CN101585841A - Guaianolide sesquiterpene dimers, preparation method thereof and use thereof - Google Patents
Guaianolide sesquiterpene dimers, preparation method thereof and use thereof Download PDFInfo
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Abstract
The invention discloses guaianolide sesquiterpene dimers, a preparation method thereof and use thereof. The guaianolide sesquiterpene dimers have a structure represented by a formula (I). The preparation method comprises the following steps: extracting an artemisia anomala herb with ethanol, removing the ethanol, collecting an extract, and separating and purifying the extract to obtain a compound of the formula (I) in which R1 represents hydroxyl and R2 represents acetoxyl, a compound of the formula (I) in which R1 represents hydro and R2 represents hydroxyl and a compound the formula (I) in which both R1 and R2 represent hydroxyl respectively; and performing series of displacement reactions on the basis of the hydroxyl compounds to obtain various guaianolide sesquiterpene dimers. Results of in vitro anticancer and anti-inflammatory activity tests show that the guaianolide sesquiterpene dimers have remarkable anticancer and anti-inflammatory activities.
Description
Technical field
The present invention relates to Guaianolide sesquiterpene dimers and preparation method thereof and application.
Background technology
All containing the compound with antitumour activity in a lot of plants, promptly is a kind of widely used cancer therapy drug as the taxol that extracts from Pacific yew (yewtree, Taxus brevifolia) bark.Also contain compound in simultaneously a lot of plants with anti-inflammatory activity.Therefore from plant milk extract, seek anticancer and anti-inflammatory drug is the research focus of present cancer and inflammation treatment.
Artemisia anomalas Artemisia anomala S.Moore has another name called Artemisia anomah S. Moore, LIUYUESHUANG, wild Herba Kalimeridis, bitter mother-in-law's dish etc." Chinese Plants will " record artemisia anomalas is a composite family Phytoconcentrol Chamomile family artemisia, and this is that China has a kind and 1 mutation.Its all herbal medicine has the effect of healing up sore and subduing swelling, dissipating blood stasis to promote menstruationg.Cure mainly diseases such as wound, metal-inflicted wound are hemorrhage, rheumatic arthralgia, scald.Still make tea with it in ground such as China south, in order to diseases such as treatment enteritis, dysentery, heatstrokes.It is reported, artemisia anomalas mainly contain compositions such as flavonoid, coumarins, volatile oil, sesquiterpenoids and aromatics (the new medical college in Jiangsu compiles. the Chinese medicine voluminous dictionary. Shanghai: the Shanghai People's Press, 2006:1303; Xiao Yongqing etc. Acta Pharmaceutica Sinica, 1984,19 (12): 909; Xiao Yongqing etc. Botany Gazette, 1986,28 (3): 307; Jakupovic J.et al, Phytochemistry.1987; 26 (10): 2777.).
Summary of the invention
The purpose of this invention is to provide Guaianolide sesquiterpene dimers and preparation method thereof.
Guaianolide sesquiterpene dimers provided by the present invention, its structure is suc as formula shown in (I):
Formula (1)
Wherein, R
1For hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl or benzyloxy carbo methoxy group;
R
2For hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl or benzyloxy carbo methoxy group.
Described R
1Specifically can be halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl or benzyloxy carbo methoxy group; Described R
2Specifically can be acetoxyl group.
Described R
1, R
2Can be simultaneously hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl or benzyloxy carbo methoxy group.
Described R
1Specifically can be hydrogen, described R
2Specifically can be hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl or benzyloxy carbo methoxy group.
In the described formula (I), work as R
1Be hydroxyl, R
2During for acetoxyl group, its structure is suc as formula shown in (II):
Formula (II)
In the described formula (I), work as R
1Be hydroxyl, R
2During for hydroxyl, its structure is suc as formula shown in (III):
Formula (III)
In the described formula (I), work as R
1Be hydrogen, R
2During for hydroxyl, its structure is suc as formula shown in (IV):
The method of compound shown in preparation formula provided by the present invention (II), formula (III) or the formula (IV) may further comprise the steps:
1) with extraction using alcohol artemisia anomalas herb, removes ethanol then, collect extract; Described extraction can be adopted refluxing extraction;
2) described extract is suspended in water, extract with sherwood oil, ethyl acetate successively;
3) ethyl acetate layer is carried out silica gel column chromatography, carry out gradient elution with chloroform and methyl alcohol, the collected volume ratio is 25: 1 the chloroform and the elution fraction of methyl alcohol mixed liquor;
4) component that described step 3) is obtained is carried out silica gel column chromatography, carries out gradient elution with sherwood oil and acetone, and the collected volume ratio is 4: 1 the sherwood oil and the elution fraction of acetone mixed solution;
5) component that described step 4) is obtained is carried out purifying with the hydroxypropyl dextrane gel, with volume ratio be 1: 1 chloroform-methanol mixed solution as elutriant, collect elution fraction;
6) component that described step 5) is obtained is carried out purifying with half preparation HPLC, and the instrument model is Waters 600 half preparative high performance liquid chromatography instrument, and W2487 dual wavelength detector detects, and used semipreparative column model is WatersPrep Nova-
HR C
187.8 * 300mm carries out the HPLC purifying, the collection retention time is the elution peak of 18.5min, 19.6min and 21min, obtains compound shown in formula (III), formula (IV) and the formula (II); Used moving phase is that volume ratio is 52: 48 a methanol-water mixture in the described HPLC purifying, and the flow velocity of described moving phase is 2ml/min.
The method of the described compound of preparation formula (I) is following 1) to 10) in any method:
1) preparation R
1Be chlorine, R
2Being the method for the described compound of formula (I) of acetoxyl group, is that described compound of formula (II) and thionyl chloride are reacted R in the formula of obtaining (I)
1Be chlorine, R
2Compound for acetoxyl group;
2) preparation R
1Be sulfydryl, R
2For the method for the described compound of formula (I) of acetoxyl group, be that described compound of formula (II) and trimethylchlorosilane are reacted, the reaction product that obtains is reacted with thiocarbamide again, obtain R in the formula (I)
1Be sulfydryl, R
2Compound for acetoxyl group;
3) preparation R
1And R
2Being all the method for the described compound of formula (I) of acetoxyl group, is that described compound of formula (II) and Acetyl Chloride 98Min. are reacted, and obtains R in the formula (I)
1And R
2Be all the compound of acetoxyl group;
4) preparation R
1Be amber acyloxy, R
2For the method for the described compound of formula (I) of acetoxyl group, be that described compound of formula (II) and succinyl oxide are reacted, obtain R in the formula (I)
1Be amber acyloxy, R
2Compound for acetoxyl group;
5) preparation R
1Be benzyloxy carbo methoxy group, R
2For the method for compound shown in the formula (I) of acetoxyl group, be that described compound of formula (II) and benzyl acetate bromide are reacted, obtain R in the formula (I)
1Be benzyloxy carbo methoxy group, R
2Compound for acetoxyl group;
6) preparation R
1And R
2Being all the method for the described compound of formula (I) of chlorine, is that described compound of formula (III) and thionyl chloride are reacted R in the formula of obtaining (I)
1And R
2Be all the compound of chlorine;
7) preparation R
1And R
2Being all the method for the described compound of formula (I) of sulfydryl, is that described compound of formula (III) and trimethylchlorosilane are reacted, and the reaction product that obtains is reacted with thiocarbamide again, obtains R in the formula (I)
1And R
2Be all the compound of sulfydryl;
8) preparation R
1Be amino, R
2For the method for the described compound of formula (I) of acetoxyl group, be that described compound of formula (II) and thionyl chloride are reacted, the reaction product that obtains is reacted with the methanol solution of ammonia again, obtain R in the formula (I)
1Be amino, R
2Compound for acetoxyl group;
9) preparation R
1Be hydrogen, R
2For the method for the described compound of formula (I) of chlorine, be that described compound of formula (IV) and thionyl chloride are reacted, obtain R in the formula (I)
1Be hydrogen, R
2Compound for chlorine;
10) preparation R
1Be hydrogen, R
2For the method for the described compound of formula (I) of acetoxyl group, be that described compound of formula (IV) and Acetyl Chloride 98Min. are reacted, obtain R in the formula (I)
1Be hydrogen, R
2Compound for acetoxyl group.
Wherein, the preparation method of formula (II), formula (III) and the described compound of formula (IV) may further comprise the steps:
1) with extraction using alcohol artemisia anomalas herb, removes ethanol then, collect extract; Described extraction can be adopted refluxing extraction;
2) described extract is suspended in water, extract with sherwood oil, ethyl acetate successively;
3) ethyl acetate layer is carried out silica gel column chromatography, carry out gradient elution with chloroform and methyl alcohol, the collected volume ratio is 25: 1 the chloroform and the elution fraction of methyl alcohol mixed liquor;
4) component that described step 3) is obtained is carried out silica gel column chromatography, carries out gradient elution with sherwood oil and acetone, and the collected volume ratio is 4: 1 the sherwood oil and the elution fraction of acetone mixed solution;
5) component that described step 4) is obtained is carried out purifying with the hydroxypropyl dextrane gel, with volume ratio be 1: 1 chloroform-methanol mixed solution as elutriant, collect elution fraction;
6) component that described step 5) is obtained is carried out purifying with half preparation HPLC, and the instrument model is Waters 600 half preparative high performance liquid chromatography instrument, and W2487 dual wavelength detector detects, and used semipreparative column model is WatersPrep Nova-
HR C
187.8 * 300mm carries out the HPLC purifying, the collection retention time is the elution peak of 18.5min, 19.6min and 21min, obtains compound shown in formula (III), formula (IV) and the formula (II); Used moving phase is that volume ratio is 52: 48 a methanol-water mixture in the described HPLC purifying, and the flow velocity of described moving phase is 2ml/min.
Another object of the present invention provides the purposes of the Guaianolide sesquiterpene dimers shown in the formula (I).
To be the compound shown in the formula (I) or its pharmacy acceptable salt prevent and/or treat application in tumour medicine and the anti-inflammatory drug in preparation to the purposes of Guaianolide sesquiterpene dimers provided by the present invention.
Guaianolide sesquiterpene dimers shown in the formula (I) or its pharmacy acceptable salt are particularly suitable for preparation and prevent and/or treat human colon carcinoma, liver cancer, cancer of the stomach, lung cancer and ovarian cancer medicine and anti-inflammatory drug.
Described tumour medicine and the anti-inflammatory drug of preventing and/or treating can import body such as muscle, intracutaneous, subcutaneous, vein, mucosal tissue by the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation; Or mixed by other materials or wrap up the back and import body.
Antitumor drug and anti-inflammatory drug so that the Guaianolide sesquiterpene dimers shown in the formula (I) or its pharmacy acceptable salt are activeconstituents when needing, can also add one or more pharmaceutically acceptable carriers in said medicine.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
With the preventing and/or treating tumour medicine and anti-inflammatory drug and can make formulations such as oral, external application, injection of Guaianolide sesquiterpene dimers or its pharmacy acceptable salt preparation, wherein oral preparations comprises tablet, capsule, granule, mixture, vina, pill etc.; External application comprises suppository, liniment, lotion, paste, the agent of transdermal card; Injection comprises injection liquid, suspension, freeze-dried powder etc.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
The present invention from the artemisia anomalas plant, extract, isolate three kinds of new Guaianolide sesquiterpene dimers compounds (artemisia anomalas dimer A, structure is suc as formula shown in (II); Artemisia anomalas dimer B, structure is suc as formula shown in (III); Artemisia anomalas dimer C, structure is suc as formula shown in (IV)), and prepare multiple Guaianolide sesquiterpene dimers compounds based on this.The present invention confirms by experiment: the Guaianolide sesquiterpene dimers compounds has the cytotoxic activity to cancer cells, this compounds has the obvious suppression effect to the Turnover of Mouse Peritoneal Macrophages COX-2 activity that lipopolysaccharides (LPS) stimulates simultaneously, can be used as the activeconstituents of anticancer and anti-inflammatory drug.
Embodiment
The extraction of embodiment 1, artemisia anomalas dimer A, artemisia anomalas dimer B and artemisia anomalas dimer C
With the artemisia anomalas herb meal of 15kg,, extract altogether 3 times with 95% alcohol reflux 3h.Decompression and solvent recovery obtains solid extract 4.52kg; Described solid extract 4kg is suspended in water, extract, collect water layer,, collect ethyl acetate layer with this water layer of ethyl acetate extraction with sherwood oil.With acetic acid ethyl ester extract through silica gel column chromatography, with 100～200 order silica gel dress post, the length of post bed is 1250cm, the internal diameter of post is 25cm, carry out gradient elution according to the flow velocity of 40ml/min successively with the chloroform and the methyl alcohol mixed liquor of following three gradients: the volume ratio of chloroform and methyl alcohol is that the volume ratio of 100: 1 mixed solution 1, chloroform and methyl alcohol is 50: 1 a mixed solution 2, and the volume ratio of chloroform and methyl alcohol is 25: 1 a mixed solution 3.Each gradient elution amount is three times of silicagel column bed volumes.Collection chloroform-methanol volume ratio is 25: 1 o'clock a elution fraction.The elution fraction of above-mentioned collection is carried out silica gel column chromatography again, with 200～300 order silica gel dress post, the length of post bed is 550cm, the internal diameter of post is 13cm, carry out gradient elution according to the flow velocity of 40ml/min successively with the sherwood oil and the acetone mixed solution of following three gradients: the volume ratio of sherwood oil and acetone is that the volume ratio of 15: 1 mixed solution 1, sherwood oil and acetone is 8: 1 a mixed solution 2, and the volume ratio of sherwood oil and acetone is 4: 1 a mixed solution 3.Each gradient elution amount is three times of silicagel column volumes.Collecting sherwood oil-acetone volume ratio is 4: 1 o'clock elution fraction; 60 ℃ of vacuum decompressions of this component are concentrated, then through hydroxypropyl dextrane gel (sephadex LH-20) purifying, with chloroform-methanol (volume ratio is 1: 1) as elutriant; Again through more than half preparation HPLC separation and purification, the instrument model is Waters 600 half preparative high performance liquid chromatography instrument with the concentrated solution behind the purifying, and W2487 dual wavelength detector detects, and used semipreparative column model is Waters PrepNova-
HR C
187.8 * 300mm.Separate as moving phase with methanol-water (volume ratio is 52: 48), flow velocity is 2ml/min.The collection retention time is the elution peak of 18.5min, 19.6min and 21min, obtain compound shown in formula (III), formula (IV) and the formula (II), 60 ℃ are carried out vacuum decompression and concentrate, and obtain 492mg artemisia anomalas dimer A (formula (II)), 86mg artemisia anomalas dimer B (formula (III)) and 58mg artemisia anomalas dimer C (formula (IV)).
Artemisia anomalas dimer A (Artanomalide A), structural formula are white amorphous powder suc as formula shown in the II, and its fusing point is 198 ℃～202 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
HRESIMS m/z：549.24830[M+H]
+(calcd for C
32H
37O
8：549.24692)；
UV(CHCL
3)λ
max 252nm；
IR (KBr) v
Max3437 (OH), 2923,1765 (gamma lactones), 1691 (exocyclic double bond) cm
-1, 1647,1617,1261,1240cm
-1
1H-NMR(CDCl
3，500MHz)：δ6.29(1H，d，J＝5.5，H-2’)，δ6.19(1H，t，J＝1.0，H-3)，δ6.08(1H，d，J＝3.0，H-13’)，δ5.81(1H，d，J＝5.5，H-3’)，δ5.36(1H，d，J＝3.0，H-13’)，δ4.78(1H，dt，J＝2.5；11.0；11.0，H-8)，δ4.06(1H，t，J＝10.0，H-6’)，δ4.02(1H，dt，J＝10.0；11.0，H-6)，δ3.26(1H，d，J＝10.0，H-5)，δ2.86(1H，d，J＝10.0，H-5’)，δ2.76(1H，m，H-7’)，δ2.68(1H，t，J＝11.0；11.0，H-7)，δ2.52(1H，d，J＝12.0，H-13)，δ2.47(1H，dd，J＝11.0；13.5，H-9)，δ2.39(3H，s，H-15)，δ2.33(3H，s，H-14)，δ2.31(1H，dd，J＝5.0；13.5，H-9)，δ2.04(1H，d，J＝12.0，H-13)，δ2.01(3H，s，H-2”)，δ1.74(2H，q，J＝7.0，H-9’)，δ1.56(2H，q，H-8’)，δ1.48(3H，s，H-14’)，δ1.45(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ194.8(C-2)，δ178.7(C-12)，δ170.2(C-4)，δ169.6(C-12’)，δ169.3(C-1”)，δ143.9(C-10)，δ140.1(C-11’)，δ138.5(C-2’)，δ136.1(C-3)，δ134.9(C-3’)，δ134.0(C-1)，δ119.2(C-13’)，δ80.1(C-6)，δ78.0(C-6’)，δ72.8(C-10’)，δ68.0(C-8)，δ66.6(C-5’)，δ63.2(C-1’)，δ61.9(C-11)，δ59.4(C-7)，δ58.2(C-4’)，δ52.0(C-5)，δ44.4(C-9)，δ43.3(C-7’)，δ39.7(C-13)，δ37.0(C-9’)，δ23.7(C-15’)，δ23.0(C-8’)，δ21.5(C-2”)，δ20.5(C-15)，δ20.2(C-14)，δ17.0(C-14’)。
Artemisia anomalas dimer B (Artanomalide B), structural formula are white amorphous powder shown in formula III, its fusing point is 196 ℃～201 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
HRESIMS m/z：507.24330[M+H]
+(calcd for C
30H
35O
7：507.23773)；
UV(CHCL
3)λ
max 251nm；
IR (KBr) v
Max3432 (OH), 2918,1762 (gamma lactones), 1684 (exocyclic double bond) cm
-1, 1636,1622,1252,1241cm
-1
1H-NMR(CDCl
3，500MHz)：δ6.24(1H，d，J＝5.0，H-2’)，δ6.17(1H，t，J＝1.0，H-3)，δ6.12(1H，d，J＝3.5，H-13’)，δ5.85(1H，d，J＝5.0，H-3’)，δ5.32(1H，d，J＝3.5，H-13’)，δ4.72(1H，dt，J＝2.5；10.5；10.5，H-8)，δ4.08(1H，t，J＝10.0，H-6’)，δ4.04(1H，dt，J＝10.0；10.5，H-6)，δ3.23(1H，d，J＝10.0，H-5)，δ2.84(1H，d，J＝10.0，H-5’)，δ2.73(1H，m，H-7’)，δ2.64(1H，t，J＝10.5；11.0，H-7)，δ2.55(1H，d，J＝12.0，H-13)，δ2.45(1H，dd，J＝11.0；13.0，H-9)，δ2.42(3H，s，H-15)，δ2.31(3H，s，H-14)，δ2.28(1H，dd，J＝5.0；13.0，H-9)，δ2.06(1H，d，J＝12.0，H-13)，δ1.78(2H，q，J＝7.0，H-9’)，δ1.56(2H，q，H-8’)，δ1.46(3H，s，H-14’)，δ1.43(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ193.9(C-2)，δ177.2(C-12)，δ170.2(C-4)，δ168.9(C-12’)，δ143.9(C-10)，δ139.2(C-11’)，δ138.7(C-2’)，δ135.6(C-3)，δ134.9(C-3’)，δ134.2(C-1)，δ118.9(C-13’)，δ80.5(C-6)，δ78.2(C-6’)，δ72.6(C-10’)，δ67.6(C-8)，δ66.9(C-5’)，δ63.2(C-1’)，δ61.9(C-11)，δ59.5(C-7)，δ58.7(C-4’)，δ52.0(C-5)，δ44.3(C-9)，δ43.1(C-7’)，δ39.6(C-13)，δ37.3(C-9’)，δ23.9(C-15’)，δ22.8(C-8’)，δ20.4(C-15)，δ20.2(C-14)，δ16.8(C-14’)。
Artemisia anomalas dimer C (Artanomalide C), structural formula are white amorphous powder suc as formula shown in the IV, and its fusing point is 195 ℃～198 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
HRESIMS m/z：491.24302[M+H]
+(calcd for C
30H
35O
6：491.24281)；
UV(CHCL
3)λ
max 252nm；
IR (KBr) v
Max3425 (OH), 2918,1762 (gamma lactones), 1696 (exocyclic double bond) cm
-1, 1643,1622,1258,1237cm
-1
1H-NMR(CDCl
3，500MHz)：δ6.26(1H，d，J＝5.5，H-2’)，δ6.17(1H，t，J＝1.0，H-3)，δ6.06(1H，d，J＝3.0，H-13’)，δ5.83(1H，d，J＝5.5，H-3’)，δ5.34(1H，d，J＝3.0，H-13’)，δ4.04(1H，t，J＝10.5，H-6’)，δ4.02(1H，dt，J＝10.5；11.0，H-6)，δ3.24(1H，d，J＝10.5，H-5)，δ2.83(1H，d，J＝10.5，H-5’)，δ2.72(1H，m，H-7’)，δ2.64(1H，t，J＝11.0；11.0，H-7)，δ2.55(1H，d，J＝12.0，H-13)，δ2.36(3H，s，H-15)，δ2.32(3H，s，H-14)，δ2.04(1H，d，J＝12.0，H-13)，δ1.92(2H，m，H-9)，δ1.74(2H，q，J＝7.0，H-9’)，δ1.56(2H，q，H-8’)，δ1.52(1H，m，H-8)，δ1.24(1H，m，H-8)，δ1.48(3H，s，H-14’)，δ1.45(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ194.8(C-2)，δ178.7(C-12)，δ170.2(C-4)，δ169.6(C-12’)，δ143.9(C-10)，δ140.1(C-11’)，δ138.5(C-2’)，δ136.1(C-3)，δ134.9(C-3’)，δ134.0(C-1)，δ119.2(C-13’)，δ80.1(C-6)，δ78.0(C-6’)，δ72.8(C-10’)，δ66.6(C-5’)，δ63.2(C-1’)，δ61.9(C-11)，δ59.4(C-7)，δ58.2(C-4’)，δ52.0(C-5)，δ43.3(C-7’)，δ39.7(C-13)，δ37.0(C-9’)，δ34.5(C-9)，δ26.5(C-8)，δ23.7(C-15’)，δ23.0(C-8’)，δ20.5(C-15)，δ20.2(C-14)，δ17.0(C-14’)。
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
The preparation of embodiment 2, other derivatives
With artemisia anomalas dimer A, the B or the C that obtain among the embodiment 1 is reactant, carries out various derivative reactions, can obtain the derivative of Guaianolide sesquiterpene dimers compd A of the present invention:
1, artemisia anomalas dimer A derivative reaction
2, artemisia anomalas dimer B derivative reaction
3, artemisia anomalas dimer C derivative reaction
Specific as follows:
1, artemisia anomalas dimer chloro thing 1 (R in the formula (I)
1Be chlorine, R
2Be acetoxyl group) preparation
The artemisia anomalas dimer A of 10mg among the embodiment 1 is dissolved in the 5ml pyridine, is added dropwise to the 0.5ml thionyl chloride under the condition of ice bath, reacted 1 hour, removal of solvent under reduced pressure promptly gets product 1.
This chloro thing 1 is a white powder, and its fusing point is 205 ℃～208 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
ESIMS m/z：567[M+H]
+(C
32H
36ClO
7).
1H-NMR(CDCl
3，500MHz)：δ6.06(1H，t，J＝1.5，H-3)，δ3.14(1H，d，J＝11.0，H-5)，δ4.13(1H，dt，J＝11.0；11.5，H-6)，δ2.82(1H，t，J＝11.5；11.5，H-7)，4.96(1H，dt，J＝2.5；11.5；11.5，H-8)，δ2.49(1H，dd，J＝11.5；13.0，H-9)，δ2.35(1H，dd，J＝3.0；13.5，H-9)，δ2.46(1H，d，J＝12.0，H-13)，δ2.12(1H，d，J＝12.0，H-13)，δ2.23(3H，s，H-14)，δ2.31(3H，s，H-15)，δ6.21(1H，d，J＝5.5，H-2’)，δ5.75(1H，d，J＝5.5，H-3’)，δ2.76(1H，d，J＝10.5，H-5’)，δ4.02(1H，t，J＝10.5，H-6’)，δ2.72(1H，m，H-7’)，δ1.52(2H，q，H-8’)，δ1.65(2H，q，J＝7.0，H-9’)，δ6.04(1H，d，J＝3.0，H-13’)，δ5.31(1H，d，J＝3.0，H-13’)，δ1.42(3H，s，H-14’)，δ1.40(3H，s，H-15’)，δ2.03(3H，s，H-2”)；
13C-NMR(CDCl
3，125MHz)：δ132.5(C-1)，δ195.2(C-2)，δ134.2(C-3)，δ172.1(C-4)，δ50.8(C-5)，δ79.8(C-6)，δ57.6(C-7)，49.5(C-8)，δ42.1(C-9)，δ142.6(C-10)，δ60.8(C-11)，δ178.2(C-12)，δ38.8(C-13)，δ19.8(C-14)，δ20.1(C-15)，δ62.9(C-1’)，δ137.6(C-2’)，δ133.8(C-3’)，δ57.7(C-4’)，δ65.8(C-5’)，δ77.4(C-6’)，δ42.6(C-7’)，δ22.6(C-8’)，δ36.5(C-9’)，δ72.1(C-10’)，δ139.1(C-11’)，δ169.2(C-12’)，δ118.6(C-13’)，δ16.8(C-14’)，δ23.3(C-15’)，δ170.2(C-1”)，δ21.2(C-2”)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
2, artemisia anomalas dimer mercapto thing 2 (R in the formula (I)
1Be sulfydryl, R
2Be acetoxyl group) preparation
The artemisia anomalas dimer A of 100mg among the embodiment 1 is dissolved in the 10ml pyridine, adds trimethylchlorosilane 20mg under the room temperature, the TLC monitoring reaction is to raw material artemisia anomalas dimer A completely dissolve, and after question response finished, removal of solvent under reduced pressure was collected resistates; Above-mentioned resistates is dissolved in the dimethyl formamide (DMF), adds thiocarbamide, the TLC monitoring reaction, adds NaOH solution and carries out saponification reaction after reaction finishes to raw material artemisia anomalas dimer A completely dissolve, and reaction finishes the back recrystallization and obtains product 2.
This mercapto is a white powder for thing 2, and its fusing point is 185 ℃～188 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
ESIMS m/z：565[M+H]
+(C
32H
37SO
7).
1H-NMR(CDCl
3，500MHz)：δ6.02(1H，t，J＝1.5，H-3)，δ3.04(1H，d，J＝10.5，H-5)，δ4.05(1H，dt，J＝10.5；11.5，H-6)，δ2.74(1H，t，J＝11.0；11.5，H-7)，3.62(1H，dt，J＝2.5；11.0；11.5，H-8)，δ2.58(1H，dd，J＝11.5；13.0，H-9)，δ2.32(1H，dd，J＝3.0；13.5，H-9)，δ2.46(1H，d，J＝12.0，H-13)，δ2.09(1H，d，J＝12.0，H-13)，δ2.21(3H，s，H-14)，δ2.26(3H，s，H-15)，δ6.17(1H，d，J＝5.5，H-2’)，δ5.71(1H，d，J＝5.5，H-3’)，δ2.71(1H，d，J＝10.5，H-5’)，δ3.92(1H，t，J＝10.5，H-6’)，δ2.69(1H，m，H-7’)，δ1.48(2H，q，H-8’)，δ1.62(2H，q，J＝7.0，H-9’)，δ6.02(1H，d，J＝3.0，H-13’)，δ5.28(1H，d，J＝3.0，H-13’)，δ1.36(3H，s，H-14’)，δ1.34(3H，s，H-15’)，δ2.03(3H，s，H-2”)；
13C-NMR(CDCl
3，125MHz)：δ132.7(C-1)，δ195.1(C-2)，δ134.8(C-3)，δ171.6(C-4)，δ51.8(C-5)，δ79.3(C-6)，δ59.8(C-7)，42.5(C-8)，δ40.5(C-9)，δ142.2(C-10)，δ60.2(C-11)，δ177.6(C-12)，δ38.2(C-13)，δ18.3(C-14)，δ21.2(C-15)，δ64.1(C-1’)，δ135.7(C-2’)，δ134.2(C-3’)，δ56.3(C-4’)，δ64.4(C-5’)，δ76.8(C-6’)，δ43.8(C-7’)，δ23.2(C-8’)，δ37.8(C-9’)，δ71.2(C-10’)，δ137.6(C-11’)，δ169.8(C-12’)，δ117.5(C-13’)，δ16.9(C-14’)，δ24.3(C-15’)，δ169.3(C-1”)，δ21.5(C-2”)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
3, artemisia anomalas dimer acetoxylation thing 3 (R in the formula (I)
1Be acetoxyl group, R
2Be acetoxyl group) preparation
The artemisia anomalas dimer A of 50mg among the embodiment 1 is dissolved in the 5ml pyridine, is added dropwise to the 1ml Acetyl Chloride 98Min. under the room temperature, the TLC monitoring reaction is to the raw material completely dissolve, and after reaction finished, removal of solvent under reduced pressure added a small amount of methylene dichloride dissolving, and organic layer is with the saturated NaHCO of 5ml
3Wash three times, dichloromethane layer is with anhydrous sodium sulfate drying, filters, and is evaporated to driedly, promptly gets product 3.
This acetoxylation thing 3 is a white powder.
Structural identification:
ESIMS m/z：591[M+H]
+(C
34H
39O
9).
1H-NMR(CDCl
3，500MHz)：δ6.19(1H，t，J＝1.5，H-3)，δ3.26(1H，d，J＝10.5，H-5)，δ4.05(1H，dt，J＝10.5；11.5，H-6)，δ2.74(1H，t，J＝11.0；11.5，H-7)，4.88(1H，dt，J＝2.5；11.0；11.5，H-8)，δ2.48(1H，dd，J＝11.5；13.0，H-9)，δ2.29(1H，dd，J＝3.0；13.5，H-9)，δ2.59(1H，d，J＝12.0，H-13)，δ2.02(1H，d，J＝12.0，H-13)，δ2.31(3H，s，H-14)，δ2.36(3H，s，H-15)，δ6.26(1H，d，J＝5.5，H-2’)，δ5.56(1H，d，J＝5.5，H-3’)，δ2.62(1H，d，J＝10.5，H-5’)，δ3.94(1H，t，J＝10.5，H-6’)，δ2.62(1H，m，H-7’)，δ1.62(2H，q，H-8’)，δ1.76(2H，q，J＝7.0，H-9’)，δ6.02(1H，d，J＝3.0，H-13’)，δ5.28(1H，d，J＝3.0，H-13’)，δ1.32(3H，s，H-14’)，δ1.28(3H，s，H-15’)，δ2.01(3H，s，H-2”)，δ2.02(3H，s，H-2”’)；
13C-NMR(CDCl
3，125MHz)：δ134.2(C-1)，δ194.8(C-2)，δ135.8(C-3)，δ170.2(C-4)，δ51.9(C-5)，δ80.3(C-6)，δ58.2(C-7)，70.2(C-8)，δ43.2(C-9)，δ143.2(C-10)，δ61.2(C-11)，δ176.2(C-12)，δ40.3(C-13)，δ20.2(C-14)，δ20.6(C-15)，δ63.6(C-1’)，δ134.2(C-2’)，δ135.5(C-3’)，δ58.3(C-4’)，δ66.4(C-5’)，δ77.2(C-6’)，δ44.6(C-7’)，δ23.6(C-8’)，δ38.2(C-9’)，δ72.4(C-10’)，δ138.6(C-11’)，δ169.2(C-12’)，δ118.5(C-13’)，δ17.4(C-14’)，δ23.6(C-15’)，δ169.3(C-1”)，δ22.5(C-2”)，δ169.1(C-1”’)，δ22.2(C-2”’)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
4, artemisia anomalas dimer succinyl-oxide compound 4 (R in the formula (I)
1Be amber acyloxy, R
2Be acetoxyl group) preparation:
The artemisia anomalas dimer A of 100mg among the embodiment 1 is dissolved in the 10ml tetrahydrofuran (THF) (THF), add 25mg succinyl oxide and 5mg 4-Dimethylamino pyridine (DMAP) under the room temperature, the TLC monitoring reaction is to raw material artemisia anomalas dimer A completely dissolve, after reaction finishes, removal of solvent under reduced pressure, column chromatography for separation (eluent is that volume ratio is 100: 3 the methylene dichloride and the mixed solution of methyl alcohol) promptly gets product 4.
This succinyl-oxide compound 4 is a white powder.
Structural identification:
ESIMS m/z：649[M+H]
+(C
36H
41O
11).
1H-NMR(CDCL
3，500MHz)：δ6.13(1H，t，J＝1.5，H-3)，δ3.22(1H，d，J＝10.5，H-5)，δ4.02(1H，dt，J＝11.0；11.0，H-6)，δ2.82(1H，t，J＝11.0；11.0，H-7)，4.94(1H，dt，J＝2.5；11.0；11.5，H-8)，δ2.33(1H，dd，J＝11.5；13.0，H-9)，δ2.24(1H，dd，J＝3.0；13.5，H-9)，δ2.46(1H，d，J＝12.0，H-13)，δ2.06(1H，d，J＝12.0，H-13)，δ2.24(3H，s，H-14)，δ2.31(3H，s，H-15)，δ6.21(1H，d，J＝5.5，H-2’)，δ5.32(1H，d，J＝5.5，H-3’)，δ2.52(1H，d，J＝10.5，H-5’)，δ3.82(1H，t，J＝10.5，H-6’)，δ2.54(1H，m，H-7’)，δ1.54(2H，q，H-8’)，δ1.68(2H，q，J＝7.0，H-9’)，δ6.02(1H，d，J＝3.0，H-13’)，δ5.28(1H，d，J＝3.0，H-13’)，δ1.32(3H，s，H-14’)，δ1.28(3H，s，H-15’)，δ2.52(2H，m，H-2”)，δ2.62(2H，m，H-3”)，δ2.04(3H，s，H-2”’)；
13C-NMR(CDCL
3，125MHz)：δ134.2(C-1)，δ194.8(C-2)，δ135.8(C-3)，δ170.2(C-4)，δ51.9(C-5)，δ80.3(C-6)，δ57.6(C-7)，68.5(C-8)，δ43.8(C-9)，δ143.2(C-10)，δ61.2(C-11)，δ176.2(C-12)，δ40.3(C-13)，δ20.2(C-14)，δ20.6(C-15)，δ63.6(C-1’)，δ134.2(C-2’)，δ135.5(C-3’)，δ58.3(C-4’)，δ66.4(C-5’)，δ77.2(C-6’)，δ44.6(C-7’)，δ23.6(C-8’)，δ38.2(C-9’)，δ72.4(C-10’)，δ138.6(C-11’)，δ169.2(C-12’)，δ118.5(C-13’)，δ17.4(C-14’)，δ23.6(C-15’)，δ172.8(C-1”)，δ29.2(C-2”)，δ31.5(C-3”)，δ174.5(C-4”)，δ169.1(C-1”’)，δ22.2(C-2”’)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
5, artemisia anomalas dimer benzyloxy carbo methoxy group derivative 5 (R in the formula (I)
1Be benzyloxy carbo methoxy group, R
2Be acetoxyl group) preparation:
The artemisia anomalas dimer A of 100mg among the embodiment 1 is dissolved among the 10ml DMF, and 0 ℃ adds 15mgNaH down, after the reaction 15min, adds 60mg benzyl acetate bromide (BrCH
2COOCH
2C
6H
5), being warming up to 50 ℃ of reactions, the TLC monitoring reaction is to raw material artemisia anomalas dimer A completely dissolve, and after reaction finished, removal of solvent under reduced pressure promptly got product 5.
This benzyloxy carbo methoxy group derivative 5 is a white powder.
Structural identification:
ESIMS m/z：697[M+H]
+(C
41H
45O
10).
1H-NMR(CDCL
3，500MHz)：δ6.12(1H，t，J＝1.5，H-3)，δ3.35(1H，d，J＝10.5，H-5)，δ4.02(1H，dt，J＝10.5；11.0，H-6)，δ2.74(1H，t，J＝11.0；11.0，H-7)，4.24(1H，dt，J＝2.5；11.0；11.0，H-8)，δ2.21(1H，dd，J＝11.5；13.0，H-9)，δ1.96(1H，dd，J＝3.0；13.5，H-9)，δ2.62(1H，d，J＝12.0，H-13)，δ2.14(1H，d，J＝12.0，H-13)，δ2.29(3H，s，H-14)，δ2.32(3H，s，H-15)，δ6.22(1H，d，J＝5.5，H-2’)，δ5.53(1H，d，J＝5.5，H-3’)，δ2.48(1H，d，J＝10.5，H-5’)，δ3.82(1H，t，J＝10.5，H-6’)，δ2.62(1H，m，H-7’)，δ1.64(2H，q，H-8’)，δ1.82(2H，q，J＝7.0，H-9’)，δ6.02(1H，d，J＝3.0，H-13’)，δ5.34(1H，d，J＝3.0，H-13’)，δ1.30(3H，s，H-14’)，δ1.25(3H，s，H-15’)，δ4.32(2H，d，J＝13.0，H-1”)，δ5.32(2H，d，J＝12.5，H-3”)，δ7.35(5H，m，H-Ar)，δ2.02(3H，s，H-2”’)；
13C-NMR(CDCL
3，125MHz)：δ133.5(C-1)，δ194.2(C-2)，δ135.2(C-3)，δ169.2(C-4)，δ52.4(C-5)，δ80.1(C-6)，δ57.2(C-7)，72.5(C-8)，δ42.3(C-9)，δ142.8(C-10)，δ60.5(C-11)，δ175.4(C-12)，δ39.4(C-13)，δ20.5(C-14)，δ21.2(C-15)，δ62.9(C-1’)，δ133.7(C-2’)，δ134.5(C-3’)，δ57.6(C-4’)，δ65.4(C-5’)，δ75.2(C-6’)，δ43.9(C-7’)，δ23.3(C-8’)，δ36.2(C-9’)，δ73.4(C-10’)，δ136.2(C-11’)，δ170.3(C-12’)，δ119.2(C-13’)，δ18.6(C-14’)，δ22.8(C-15’)，δ64.9(C-1”)，δ168.5(C-2”)，δ68.9(C-3”)，δ140.5(Ar-C-1)，δ126.6(Ar-C-2；6)，δ128.9(Ar-C-3；5)，δ127.4(Ar-C-4)，δ169.1(C-1”’)，δ22.6(C-2”’)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
6, the two chloro thing 6 (R in the formula (I) of artemisia anomalas dimer
1And R
2Be all chlorine) preparation
The artemisia anomalas dimer B of 8mg among the embodiment 1 is dissolved in the 5ml pyridine, is added dropwise to the 0.5ml thionyl chloride under the condition of ice bath, reacted 1 hour,, promptly get product 6 in removal of solvent under reduced pressure.
This pair chloro thing 6 is a white powder, and its fusing point is 207 ℃～210 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
ESIMS m/z：543[M+H]
+(C
30H
33Cl
2O
5).
1H-NMR(CDCl
3，500MHz)：δ6.04(1H，t，J＝1.5，H-3)，δ3.16(1H，d，J＝11.0，H-5)，δ4.11(1H，dt，J＝11.0；11.5，H-6)，δ2.81(1H，t，J＝11.5；11.5，H-7)，4.94(1H，dt，J＝2.5；11.5；11.5，H-8)，δ2.49(1H，dd，J＝11.5；13.0，H-9)，δ2.35(1H，dd，J＝3.0；13.5，H-9)，δ2.42(1H，d，J＝12.0，H-13)，δ2.16(1H，d，J＝12.0，H-13)，δ2.18(3H，s，H-14)，δ2.28(3H，s，H-15)，δ6.18(1H，d，J＝5.5，H-12’)，δ5.72(1H，d，J＝5.5，H-3’)，δ2.74(1H，d，J＝10.5，H-5’)，δ4.06(1H，t，J＝10.5，H-6’)，δ2.76(1H，m，H-7’)，δ1.50(2H，q，H-8’)，δ1.64(2H，q，J＝7.0，H-9’)，δ6.02(1H，d，J＝3.0，H-13’)，δ5.29(1H，d，J＝3.0，H-13’)，δ1.42(3H，s，H-14’)，δ1.37(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ132.2(C-1)，δ194.9(C-2)，δ134.8(C-3)，δ172.2(C-4)，δ50.9(C-5)，δ79.2(C-6)，δ57.4(C-7)，49.6(C-8)，δ41.7(C-9)，δ141.5(C-10)，δ60.2(C-11)，δ178.4(C-12)，δ38.6(C-13)，δ19.8(C-14)，δ20.4(C-15)，δ62.7(C-1’)，δ137.8(C-2’)，δ133.6(C-3’)，δ57.4(C-4’)，δ65.4(C-5’)，δ77.2(C-6’)，δ42.7(C-7’)，δ22.9(C-8’)，δ39.2(C-9’)，δ58.4(C-10’)，δ138.7(C-11’)，δ168.9(C-12’)，δ117.8(C-13’)，δ16.7(C-14’)，δ23.2(C-15’)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
7, the two mercapto thing 7 (R in the formula (I) of artemisia anomalas dimer
1And R
2Be all sulfydryl) preparation
The artemisia anomalas dimer B of 30mg among the embodiment 1 is dissolved in the 10ml pyridine, adds trimethylchlorosilane 15mg under the room temperature, the TLC monitoring reaction is to raw material artemisia anomalas dimer B completely dissolve, and after question response finished, removal of solvent under reduced pressure was collected resistates; Above-mentioned resistates is dissolved in the dimethyl formamide (DMF), adds thiocarbamide, the TLC monitoring reaction, adds NaOH solution and carries out saponification reaction after reaction finishes to raw material artemisia anomalas dimer B completely dissolve, and reaction finishes the back recrystallization and obtains product 7.
This pair mercapto is a white powder for thing 7, and its fusing point is 181 ℃～184 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
ESIMS m/z：539[M+H]
+(C
30H
35S
2O
5).
1H-NMR(CDCl
3，500MHz)：δ6.11(1H，t，J＝1.5，H-3)，δ3.08(1H，d，J＝10.5，H-5)，δ4.02(1H，dt，J＝10.5；11.0，H-6)，δ2.68(1H，t，J＝11.0；11.0，H-7)，3.60(1H，dt，J＝2.5；11.0；11.5，H-8)，δ2.48(1H，dd，J＝11.5；13.0，H-9)，δ2.35(1H，dd，J＝3.0；13.5，H-9)，δ2.42(1H，d，J＝12.0，H-13)，δ2.02(1H，d，J＝12.0，H-13)，δ2.16(3H，s，H-14)，δ2.24(3H，s，H-15)，δ6.13(1H，d，J＝5.5，H-2’)，δ5.68(1H，d，J＝5.5，H-3’)，δ2.67(1H，d，J＝10.5，H-5’)，δ3.87(1H，t，J＝10.5，H-6’)，δ2.62(1H，m，H-7’)，δ1.49(2H，q，H-8’)，δ1.74(2H，q，J＝7.0，H-9’)，δ6.01(1H，d，J＝3.5，H-13’)，δ5.24(1H，d，J＝3.5，H-13’)，δ1.32(3H，s，H-14’)，δ1.30(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ132.2(C-1)，δ194.6(C-2)，δ132.7(C-3)，δ170.4(C-4)，δ51.2(C-5)，δ79.6(C-6)，δ59.8(C-7)，35.3(C-8)，δ42.5(C-9)，δ140.6(C-10)，δ60.2(C-11)，δ175.8(C-12)，δ38.7(C-13)，δ17.6(C-14)，δ21.2(C-15)，δ64.1(C-1’)，δ132.8(C-2’)，δ132.6(C-3’)，δ56.3(C-4’)，δ64.6(C-5’)，δ76.2(C-6’)，δ45.8(C-7’)，δ22.8(C-8’)，δ36.5(C-9’)，δ50.2(C-10’)，δ135.6(C-11’)，δ168.4(C-12’)，δ115.6(C-13’)，δ16.6(C-14’)，δ24.2(C-15’)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
8, artemisia anomalas dimer amide 8 (R in the formula (I)
1Be amino, R
2Be acetoxyl group) preparation
The artemisia anomalas dimer A of 8mg among the embodiment 1 is dissolved in the 5ml pyridine, be added dropwise to the 0.5ml thionyl chloride under the condition of ice bath, reacted 1 hour, removal of solvent under reduced pressure, the thick product of gained is dissolved in the anhydrous methylene chloride (DCM), the methanol solution (1M) that adds 1ml ammonia, stirring at room TLC monitoring reaction disappears to the chloro thing, and concentrating under reduced pressure promptly gets product 8.
This ammonia is white powder for thing 8.Structural identification:
ESIMS m/z：548[M+H]
+(C
32H
38NO
7).
1H-NMR(CDCl
3，500MHz)：δ6.14(1H，t，J＝1.5，H-3)，δ3.12(1H，d，J＝11.0，H-5)，δ4.06(1H，dt，J＝11.0；11.0，H-6)，δ2.32(1H，t，J＝11.0；11.0，H-7)，2.73(1H，dt，J＝2.0；11.0；11.5，H-8)，δ2.34(1H，dd，J＝11.5；13.5，H-9)，δ2.12(1H，dd，J＝3.0；13.5，H-9)，δ2.45(1H，d，J＝12.0，H-13)，δ2.06(1H，d，J＝12.0，H-13)，δ2.12(3H，s，H-14)，δ2.28(3H，s，H-15)，δ6.17(1H，d，J＝5.5，H-2’)，δ5.62(1H，d，J＝5.5，H-3’)，δ2.62(1H，d，J＝10.5，H-5’)，δ3.81(1H，t，J＝10.5，H-6’)，δ2.62(1H，m，H-7’)，δ1.52(2H，q，H-8’)，δ1.70(2H，q，J＝7.0，H-9’)，δ6.01(1H，d，J＝3.5，H-13’)，δ5.22(1H，d，J＝3.5，H-13’)，δ1.36(3H，s，H-14’)，δ1.28(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ131.2(C-1)，δ194.8(C-2)，δ132.4(C-3)，δ170.5(C-4)，δ51.4(C-5)，δ78.2(C-6)，δ42.3(C-7)，46.2(C-8)，δ40.1(C-9)，δ143.6(C-10)，δ56.2(C-11)，δ176.2(C-12)，δ32.7(C-13)，δ17.4(C-14)，δ21.5(C-15)，δ64.2(C-1’)，δ133.4(C-2’)，δ132.6(C-3’)，δ56.6(C-4’)，δ64.2(C-5’)，δ76.2(C-6’)，δ45.6(C-7’)，δ22.4(C-8’)，δ36.6(C-9’)，δ50.1(C-10’)，δ135.2(C-11’)，δ168.2(C-12’)，δ115.4(C-13’)，δ16.7(C-14’)，δ24.4(C-15’)；
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
9, artemisia anomalas dimer chloro thing 9 (R in the formula (I)
1Be hydrogen, R
2Be chlorine) preparation
The artemisia anomalas dimer C of 8mg among the embodiment 1 is dissolved in the 5ml pyridine, is added dropwise to the 0.5ml thionyl chloride under the condition of ice bath, reacted 1 hour, removal of solvent under reduced pressure promptly gets product 9.
This chloro thing 9 is a white powder, and its fusing point is 198 ℃～202 ℃, and used instrument is an X4 type micro melting point apparatus (thermometer is not proofreaied and correct).
Structural identification:
ESIMS m/z：509[M+H]
+(C
30H
34ClO
5).
1H-NMR(CDCl
3，500MHz)：δ6.18(1H，d，J＝5.5，H-2’)，δ6.12(1H，t，J＝1.0，H-3)，δ6.02(1H，d，J＝3.0，H-13’)，δ5.81(1H，d，J＝5.5，H-3’)，δ5.31(1H，d，J＝3.0，H-13’)，δ3.98(1H，t，J＝11.0，H-6’)，δ3.95(1H，dt，J＝11.0；11.0，H-6)，δ3.21(1H，d，J＝10.5，H-5)，δ2.80(1H，d，J＝10.5，H-5’)，δ2.69(1H，m，H-7’)，δ2.62(1H，t，J＝11.0；11.0，H-7)，δ2.51(1H，d，J＝12.0，H-13)，δ2.32(3H，s，H-15)，δ2.27(3H，s，H-14)，δ2.02(1H，d，J＝12.0，H-13)，δ1.89(2H，m，H-9)，δ1.68(2H，q，J＝7.0，H-9’)，δ1.52(2H，q，H-8’)，δ1.48(1H，m，H-8)，δ1.20(1H，m，H-8)，δ1.46(3H，s，H-14’)，δ1.65(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ194.2(C-2)，δ178.6(C-12)，δ170.3(C-4)，δ169.2(C-12’)，δ143.2(C-10)，δ140.3(C-11’)，δ138.2(C-2’)，δ135.8(C-3)，δ133.7(C-3’)，δ133.8(C-1)，δ119.2(C-13’)，δ80.5(C-6)，δ77.2(C-6’)，δ66.3(C-5’)，δ63.2(C-1’)，δ61.9(C-11)，δ60.8(C-10’)，δ59.4(C-7)，δ58.2(C-4’)，δ52.0(C-5)，δ43.3(C-7’)，δ39.7(C-13)，δ39.6(C-9’)，δ34.5(C-9)，δ27.2(C-15’)，δ26.5(C-8)，δ23.0(C-8’)，δ20.3(C-15)，δ20.2(C-14)，δ17.2(C-14’)。
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
10, artemisia anomalas dimer acetoxylation thing 10 (R in the formula (I)
1Be hydrogen, R
2Be acetoxyl group) preparation
The artemisia anomalas dimer C of 35mg among the embodiment 1 is dissolved in the 5ml pyridine, is added dropwise to the 1ml Acetyl Chloride 98Min. under the room temperature, the TLC monitoring reaction is to the raw material completely dissolve, and after reaction finished, removal of solvent under reduced pressure added a small amount of methylene dichloride dissolving, and organic layer is with the saturated NaHCO of 5ml
3Wash three times, dichloromethane layer is with anhydrous sodium sulfate drying, filters, and is evaporated to driedly, promptly gets product 10.
This acetoxylation thing 10 is a white powder.
Structural identification:
ESIMS m/z：533[M+H]
+(C
32H
37O
7).
1H-NMR(CDCl
3，500MHz)：δ6.22(1H，d，J＝5.5，H-2’)，δ6.14(1H，t，J＝1.0，H-3)，δ6.03(1H，d，J＝3.5，H-13’)，δ5.76(1H，d，J＝5.5，H-3’)，δ5.33(1H，d，J＝3.5，H-13’)，δ3.95(1H，t，J＝11.0，H-6’)，δ3.92(1H，dt，J＝11.0；11.0，H-6)，δ3.18(1H，d，J＝10.5，H-5)，δ2.82(1H，d，J＝10.5，H-5’)，δ2.72(1H，m，H-7’)，δ2.64(1H，t，J＝11.0；11.0，H-7)，δ2.52(1H，d，J＝12.0，H-13)，δ2.32(3H，s，H-15)，δ2.25(3H，s，H-14)，δ2.06(1H，d，J＝12.0，H-13)，δ2.05(3H，s，H-2”)，δ1.88(2H，m，H-9)，δ1.70(2H，q，J＝7.0，H-9’)，δ1.52(2H，q，H-8’)，δ1.46(1H，m，H-8)，δ1.18(1H，m，H-8)，δ1.48(3H，s，H-14’)，δ1.65(3H，s，H-15’)；
13C-NMR(CDCl
3，125MHz)：δ194.2(C-2)，δ178.6(C-12)，δ170.3(C-4)，δ169.2(C-12’)，δ169.0(C-1”)，δ143.2(C-10)，δ140.3(C-11’)，δ138.2(C-2’)，δ135.8(C-3)，δ133.7(C-3’)，δ133.8(C-1)，δ119.2(C-13’)，δ81.2(C-10’)，δ80.5(C-6)，δ77.2(C-6’)，δ66.3(C-5’)，δ61.9(C-11)，δ60.8(C-1’)，δ59.4(C-7)，δ58.2(C-4’)，δ52.0(C-5)，δ43.3(C-7’)，δ39.7(C-13)，δ36.2(C-9’)，δ34.5(C-9)，δ26.5(C-8)，δ23.0(C-8’)，δ21.5(C-2”)，δ20.3(C-15)，δ20.2(C-14)，δ20.2(C-15’)，δ17.2(C-14’)。
Above-mentioned collection of illustrative plates result shows that the gained compound structure is correct.
Embodiment 3, Guaianolide sesquiterpene dimers compound anti-cancering activity
1, experimental cell
Human colon cancer cell strain HCT-8, human hepatoma cell strain Bel
7402, human stomach cancer cell line BGC
823, human lung carcinoma cell line A549, human oophoroma cell line A2780.
Above-mentioned cell strain is incubated at respectively in the RPMI1640 complete culture solution that adds 10% deactivation newborn calf serum.Add 100IU/mL penicillin and 100 μ g/mL Streptomycin sulphates and 10mM HEPES in the nutrient solution, and place 37 ℃, 5%CO
2Cultivate in the incubator.Experiment all is in logarithmic phase with cell.
2, experiment medicine
8 kinds of Guaianolide sesquiterpene dimers compounds that prepare among the embodiment 1-2: artemisia anomalas dimer A, artemisia anomalas dimer B, artemisia anomalas dimer chloro thing 1, artemisia anomalas dimer mercapto thing 2, artemisia anomalas dimer acetoxylation thing 3, artemisia anomalas dimer succinyl-oxide compound 4, artemisia anomalas dimer benzyloxy carbo methoxy group derivative 5, the two mercapto things 7 of artemisia anomalas dimer; And with taxol (Beijing XieHe medicine Factory, product batch number: 060103) as the positive control medicine.With the substratum compound concentration is the drug solution of 10nM-100 μ M.
3, the anticancer cytoactive of cell is measured
Adopt mtt assay to measure:
The cell in vegetative period of taking the logarithm after trypsinase-EDTA Digestive system digestion, is mixed with single cell suspension, and in 96 orifice plates, every hole adds 100 μ l, HCT-8, Bel with cell suspension inoculation
7402, BGC
823, A549 and A2780 inoculum density be respectively 6 * 10
4/ ml, 6 * 10
4/ ml, 5 * 10
4/ ml, 1 * 10
5/ ml, 7 * 10
4/ ml and 5 * 10
4/ ml, cultivate after 24 hours, drug solution by group distance 8 kinds of Guaianolide sesquiterpene dimers compounds of 1: 10 usefulness nutrient solution (1640 substratum that promptly contain 10% foetal calf serum) dilution and positive control medicine taxol, make every kind of drug concentrations be respectively 100 μ M, 10 μ M, 1 μ M, 0.1 μ M, 0.01 μ M, continue to cultivate 72 hours.Then, every hole adds 50 μ l MTT, 37 ℃ hatch 4 hours after, abandon substratum and MTT, every hole adds 200 μ l DMSO dissolving MTT first hairpin particle immediately, behind the microoscillator vibration mixing, measure optical density(OD) (OD) value with microplate reader, reference wavelength is 450nm, the detection wavelength is 570nm, at last, calculate the inhibiting rate of medicine, and calculate IC according to middle efficacious prescriptions journey to tumour cell according to following formula
50Value:
Inhibiting rate (%)=(the average OD value of the control group-average OD value of administration the group)/average OD value of control group * 100% (OD wherein
Contrast, OD
ExperimentFor deducting OD
BlankEmpirical value).
4, experimental result
The various medicines that experiment records are to the IC of 5 kinds of cancer cells
50Be worth as shown in table 1:
The cell toxicity test result of table 1 Guaianolide sesquiterpene dimers compound
Table 1 data show that 8 kinds of Guaianolide sesquiterpene dimers compounds of the present invention all have the cytotoxic activity of anticancer cell in various degree, and wherein artemisia anomalas dimer A is better active to colorectal carcinoma, liver cancer and ovarian cancer; Artemisia anomalas dimer B is better active to colorectal carcinoma and ovarian cancer; 1 pair of five kinds of cancer cells inhibiting rate of artemisia anomalas dimer chloro thing are all better; 2 pairs of liver cancer of artemisia anomalas dimer mercapto thing and ovarian cancer are better active; 3 pairs of artemisia anomalas dimer acetoxylation things all the other four kinds of cancer cells inhibiting rates except that lung cancer are better; 4 pairs of lung cancer of artemisia anomalas dimer succinyl-oxide compound and ovarian cancer are better active and 5 pairs of colons of artemisia anomalas dimer benzyloxy carbo methoxy group derivative and lung carcinoma cell inhibiting rate are better; Two 7 pairs of liver cancer of mercapto thing of artemisia anomalas dimer and ovarian cancer are better active.Can reach a conclusion thus is the cytotoxic activity that 8 kinds of Guaianolide sesquiterpene dimers compounds of the present invention all have anticancer cell in various degree, can be used for treatment for cancer.
Embodiment 4, Guaianolide sesquiterpene dimers compound anti-inflammatory activity
1. reagent and instrument
Laboratory animal: C
57The BL/6J mouse, male, 16～18g purchases the Experimental Animal Center in the Chinese Academy of Medical Sciences.Reagent: East Asia is put and is exempted from the PGE of institute
2Detection kit (Chinese People's Liberation Army General Hospital); 4% sodium thioglycollate substratum; 5% new-born calf serum RPMI, 1640 substratum; D-Hank ' s physiological buffer.Instrument: whizzer, cell culture incubator.
2. laboratory sample and compound method
4 kinds of Guaianolide sesquiterpene dimers compounds that prepare among the embodiment 1-2: artemisia anomalas dimer A, artemisia anomalas dimer B, artemisia anomalas dimer chloro thing 1, artemisia anomalas dimer mercapto thing 2; As the positive control medicine, the storing solution with DMSO is made into 0.1mol/L is diluted to 10 with PBS during experiment with celecoxib (Celecoxib)
-5Mol/L.
3, cell anti-inflammatory cytoactive is measured
Every C
57The BL/6J mouse peritoneal is injected 4% sodium thioglycollate substratum 1ml, injection back the 4th day is the mouse sacrificed by decapitation, abdominal injection D-Hank ' s physiological buffer 6～8ml, fully liquid in the sucking-off abdominal cavity slowly after the massage, repeat again to wash the abdominal cavity once, merge cell suspension.The centrifugal 5min of 1000rpm, the supernatant that carefully inclines, cell is resuspended with RPMI 1640 substratum, and cell concn is adjusted into 1 * 10
6Individual/ml, be inoculated in the cell plate of 48 holes (0.5ml/ hole).37 ℃, 5%CO
2Adherent culture 2h.The substratum that inclines uses D-Hank ' s physiological buffer to wash twice, removes not attached cell, and it is stand-by that every hole adds RPMI 1640 substratum that contain 5% new-born calf serum.Measure cytoactive with the trypan blue exclusion method, the Giemsa staining checks that the scavenger cell percentage should be greater than 95% in the gained cell.
Different pharmaceutical is added in the Turnover of Mouse Peritoneal Macrophages in above-mentioned 48 orifice plates, 37 ℃, 5%CO
2Culturing cell 60min in the incubator adds final concentration 1mg/L lipopolysaccharides (LPS) again, continues culturing cell 12h.Cultivate and finish, the collecting cell supernatant liquor uses East Asia to put and exempts from the PGE of institute
2Detection kit is measured PGE in the cell culture supernatant
2(PGE
2) content, with following formula computerized compound to the active restraining effect of COX-2.A wherein
LPS, A
tAnd A
cRepresent the LPS group respectively, PGE in testing compound group and the blank group cells and supernatant
2Concentration, IR% represents inhibiting rate.
IR(％)＝(A
LPS-A
t)/(A
LPS-A
c)×100％
4, experimental result
The various medicines that experiment records are as shown in table 2 to the active influence of Turnover of Mouse Peritoneal Macrophages COX-2:
Table 2 Guaianolide sesquiterpene dimers compound is to the active influence of Turnover of Mouse Peritoneal Macrophages COX-2
| Group | Dosage | PGE 2Concentration (ng/10 5cell) | Inhibiting rate (%) |
| Blank | 0.10±0.06 | ||
| LPS | 1μg/ml | 22.89±18.69 | |
| Artemisia anomalas dimer A | 10 -5mol/L | 0.22±0.10 | 99.5 |
| Artemisia anomalas dimer B | 10 -5mol/L | 0.48±0.13 | 98.4 |
| Artemisia anomalas dimer chloro thing 1 | 10 -5mol/L | 0.51±0.31 | 98.2 |
| Artemisia anomalas dimer mercapto is for thing 2 | 10 -5mol/L | 0.32±0.14 | 96.4 |
Table 2 data show that 4 kinds of Guaianolide sesquiterpene dimers compounds of the present invention are 10
-5During mol/L concentration, the Turnover of Mouse Peritoneal Macrophages COX-2 activity that LPS is stimulated all has the obvious suppression effect, so this compounds has anti-inflammatory activity in various degree.
Claims (10)
1, structure is suc as formula the compound shown in (I):
Formula (1)
Wherein, R
1For hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl or benzyloxy carbo methoxy group;
R
2For hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl, benzyloxy carbo methoxy group.
2, compound according to claim 1 is characterized in that: described R
1Be hydroxyl, described R
2Be acetoxyl group.
3, compound according to claim 1 is characterized in that: described R
1And R
2Be all hydroxyl.
4, compound according to claim 1 is characterized in that: described R
1Be hydrogen, described R
2Be hydroxyl.
5, a kind of method for preparing claim 2,3 or 4 described compounds may further comprise the steps:
1) with extraction using alcohol artemisia anomalas herb, removes ethanol then, collect extract;
2) described extract is suspended in water, extract with sherwood oil, ethyl acetate successively;
3) ethyl acetate layer is carried out silica gel column chromatography, carry out gradient elution with chloroform and methyl alcohol, the collected volume ratio is 25: 1 the chloroform and the elution fraction of methyl alcohol mixed liquor;
4) component that described step 3) is obtained is carried out silica gel column chromatography, carries out gradient elution with sherwood oil and acetone, and the collected volume ratio is 4: 1 the sherwood oil and the elution fraction of acetone mixed solution;
5) component that described step 4) is obtained is carried out purifying with the hydroxypropyl dextrane gel, with volume ratio be 1: 1 chloroform-methanol mixed solution as elutriant, collect elution fraction;
6) component that described step 5) is obtained is carried out purifying with half preparation HPLC, obtains described compound of claim 2 or the described compound of claim 3 or the described compound of claim 4; Used moving phase is that volume ratio is 52: 48 a methanol-water mixture in the described HPLC purifying.
6, the method for preparing the described compound of claim 1 is following 1) to 10) in any method:
1) preparation R
1Be chlorine, R
2Being the method for the described compound of claim 1 of acetoxyl group, is the described compound of claim 2 and thionyl chloride to be reacted obtain R in the claim 1
1Be chlorine, R
2Compound 1 for acetoxyl group;
2) preparation R
1Be sulfydryl, R
2For the method for the described compound of claim 1 of acetoxyl group, be that described compound of claim 2 and trimethylchlorosilane are reacted, the reaction product that obtains is reacted with thiocarbamide again, obtain R in the claim 1
1Be sulfydryl, R
2Compound 2 for acetoxyl group;
3) preparation R
1Be acetoxyl group, R
2For the method for the described compound of claim 1 of acetoxyl group, be that described compound of claim 2 and Acetyl Chloride 98Min. are reacted, obtain R in the claim 1
1Be acetoxyl group, R
2Compound 3 for acetoxyl group;
4) preparation R
1Be amber acyloxy, R
2For the method for the described compound of claim 1 of acetoxyl group, be that described compound of claim 2 and succinyl oxide are reacted, obtain R in the claim 1
1Be amber acyloxy, R
2Compound 4 for acetoxyl group;
5) preparation R
1Be benzyloxy carbo methoxy group, R
2For the method for the described compound of claim 1 of acetoxyl group, be that described compound of claim 2 and benzyl acetate bromide are reacted, obtain R in the claim 1
1Be benzyloxy carbo methoxy group, R
2Compound 5 for acetoxyl group;
6) preparation R
1And R
2Be all chlorine the method for the described compound of claim 1, be that described compound of claim 3 and thionyl chloride are reacted, obtain R in the claim 1
1And R
2Be all the compound 6 of chlorine;
7) preparation R
1And R
2Be all sulfydryl the method for the described compound of claim 1, be that described compound of claim 3 and trimethylchlorosilane are reacted, the reaction product that obtains is reacted with thiocarbamide again, obtain R in the claim 1
1And R
2Be all the compound 7 of sulfydryl;
8) preparation R
1Be amino, R
2For the method for the described compound of claim 1 of acetoxyl group, be that described compound of claim 2 and thionyl chloride are reacted, the reaction product that obtains is reacted with the methanol solution of ammonia again, obtain R in the claim 1
1Be amino, R
2Compound 8 for acetoxyl group;
9) preparation R
1Be hydrogen, R
2For the method for the described compound of claim 1 of chlorine, be that described compound of claim 4 and thionyl chloride are reacted, obtain R in the claim 1
1Be hydrogen, R
2Compound 9 for chlorine;
10) preparation R
1Be hydrogen, R
2For the method for the described compound of claim 1 of acetoxyl group, be that described compound of claim 4 and Acetyl Chloride 98Min. are reacted, obtain R in the claim 1
1Be hydrogen, R
2Compound 10 for acetoxyl group.
7, method according to claim 6 is characterized in that: the preparation method of described claim 2 or claim 3 or the described compound of claim 4 may further comprise the steps:
1) with extraction using alcohol artemisia anomalas herb, removes ethanol then, collect extract;
2) described extract is suspended in water, extract with sherwood oil, ethyl acetate successively;
3) ethyl acetate layer is carried out silica gel column chromatography, carry out gradient elution with chloroform and methyl alcohol, the collected volume ratio is 25: 1 the chloroform and the elution fraction of methyl alcohol mixed liquor;
4) component that described step 3) is obtained is carried out silica gel column chromatography, carries out gradient elution with sherwood oil and acetone, and the collected volume ratio is 4: 1 the sherwood oil and the elution fraction of acetone mixed solution;
5) component that described step 4) is obtained is carried out purifying with the hydroxypropyl dextrane gel, with volume ratio be 1: 1 chloroform-methanol mixed solution as elutriant, collect elution fraction;
6) component that described step 5) is obtained is carried out purifying with half preparation HPLC, obtains claim 2 or claim 3 or the described compound of claim 4; Used moving phase is that volume ratio is 52: 48 a methanol-water mixture in the described HPLC purifying.
8, the compound shown in the formula (I) or its pharmacy acceptable salt prevent and/or treat application in tumour medicine and/or the anti-inflammatory drug in preparation,
Formula (I)
Wherein, R
1For hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl, benzyloxy carbo methoxy group;
R
2For hydrogen, halogen, methyl, ethyl, hydroxyl, alkoxyl group, sulfydryl, amino, hydroxyl for alkoxyl group, carboxylic for alkoxyl group, acyloxy, carboxyl, benzyloxy carbo methoxy group.
9, a kind of tumour and/or antiphlogistic medicine of preventing and/or treating, its effective constituent is the compound shown in the formula (I) or its pharmacy acceptable salt.
10, application according to claim 8 or medicine according to claim 9 is characterized in that: described tumour is any in human colon carcinoma, people's liver cancer, people's cancer of the stomach, people's lung cancer and the human ovarian cancer.
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