoxy, alpha-substituted acetoxyl group isovaleryl, beta substitution acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl, isopentene group, o-hydroxy formoxyl, 1～5 unitary glycosidic bond of hydrogen, hydroxyl, alkoxyl, 1～4 carbon.
This type cinnamate compounds is distributed in botanic many kind of plant, can from plant, prepare and get by extraction separation, also can use the chemosynthesis mode to obtain.
The inventor has accumulated more than 4000 kind of chemical compound through basic research for many years; And set up the natural product storehouse; Through chemical compound in the storehouse is carried out virtual screening; Through the active checking in inside and outside, the result has found that above-mentioned cinnamate compounds dialogue triolefin A4 hydrolytic enzyme has specific inhibitory effect again.
The results showed that cinnamate compounds of the present invention has LTA4H inhibitory action preferably, IC
50Between 50～240nM.
Pharmaceutical composition of the present invention is an active component by the cinnamate compounds, forms with one or more pharmaceutically acceptable carriers.Wherein, the weight content of active component is 0.1-99.5%.
Pharmaceutical composition of the present invention can be used for preparing the medicine that suppresses the leukotriene A hydrolytic enzyme, is used to treat asthma, systemic lupus erythematosus (sle), inflammation, myocardial infarction, nonsmall-cell lung cancer, acute myeloid leukaemia, solid tumor.
Said pharmaceutically acceptable carrier is meant the pharmaceutical carrier that pharmaceutical field is conventional, for example: diluent, excipient such as water etc.; Filler such as starch, sucrose etc.; Binding agent such as cellulose derivative, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerol; Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Surfactant such as hexadecanol; Absorption carrier such as Kaolin and soap clay; Lubricant such as Pulvis Talci, calcium stearate and magnesium and Polyethylene Glycol etc.Can also in compositions, add other adjuvant such as flavouring agent, sweeting agent etc. in addition.
The compounds of this invention can compositions form administered through oral, snuffing go into, the mode of rectum or parenteral is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, powder, granule, capsule etc. or process liquid preparation such as water or oil-suspending agent or other liquid preparation such as syrup, elixir etc.; When being used for parenteral, can be made into solution, water or the oiliness suspending agent etc. of injection.Preferred form is tablet, coated tablet, capsule, suppository, nasal spray and injection.
The various dosage forms of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.
Description of drawings
(cell membrane phospholipid discharges arachidonic acid (AA) after by phospholipase A2 (PLA2) hydrolysis to the effect sketch map of Fig. 1 leukotriene A hydrolytic enzyme (LTA4H) in the arachidonic acid metabolic passage; AA is attached to 5-LOX activator protein (FLAP); And given the 5-lipoxygenase (5-LO) of having transferred to nuclear membrane by its submission; Be oxidized to 5-hydroperoxidation eicosatetraenoic acid (5-HPETE) by 5-LO, 5-HPETE further is converted into 5-HETE, or under the 5-LO effect, further is oxidized to LTA4; LTA4 is unstable, is hydrolyzed to LTB4 by leukotriene A hydrolytic enzyme (LTA4H) very soon.In this passage, 5-LO and LTA4H are the metabolic key enzymes of AA.)
The specific embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.
Embodiment 1: preparation Flos Caryophylli Radix Incarvilleae Delavayi ester first ((+) 2-(1-hydroxyl-4-oxocyclohexyl) ethylcaffeate, (+) 2-(1-hydroxyl-4-oxo cyclohexyl) caffeic acetate)
The dry herb of Flos Caryophylli Radix Incarvilleae Delavayi (Incarvillea Mairei var.Grandiflora) extracts 3 times with 80% alcohol heating reflux, each 2 hours, merge extractive liquid,, be concentrated near do total extract extractum.Total extract extractum adds 2%HCl with the water suspendible, and filter adjust pH to 2～3, and filtering residue is placed.Filtrating adds ammonia adjust pH to 11, uses chloroform extraction, gets chloroform extract.Surplus water liquid adjust pH to 7 is used petroleum ether, ethyl acetate, n-butanol extraction respectively, obtains ethyl acetate extract, petroleum ether part, n-butanol portion and water position.
With ethyl acetate extract through silica gel (200～300 order) column chromatography; Petroleum ether: ethyl acetate (100: 1～5: 1) and chloroform: methanol (100: 1～1: 1) gradient elution and Sephadex LH-20 column chromatography (dextran gel column chromatography); Thin layer chromatography is followed the tracks of and is detected; Collect stream part of Flos Caryophylli Radix Incarvilleae Delavayi ester first enrichment, after the liquid chromatograph preparation gets Flos Caryophylli Radix Incarvilleae Delavayi ester first.
Cinnamate compounds Flos Caryophylli Radix Incarvilleae Delavayi ester first of the present invention ((+) 2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate) is the sepia solid, is soluble in methanol, and the electron spray ion massspectrum provides quasi-molecular ion peak m/z 343 [M+Na]
+, the accurate mass number that high resolution mass spectrum draws this chemical compound is 343.1159 [M+Na]
+, calculate that its molecular formula is C
17H
20O
6(value of calculation C
17H
20O
6Na 343.1158).The structure of Flos Caryophylli Radix Incarvilleae Delavayi ester first is passed through
1H-NMR,
13C-NMR, means such as 2D-NMR are proved conclusively.
1H with
13The C nuclear magnetic resonance data is seen table 1.
Embodiment 2: preparation red pineapple flower ester first (2-(1,4-dihydroxy cyclohexyl) ethyl caffeate, 2-(1,4-dihydroxy cyclohexyl) caffeic acetate)
The dry herb of red pineapple flower (Incarvillea delavayi Bur.et Franch) extracts 3 times with 80% alcohol heating reflux, each 2 hours, merge extractive liquid,, be concentrated near do total extract extractum.Total extract extractum adds 2%HCl with the water suspendible, and filter adjust pH to 2～3, and filtering residue is placed.Filtrating adds ammonia adjust pH to 11, uses chloroform extraction, gets chloroform extract.Surplus water liquid adjust pH to 7 is used petroleum ether, ethyl acetate, n-butanol extraction respectively, obtains ethyl acetate extract, petroleum ether part, n-butanol portion and water position.
With ethyl acetate extract through silica gel (200～300 order) column chromatography; Petroleum ether: ethyl acetate (100: 1～5: 1) and chloroform: methanol (100: 1～1: 1) gradient elution and Sephadex LH-20 column chromatography; Thin layer chromatography is followed the tracks of and is detected; Collect stream part of red pineapple flower ester first enrichment, after the liquid chromatograph preparation gets red pineapple flower ester first.
Cinnamate derivative compound of red pineapple flower ester first of the present invention (2-(1,4-dihydroxy cyclohexyl) ethylcaffeate) is a yellow oil, is soluble in methanol, and the electron spray ion massspectrum provides quasi-molecular ion peak m/z 345 [M+Na]
+, the accurate mass number that high resolution mass spectrum draws this chemical compound is 321.1342 [M-H]
-, calculate that its molecular formula is C
17H
22O
6(value of calculation C
17H
21O
6, 321.1338).The structure of red pineapple flower ester first is passed through
1H-NMR,
13C-NMR, means such as 2D-NMR are proved conclusively.
1H with
13The C nuclear magnetic resonance data is seen table 1.
Table 1 Flos Caryophylli Radix Incarvilleae Delavayi ester first and red pineapple flower ester first
1H with
13C nuclear magnetic resonance data (CD
3OD)
**
1H-NMR?spectrum?were?recorded?in?600MHz，
13C-NMR?spectrum?were?recordedin?150MHz?in?CD
3OD
Embodiment 3: the inhibitory action of cinnamate compounds dialogue triolefin A4 hydrolytic enzyme
One, experimental technique:
The preparation of substrate
The LTA4 substrate is by the preparation of LTA4 methyl ester, and preparation condition is: nitrogen, and NaOH 67M equivalent, room temperature was reacted 40 minutes.Before the use, the LTA4 substrate should be frozen at-80 ℃ with the form of free acid.The mensuration of LTA4H hydrolytic enzyme activities
Chemical compound to be tested is all processed the fluid storage of 10mM in dimethyl sulfoxine, dilute during mensuration, and the ultimate density of dimethyl sulfoxine is no more than 0.1%.Under the room temperature condition; Assay buffer (0.1M potassium phosphate at 50 μ l; PH 7.4,5mg/ml defat calf serum) in the test compounds of variable concentrations cultivation recombined human LTA4H (36ng) 10 minutes, using assay buffer then is 200 μ 1 with this solution dilution; The substrate (LTA4) (ultimate density 40ng/ml, the 0.13mM that add 25 μ l again; Termination capacity 225 μ l).After at room temperature depositing 10-30 minute, with 20 times of cessation reactions of assay buffer dilution.The amount of the LTB4 that produces is measured (Cayman chemical, the U.S.) with the EIA method.Recombinase active is suppressed to peaked compound concentration at 50% o'clock and calculates with the method for GraphPad nonlinear regression.
Two, experimental result:
The cinnamate compounds has LTA4H inhibitory action preferably, IC
50Between 50～240nM.
Embodiment 4: the preparation of preparation cinnamate compounds
Tablet: active component 20mg
Lactose 177mg
Corn starch 50mg
Magnesium stearate 3mg
Method for preparing: active component, lactose and starch are mixed, and water is evenly moistening, sieves the mixture after moistening and drying, after sieve, adds magnesium stearate, then with the mixture tabletting, and every heavy 250mg, active component content is 20mg.
Claims (4)
1. the application of Flos Caryophylli Radix Incarvilleae Delavayi ester first (+) 2-(1-hydroxyl-4-oxo cyclohexyl) caffeic acetate's chemical compound in preparation leukotriene A hydrolytic enzyme functional regulating medicine is characterized in that said chemical compound has following structural formula:
2. application as claimed in claim 1 is characterized in that the medicine of described medicine for treatment asthma, systemic lupus erythematosus (sle), inflammation, myocardial infarction, acute myeloid leukaemia or solid tumor.
3. application as claimed in claim 2 is characterized in that the medicine of described medicine for the treatment nonsmall-cell lung cancer.
4. application as claimed in claim 1; It is characterized in that described medicine oral agents, injection, suppository or nasal spray that to be Flos Caryophylli Radix Incarvilleae Delavayi ester first (+) 2-(1-hydroxyl-4-oxo cyclohexyl) caffeic acetate's chemical compound form as active component and acceptable carrier pharmaceutically, the weight content of said active component is 0.1-99.5%.
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| CN110169963A (en) * | 2019-06-26 | 2019-08-27 | 中南民族大学 | Application of the p-Coumaric Acid as preparation for the drug of diastole airway smooth muscle |
| CN114507264A (en) * | 2022-01-06 | 2022-05-17 | 湖南中医药大学 | Monomer chrysanthemin A extracted from golden-silk chrysanthemums and extraction method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1352628A (en) * | 1999-05-27 | 2002-06-05 | 哈尔曼及赖默股份有限公司 | Method of producing alkoxy cinnamic acid ester |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1352628A (en) * | 1999-05-27 | 2002-06-05 | 哈尔曼及赖默股份有限公司 | Method of producing alkoxy cinnamic acid ester |
Non-Patent Citations (1)
| Title |
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| Wei Yuan et al.Development of Selective Tight-Binding Inhibitors of Leukotriene A4 Hydrolase.《J. Med. Chem.》.1993,第36卷(第2期),第212页第1栏表2和第213页结构式17. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20160070891A (en) * | 2014-12-10 | 2016-06-21 | 강원대학교산학협력단 | Composition comprising caffeoylglycolic acid methyl ester or 1-O-caffeoylglycerol for preventing or treating inflammatory diseases |
| KR101648400B1 (en) * | 2014-12-10 | 2016-08-17 | 강원대학교산학협력단 | Composition comprising caffeoylglycolic acid methyl ester or 1-O-caffeoylglycerol for preventing or treating inflammatory diseases |
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| CN101513426A (en) | 2009-08-26 |
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