CN101422467A - Immunosuppressant containing Withanolide type compound - Google Patents
Immunosuppressant containing Withanolide type compound Download PDFInfo
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Abstract
The invention discloses an immunosuppressor which containing a compound shown in the following general formula I and/or the general formula II, or an optical isomer thereof; wherein, R1, R2, R3, R4, R5, R6 and R7 are selected from H, OH, O-acyl, OMe, OEt, O<n>Pr, O<i>Pr, F, Cl, Br, NH2, NO2 or CN; wherein, site 5 and site 6 are an epoxy bond or a double bond; in the general formula I, the ether linkages of site 14 and site 27 are connected or disconnected; in the general formula II, the sites 14 and 15 and the sites 16 and 17 are the epoxy bond or the double bond, or a plant extract containing the compound. The immunosuppressor has stronger immuno-suppression effect, generates repression function to T and B lymphocyte periods which are excessively proliferated, and can be used for curing the self immunological diseases and relevant diseases.
Description
Technical field
The present invention relates to the immunosuppressant technical field, more specifically, be meant a kind of immunosuppressant of the Withanolide of containing type chemical compound.
Background technology
The Withanolide type compound is the chemical compound that a class has the lumistane type of 28 carbon atoms, and its its specific structure is the side chain (referring to following Withanolide framing structure) that 22 and 26 carbon are connected to form a δ lactonic ring.
Withanolide not only can be used for representing 22 of lumistane type, and the 26-lactone also can be used for representing the chemical compound that all sources of students are relevant.The former is classic Withanolide type chemical compound, the Withanolide type chemical compound that latter's right and wrong are classic.These chemical compounds mainly are distributed in several genus of Solanaceae, as Physalis, and Withania, Datura, Jaborosa, Dunalia, Salpichroa, Deprea, Solanum, Vassobia, Exodeconus, Hyoscyamus, Iochroma, (P.Chirsten.Withanolide such as Discopodium, Pharm.zeit., 1989,18,129-139. and E.Glotter.Withanolides and related ergostane-type steroids, Nat.Prod.Reports, 1991,8,415-440.).
The biological activity of Withanolide type chemical compound is varied, comprise antibiotic, antiinflammatory, antiviral, antimicrobial, antioxidation, antitumor, convulsion, immunosuppressant, cell toxicant, and inhibition activity (A.S.Veleiro, the J.C.Oberti of acetylcholinesterase, G.Burton, in ' Studies in Natural Products Chemistry, (Part L) Bioactive Natural Products ', Ed.Atta-ur-Rahman, Elsevier, Amsterdam, 2005, Vol.32.p.1019.).Pass through literature survey, (Physalis alkekengi) is with contain a large amount of Withanolide type chemical compounds in the Herba Physalis pubescentis (Physalis angulata) for some plants of Solanaceae of discovery China such as Calyx seu fructus physalis, and these plant amedica are commonly used to as antiphlogistic medicine among the people, treat disease (Institute of Botany, Chinese Academy of Sciences etc., Chinese Plants will, the 67th bundling the 1st fascicles such as some arthritis, Beijing, Science Press, 1978,53-59).
But it is, all unclear for the antiphlogistic mechanism of action of these plant components and the Withanolide type chemical compound that specifically contains and these chemical compounds characteristic separately.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings at above existence, a kind of immunosuppressant of the Withanolide of containing type chemical compound is provided, this immunosuppressant has stronger immunosuppressive action, effect is checked in excessive value-added T, the generation of bone-marrow-derived lymphocyte cycle, be can be used for treatment autoimmune disease and relevant disease.
To achieve these goals, the technical solution used in the present invention is as follows:
The present invention at first provides a kind of immunosuppressant of the Withanolide of containing type chemical compound, is characterized in, described immunosuppressant comprises chemical compound or its optical isomer shown in following general formula I and/or the general formula I I:
Wherein, R1, R2, R3, R4, R5, R6, R7 are selected from H, OH, O-acyl, OMe, OEt, O
nPr, O
iPr, F, Cl, Br, NH
2, NO
2Or CN, wherein 5,6 is epoxy or two key, and 14,27 ehter bonds connect or disconnection in the general formula I, and 14,15 and 16,17 is epoxy and two keys among the general formula I I.
Chemical compound comprises Physalin A shown in the described general formula I, Physalin B, Physalin D, Physalin H, 2,3-Dihydrophysalin D, 13-Acetoxyphysalin D, Physalin L, Physalin N, Physalin O, one or more of Isophysalin B and Isophysalin G:
Chemical compound comprises Physagulin L shown in the described general formula I I, Physagulin M, Physagulin N, PhysagulinJ, Physagulin O, Withagulatin A, Physagulin A, Withaminimin, Physagulin B, PhysagulinC, Pubesenolide, Physagulin I, one or more of Physagulin F and Physagulin K:
Chemical compound shown in the described general formula I is Physalin H, and chemical compound shown in the described general formula I I is Physagulin B and/or Physagulin I.
The present invention also provides a kind of immunosuppressant, is characterized in, described immunosuppressant comprises plant extract, and described plant extract contains the chemical compound shown in above-mentioned general formula I or the general formula I I or its optical isomer.
Described plant extract Wei Herba Physalis pubescentis overground part extract or Calyx seu fructus physalis overground part extract.
The application of described immunosuppressant in the medicine of preparation treatment autoimmune disease.
Described autoimmune disease is rheumatoid arthritis, autoimmune hepatitis, insulin-dependent diabetes, ulcerative colitis, multiple sclerosis, scleroderma, myasthenia gravis, multiple myositis, autoimmunity cytopenia, vasculitis syndrome or systemic lupus erythematosus (sle).
The application in the medicine of the dysfunction that has tissue injury or infection due to disease and the relevant disease, anaphylactic disease, the graft versus host disease due to transplanting by bone marrow (hematopoietic stem cell) of exempting from service in preparation treatment inflammatory reaction, fibrosis or by self of described immunosuppressant.
Described anaphylactic disease is bronchial asthma, allergic rhinitis, atopic dermatitis or pollinosis.
Beneficial effect of the present invention is as follows:
1. the immunosuppressant that contains withanolide type chemical compound of the present invention, because its withanolide type chemical compound that contains has stronger immunosuppressive action, effect is checked in excessive value-added T, the generation of bone-marrow-derived lymphocyte cycle, especially wherein Compound P hysalin H, Physagulin B and Physagulin I demonstrate the immunosuppressive activity of the luxuriant rhzomorph of ring (CsA).
2. the immunosuppressant of the withanolide of containing type chemical compound of the present invention has the characteristics of low toxicity and stronger immunosuppressive activity.
3. the separation method of withanolide type compound monomer of the present invention is easy, cost is low.
Description of drawings
Fig. 1 is a HMBC correlogram of measuring Compound P hysagulin L.
Fig. 2 is a HMBC correlogram of measuring Compound P hysagulin M.
Fig. 3 is a HMBC correlogram of measuring Compound P hysagulin N.
Fig. 4 is a HMBC correlogram of measuring Compound P hysagulin O.
The specific embodiment
Some Solanaceae monkey flowers of China's growth, for example (Physalis allelengi) is with Herba Physalis pubescentis (Physalisangulata) has heat-clearing and toxic substances removing to Calyx seu fructus physalis, throat, tonneau two effect just cures mainly laryngopharynx swelling and pain, swelling and aching of gum; urine leaching is puckery; constipation, impetigo, eczema (" China's book on Chinese herbal medicine " editorial board compiles. China's book on Chinese herbal medicine [M]).
The present invention at first extracts the aerial parts of slurry, Herba Physalis pubescentis, obtains Calyx seu fructus physalis extract respectively with the Herba Physalis pubescentis extract separates the chemical compound that obtains 11 physalin skeletons to the Calyx seu fructus physalis aerial parts, be respectively: Physalin A, Physalin B, Physalin D, Physalin H, 2,3-Dihydrophysalin D, 13-Acetoxyphysalin D, Physalin L, Physalin N, Physalin O, Isophysalin B, Isophysalin G; Dui Herba Physalis pubescentis aerial parts separates the chemical compound that obtains 14 classical withanolide skeletons, is respectively: Physagulin L, Physagulin M, Physagulin N, Physagulin J, Physagulin O, Withagulatin A, Physagulin A, Withaminimin, Physagulin B, Physagulin C, Pubesenolide, Physagulin I, Physagulin F, Physagulin K.
Said extracted thing and chemical compound are carried out the immunobiologic activity analysis, find that above-mentioned substance all can effectively suppress T, B cell proliferation, Compound P hysalin H especially, Physagulin B and Physagulin I have the activity that is better than encircling luxuriant rhzomorph.
Therefore, above-claimed cpd or extract all can be used to prepare immune suppressant drug, and Calyx seu fructus physalis extract is with the Herba Physalis pubescentis extract can be freeze-dried powder form or liquid form.
The immunosuppressive activity of Withanolide composition of the present invention, low toxicity is suitable for people and mammal per os or non-oral administration.
The immunosuppressive activity of Withanolide composition provided by the invention does not have specific restriction aspect dosage form, can be used as peroral administration powder, pill, tablet, solid type preparation such as capsule also can be used as para-oral external agent, ointment sticks agent, injection.
The immunosuppressive activity of Withanolide composition provided by the invention can cooperate with the auxiliary material that does not influence pharmacotoxicological effect usually and make per os or para-oral preparation.
The immunosuppressive activity of Withanolide composition provided by the invention can be through aqueous solvent (as distilled water), water soluble preparation (as normal saline), and fatsolvent (as siritch) equal solvent is modulated with conventional method.
The immunosuppressive activity of Withanolide composition provided by the invention can go up adding ingredient (diluent, coloring agent, the tranquilizer that allows with the pharmacology usually, interfacial agent, cosolvent, buffer agent, correctives, spice, preservative agent, sugar-coat agent) combined, be used for per os or non-per os dosage form.
The immunosuppressive activity of Withanolide composition provided by the invention usually can with the diluted composition that allows on the pharmacology and to be molded into branch combined on the dosage form, be used for per os or non-per os dosage form.
The immunosuppressive activity of Withanolide composition provided by the invention is meant tablet, pill, granule, powder or capsule.Non-per os dosage form is meant intravenous injection, intramuscular dose, and agent, rectum, anus or vagina administration are bathed in the subcutaneous injection agent.
For further understanding the present invention, be described further below in conjunction with specific embodiment.
Embodiment 1 total Withanolide screening compound sample preparation
1. the total Withanolide screening compound of Calyx seu fructus physalis sample preparation
Calyx seu fructus physalis 500g concentrates with 85% alcohol reflux three times, by macroporous adsorbent resin (D101 type), washes, uses 75% ethanol elution then with 10% distillation earlier, and 75% ethanol elution position concentrating under reduced pressure must send extracorporeal biology assess sample 1 (54g).
2. the total withanolide screening compound of Herba Physalis pubescentis sample preparation:
Herba Physalis pubescentis 500g concentrates with 85% alcohol reflux three times, by macroporous adsorbent resin (D101 type), washes, uses 60% ethanol elution then with distillation earlier, and 60% ethanol elution position concentrating under reduced pressure must send extracorporeal biology assess sample 2 (90g).
The separation of Withanolide type chemical compound in embodiment 2 Calyx seu fructus physaliss
Calyx seu fructus physalis (Physalis allelengi) overground part picks up from Nanchuan, Chongqing City county, gathers and be accredited as the little Calyx seu fructus physalis Physalis allelengi of plant of Solanaceae through botanical garden, Chongqing City teacher Yi Sirong.Specimen is deposited in modernization of cmm center, Shanghai.
Calyx seu fructus physalis aerial parts (5.0Kg), extract 3 times with 3 times of amount ethanol mercerations, each 2 days, merging filtrate, concentrating under reduced pressure gets extractum (1.8kg), with the low amounts of water dissolving, use chloroform extraction, obtain chloroform part (197g), chloroform is partly gone up D-101 type macroporous resin, use 25%, 75%, 95% ethanol elution to get 3 positions (Fr.A-C) respectively.Fr.B (24.4g) carries out at the position MCI column chromatography (MCI gel CHP 20P H
2O/Me
2CO 1:1) obtains 4 positions (Fr.B.1-B.4).Fr.B.1 ODS column chromatography (RP-18; MeOH/H
2O 40:60) obtain Physalin D (37mg), 2,3-Dihydrophysalin (14mg) and Physalin H (40mg).Fr.B.2 ODS column chromatography (RP-18; MeOH/H
2O 50:50) obtains Physalin A (19mg), Isohysalin B (25mg) and Isophysalin G (34mg).Fr.B.3 ODS column chromatography (RP-18; MeOH/H
2O 60:40) obtains 13-Acetoxylphysalin D (14mg), Physalin L (29mg), Physalin N (14mg) and Physalin O (27mg).Fr.B.4 gel filtration chromatography (Sephadex LH-20; MeOH) Physalin B (120mg).
Above-mentioned separated product is the chemical compound of 11 physalin skeletons, and its structure is passed through
1H NMR and
13C-NMR determines that determination data and structural formula are as follows respectively:
Compound P hysalin A
The unformed powder of white, EI-MS:526, molecular formula: C
28H
30O
10
1H-NMR(DMSO-d
6)：δ?5.84(1H，dd，J＝2.5，10.0Hz，H-2)，6.79(1H，ddd，J＝2.5，4.5，10.0Hz，H-3)，2.93(1H，dd，J＝4.6，22.1Hz，H-4a)，3.26(1H，br.d，J＝22.1Hz，H-4b)，5.75(1H，dd，J＝5.9，2.0Hz，H-6)，1.59(3H，s，H
3-19)，1.93(3H，s，H
3-21)，4.56(1H，t，J＝3.1Hz，H-22)，6.67(1H，s，H-27a)，5.74(1H，s，H-27b)，1.16(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?203.3(s，C-1)，127.4(d，C-2)，145.7(d，C-3)，32.7(t，C-4)，140.1(s，C-5)，126.1(d，C-6)，63.1(d，C-7)，46.3(d，C-8)，28.7(d，C-9)，54.1(s，C-10)，24.1(t，C-11)，29.5(t，C-12)，82.6(s，C-13)，101.8(s，C-14)，211.1(s，C-15)，53.7(d，C-16)，82.6(s，C-17)，172.2(s，C-18)，26.9(q，C-19)，79.9(s，C-20)，21.5(q，C-21)，76.8(d，C-22)，31.4(t，C-23)，36.5(s，C-24)，139.1(d，C-25)，163.8(s，C-26)，133.5(t，C-27)，15.5(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J.Chem.Soc., Perkin Trans.1 1975,1370-1374) Bao Dao Physalin A spectral data unanimity is so this chemical compound is confirmed as Physalin A.
Compound P hysalin B
The unformed powder of white, EI-MS:510, molecular formula: C
28H
30O
9
1H-NMR(DMSO-d
6)：δ?5.80(1H，dd，J＝2.2，10.0Hz，H-2)，6.89(1H，ddd，J＝2.2，4.9，10.0Hz，H-3)，2.88(1H，dd，J＝4.9，20.1Hz，H-4a)，3.26(1H，br.d，J＝20.1Hz，H-4b)，5.59(1H，d，J＝5.9Hz，H-6)，1.09(3H，s，H
3-19)，4.56(1H，d，J＝3.1，2.2Hz，H-22)，3.61(1H，dd，J＝14.3，1.4Hz，H-27a)，4.27(1H，d，J＝14.3，4.2Hz，H-27b)，1.18(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?202.3(s，C-1)，126.7(d，C-2)，146.0(d，C-3)，32.3(t，C-4)，135.5(s，C-5)，123.4(d，C-6)，24.4(t，C-7)，40.2(d，C-8)，33.1(d，C-9)，52.0(s，C-10)，24.2(t，C-11)，25.6(t，C-12)，78.2(s，C-13)，106.3(s，C-14)，209.4(s，C-15)，54.2(d，C-16)，80.7(s，C-17)，171.8(s，C-18)，16.8(q，C-19)，80.3(s，C-20)，21.7(q，C-21)，76.3(d，C-22)，31.4(t，C-23)，30.5(s，C-24)，49.4(d，C-25)，167.0(s，C-26)，60.6(t，C-27)，24.4(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J.Chem.Soc., Perkin Trans.1 1975,1370-1374) Bao Dao Physalin B spectral data unanimity is so this chemical compound is confirmed as Physalin B.
Compound P hysalin D
The unformed powder of white, EI-MS:544, molecular formula: C
28H
32O
11
1H-NMR(DMSO-d
6)：δ?5.71(1H，dd，J＝2.0，10.2Hz，H-2)，6.63(1H，ddd，J＝2.0，4.9，10.2Hz，H-3)，1.98(1H，dd，J＝4.9，20.1Hz，H-4a)，3.11(1H，br.d，J＝20.1Hz，H-4b)，4.25(s，5-OH)，3.49(1H，m，H-6)，4.90(d，J
OH，6＝4.2Hz，6-OH)，5.77(s，13-OH)，1.11(3H，s，H
3-19)，1.82(3H，s，H
3-21)，4.56(1H，d，J＝3.1，2.2Hz，H-22)，3.58(1H，d，J＝13.3，H-27a)，4.26(1H，dd，J＝13.3，4.6Hz，H-27b)，1.18(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?204.3(s，C-1)，127.1(d，C-2)，142.9(d，C-3)，36.9(t，C-4)，82.3(s，C-5)，72.5(d，C-6)，26.7(t，C-7)，38.4(d，C-8)，30.9(d，C-9)，54.3(s，C-10)，24.2(t，C-11)，25.6(t，C-12)，78.3(s，C-13)，106.3(s，C-14)，210.0(s，C-15)，54.2(d，C-16)，80.7(s，C-17)，171.8(s，C-18)，14.0(q，C-19)，80.3(s，C-20)，21.7(q，C-21)，76.3(d，C-22)，31.4(t，C-23)，30.5(s，C-24)，49.4(d，C-25)，167.0(s，C-26)，60.6(t，C-27)，24.4(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J.Chem.Soc., Perkin Trans.1 1975,1370-1374) Bao Dao Physalin D spectral data unanimity is so this chemical compound is confirmed as Physalin D.
Compound P hysalin H
The unformed powder of white, EI-MS:562, molecular formula: C
28H
31ClO
10
1H-NMR(DMSO-d
6)：δ?5.83(1H，dd，J＝2.5，10.0Hz，H-2)，6.79(1H，ddd，J＝2.3，4.9，10.0Hz，H-3)，2.46(1H，dd，J＝4.9，21.1Hz，H-4a)，3.48(1H，br.d，J＝21.1Hz，H-4b)，3.89(1H，dt，J＝5.2，3.0，3.1Hz，H-6)，5.69(d，JOH，6＝5.2Hz，6-OH)，6.06(s，13-OH)，1.23(3H，s，H3-19)，1.82(3H，s，H
3-21)，4.56(1H，d，J＝3.1，2.2Hz，H-22)，3.60(1H，dd，J＝13.3，1.2Hz，H-27a)，4.27(1H，d，J＝13.3，4.6Hz，H-27b)，1.18(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?200.3(s，C-1)，127.1(d，C-2)，142.9(d，C-3)，36.9(t，C-4)，82.3(s，C-5)，72.5(d，C-6)，26.7(t，C-7)，38.4(d，C-8)，30.9(d，C-9)，54.3(s，C-10)，24.2(t，C-11)，25.6(t，C-12)，78.3(s，C-13)，106.3(s，C-14)，209.4(s，C-15)，54.2(d，C-16)，80.7(s，C-17)，171.8(s，C-18)，14.0(q，C-19)，80.3(s，C-20)，21.7(q，C-21)，76.3(d，C-22)，31.4(t，C-23)，30.5(s，C-24)，49.4(d，C-25)，167.0(s，C-26)，60.6(t，C-27)，24.4(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J Chem.Soc., Perkin Trans.1 1975,1370-1374) Bao Dao Physalin H spectral data unanimity is so this chemical compound is confirmed as Physalin H.
Chemical compound 2,3-Dihydrophysalin D
The unformed powder of white, EI-MS:546, molecular formula: C
28H
34O
11
1H-NMR(DMSO-d
6)：δ?5.71(1H，dd，J＝2.0，10.2Hz，H-2)，6.63(1H，ddd，J＝2.0，4.9，10.2Hz，H-3)，1.98(1H，dd，J＝4.9，20.1Hz，H-4a)，3.11(1H，br.d，J＝20.1Hz，H-4b)，4.25(s，5-OH)，3.49(1H，m，H-6)，4.90(d，J
OH，6＝4.2Hz，6-OH)，5.77(s，13-OH)，1.11(3H，s，H
3-19)，1.82(3H，s，H3-21)，4.56(1H，d，J＝3.1，2.2Hz，H-22)，3.58(1H，d，J＝13.3，H-27a)，4.26(1H，dd，J＝13.3，4.6Hz，H-27b)，1.18(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?215.3(s，C-1)，29.7(t，C-2)，25.0(t，C-3)，36.9(t，C-4)，80.5(s，C-5)，73.4(d，C-6)，26.7(t，C-7)，38.0(d，C-8)，30.9(d，C-9)，56.9(s，C-10)，24.5(t，C-11)，25.6(t，C-12)，77.6(s，C-13)，107.0(s，C-14)，209.8(s，C-15)，54.2(d，C-16)，78.9(s，C-17)，171.9(s，C-18)，14.6(q，C-19)，80.3(s，C-20)，21.7(q，C-21)，76.3(d，C-22)，31.4(t，C-23)，30.5(s，C-24)，49.4(d，C-25)，167.4(s，C-26)，60.6(t，C-27)，24.4(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J.Chem.Soc., Perkin Trans.1 1975,1370-1374) 2 of report, 3-Dihydrophysalin D spectral data unanimity, so this chemical compound is confirmed as 2,3-Dihydrophysalin D.
Chemical compound 13-Acetoxylphysalin D
The unformed powder of white, EI-MS:586, molecular formula: C
30H
34O
12
1H-NMR(DMSO-d
6)：δ?5.71(1H，dd，J＝2.0，10.2Hz，H-2)，6.63(1H，ddd，J＝2.0，4.9，10.2Hz，H-3)，1.98(1H，dd，J＝4.9，20.1Hz，H-4a)，3.11(1H，br.d，J＝20.1Hz，H-4b)，4.25(s，5-OH)，3.49(1H，m，H-6)，4.90(d，J
OH，6＝4.2Hz，6-OH)，5.77(s，13-OH)，1.26(3H，s，H
3-19)，1.99(3H，s，H
3-21)，4.56(1H，d，J＝3.1，2.2Hz，H-22)，3.58(1H，d，J＝13.3，H-27a)，4.26(1H，dd，J＝13.3，4.6Hz，H-27b)，1.26(3H，s，H
3-28)，2.12(3H，s，OAc)。
13C-NMR(DMSO-d
6)：δ?204.3(s，C-1)，127.1(d，C-2)，142.9(d，C-3)，36.9(t，C-4)，82.3(s，C-5)，72.5(d，C-6)，26.7(t，C-7)，38.4(d，C-8)，30.9(d，C-9)，54.3(s，C-10)，24.2(t，C-11)，25.6(t，C-12)，78.3(s，C-13)，106.3(s，C-14)，210.0(s，C-15)，54.2(d，C-16)，80.7(s，C-17)，171.8(s，C-18)，14.1(q，C-19)，80.3(s，C-20)，21.6(q，C-21)，76.3(d，C-22)，31.4(t，C-23)，30.5(s，C-24)，49.4(d，C-25)，167.0(s，C-26)，60.6(t，C-27)，24.1(q，C-28)，170.0(s，OAc)，21.5(q，OAc)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J.Chem.Soc., Perkin Trans.1 1975,1370-1374) Bao Dao Physalin D spectral data unanimity is so this chemical compound is confirmed as 13-Acetoxylphysalin D.
Compound P hysalin L
The unformed powder of white, EI-MS:528, molecular formula: C
28H
32O
10
1H-NMR(DMS0-d
6)：δ?5.86(1H，br?d，J＝10.0Hz，H-3)，6.13(1H，d，J＝10.0Hz，H-4)，5.75(1H，br?d，J＝5.1Hz，H-6)，4.60(1H，m，H-7)，5.07(1H，d，J＝4.2Hz，OH-7)，5.07(1H，s，OH-14)，1.15(3H，s，H
3-19)，1.70(3H，s，H
3-21)，4.57(1H，m，H-22)，1.17(3H，d，J＝8.2Hz，H
3-27)，1.32(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?209.2(s，C-1)，127.4(d，C-2)，126.3(d，C-3)，128.3(d，C-4)，142.9(s，C-5)，1228.0(d，C-6)，61，8(d，C-7)，45.5(d，C-8)，28.5(d，C-9)，56.3(s，C-10)，24.1(t，C-11)，29.8(t，C-12)，82.6(s，C-13)，101.3(s，C-14)，216.0(s，C-15)，53.7(d，C-16)，82.6(s，C-17)，172.2(s，C-18)，21.6(q，C-19)，79.9(s，C-20)，25.5(q，C-21)，76.8(d，C-22)，26.3(t，C-23)，35.0(s，C-24)，139.1(d，C-25)，172.0(s，C-26)，17.0(q，C-27)，15.9(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Kawai, M.et al., A new physalin from Physalisalkekengi:structure of physalin LPhytochemistry, 1987,26,3313) Bao Dao Physalin L spectral data unanimity is so this chemical compound is confirmed as Physalin L.
Compound P hysalin N
The unformed powder of white, EI-MS:526, molecular formula: C
28H
30O
10
1H-NMR(DMSO-d
6)：δ?5.84(1H，dd，J＝2.1，10.0Hz，H-2)，6.94(1H，ddd，J＝2.1，5.3，10.0Hz，H-3)，2.89(1H，m，H-4a)，3.29(1H，m，H-4b)，5.69(1H，d，J＝5.9Hz，H-6)，4.35(1H，m，H-7)，3.32(1H，m，7-OH)，1.08(3H，s，H
3-19)，1.76(3H，s，H
3-21)，4.61(1H，m，H-22)，3.67(1H，dd，J＝133，1.4Hz，H-27a)，4.33(1H，d，J＝133，4.2Hz，H-27b)，1.18(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?201.4(s，C-1)，126.7(d，C-2)，146.0(d，C-3)，32.3(t，C-4)，139.0(s，C-5)，125.4(d，C-6)，61.4(d，C-7)，44.2(d，C-8)，27.5(d，C-9)，52.6(s，C-10)，24.0(t，C-11)，25.6(t，C-12)，78.0(s，C-13)，106.3(s，C-14)，208.5(s，C-15)，52.8(d，C-16)，80.9(s，C-17)，171.6(s，C-18)，15.5(q，C-19)，80.3(s，C-20)，21.7(q，C-21)，76.1(d，C-22)，31.2(t，C-23)，30.5(s，C-24)，49.2(d，C-25)，167.2(s，C-26)，61.0(t，C-27)，24.2(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Masao Kawai, Toichi Ogura, Bunsho Makino, Akihide Matsumoto, Hatsuo Yamamura, Yasuo Butsugan and Mitsuo Hayashi, PhysalinsN and O from Physalis alkekengi Phytochemistry, 1992,31,4299-4302) Bao Dao PhysalinN spectral data unanimity is so this chemical compound is confirmed as Physalin N.
Compound P hysalin O
The unformed powder of white, EI-MS:528, molecular formula: C
28H
32O
10
1H-NMR(DMSO-d
6)：δ?5.84(1H，dd，J＝2.5，10.0Hz，H-2)，6.95(1H，ddd，J＝2.5，5.0，10.0Hz，H-3)，2.93(1H，dd，J＝4.6，22.1Hz，H-4a)，3.26(1H，br.d，J＝22.1Hz，H-4b)，5.75(1H，dd，J＝5.9，2.0Hz，H-6)，4.52(1H，dd，J＝6.5，4.5Hz，H-7)，5.00(1H，s，OH-7)，1.03(3H，s，H
3-19)，1.68(3H，s，H
3-21)，4.56(1H，t，J＝3.1Hz，H-22)，1.15(3H，s，H
3-27)，1.31(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?202.1(s，C-1)，126.9(d，C-2)，146.6(d，C-3)，32.0(t，C-4)，139.5(s，C-5)，127.3(d，C-6)，61.4(d，C-7)，46.2(d，C-8)，29.0(d，C-9)，54.1(s，C-10)，23.4(t，C-11)，29.6(t，C-12)，82.1(s，C-13)，101.0(s，C-14)，216.0(s，C-15)，53.2(d，C-16)，79.4(s，C-17)，171.9(s，C-18)，14.1(q，C-19)，82.1(s，C-20)，21.3(q，C-21)，76.2(d，C-22)，26.0(t，C-23)，34.6(s，C-24)，40.7(d，C-25)，172.0(s，C-26)，16.8(q，C-27)，25.1(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Glotter, E.; Kirson, I.; Abraham, A.; Sethi, P.D.; Subramanian, S.S.J.Chem.Soc., Perkin Trans.1 1975,1370-1374) Bao Dao Physalin O spectral data unanimity is so this chemical compound is confirmed as Physalin O.
Compound I sophysalin B
The unformed powder of white, EI-MS:510, molecular formula: C
28H
30O
9
1H-NMR(DMSO-d
6)：δ?2.79(1H，dd，J＝20.2，4.7Hz，H-2a)，3.32(1H，br.d?J＝20.2Hz，H-2b)，5.60(1H，m，H-3)，6.07(1H，dd，J＝9.7，H-4)，5.68(1H，br.d?H-6)，1.27(3H，s，H
3-19)，1.98(3H，s，H
3-21)，4.56(1H，d，J＝3.5，H-22)，3.77(1H，dd，J＝13.3，H-27a)，4.54(1H，d，J＝13.3，4.2Hz，H-27b)，1.33(3H，s，H
3-28)。
13C-NMR(DMSO-d
6)：δ?208.0(s，C-1)，39.4(t，C-2)，121.3(d，C-3)，126.5(d，C-4)，139.5(s，C-5)，128.8(d，C-6)，25.8(t，C-7)，39.2(d，C-8)，33.1(d，C-9)，56.4(s，C-10)，24.5(t，C-11)，26.5(t，C-12)，79.8(s，C-13)，107.7(s，C-14)，214.1(s，C-15)，55.0(d，C-16)，80.3(s，C-17)，172.1(s，C-18)，25.3(q，C-19)，81.0(s，C-20)，21.4(q，C-21)，76.9(d，C-22)，32.0(t，C-23)，31.2(s，C-24)，51.0(d，C-25)，166.6(s，C-26)，60.6(t，C-27)，19.3(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Reiko Sunayama, Masanori Kuroyanagi, Physalin and Neophysalins from Physalis alkekengi var.francheti and their differentiationinducing activity, Phytochemistry, 1993,34,529-533) Bao Dao Isophysalin B spectral data unanimity is so this chemical compound is confirmed as Isophysalin B.
Compound I sophysalin G
The unformed powder of white, EI-MS:526, molecular formula: C
28H
30O
10
1H-NMR(CDCl
3)：δ?3.12(1H，dd，J＝7.2，12.5Hz，H-2a)，2.87(1H，m，H-2b)，4.69(1H，m，H-3)，5.58(1H，d，J＝3.5Hz，H-4)，6.19(1H，d，J＝10Hz，H-6)，6.13(1H，dd，J＝10.4，2.5Hz，H-7)，1.40(3H，s，H
3-19)，1.95(3H，s，H
3-21)，4.54(1H，br?t，J＝2.5Hz，H-22)，3.82(1H，dd，J＝13.5Hz，H-27a)，4.61(1H，d，J＝13.5，4.5Hz，H-27b)，1.27(3H，s，H
3-28)。
13C-NMR(CDCl
3)：δ?207.7(s，C-1)，44.7(t，C-2)，69.0(d，C-3)，126.6(d，C-4)，141.2(s，C-5)，128.0(d，C-6)，126.0(d，C-7)，44.2(d，C-8)，32.5(d，C-9)，55.2(s，C-10)，26.1(t，C-11)，25.6(t，C-12)，81.0(s，C-13)，106.3(s，C-14)，213.4(s，C-15)，51.2(d，C-16)，80.7(s，C-17)，172.2(s，C-18)，24.9(q，C-19)，79.8(s，C-20)，21.2(q，C-21)，77.0(d，C-22)，32.4(t，C-23)，31.1(s，C-24)，50.6(d，C-25)，167.2(s，C-26)，61.1(t，C-27)，20.3(q，C-28)。
Its
1HNMR reaches
13CNMR data and document (Reiko Sunayama, Masanori Kuroyanagi, Physalinand Neophysalins from Physalis alkekengi var.franchetiand their differentiation inducingactivity, Phytochemistry, 1993,34,529-533) Bao Dao Isophysalin G spectral data unanimity is so this chemical compound is confirmed as Isophysalin G.
The separation of Withanolide type chemical compound in embodiment 3 Herba Physalis pubescentis
Herba Physalis pubescentis (Physalis angulata L) overground part picks up from Nanchuan, Chongqing City county, and teacher Yi Sirong through the botanical garden, Chongqing City gathers and is accredited as the little Calyx seu fructus physalis Physalis angulata of plant of Solanaceae L specimen and deposits in modernization of cmm center, Shanghai.
5.0Kg Herba Physalis pubescentis (Physalis angulata L) aerial parts, extract three times with 85% methanol heat, get extractum 0.9Kg, polyamide column chromatography separates, 100% distilled water eluting part, 60% methanol-eluted fractions part, 80% methanol-eluted fractions part (containing chlorophyll), 60% methanol-eluted fractions part (921g) silica gel column chromatography (petroleum ether/acetone 5:1-1:1) obtains four positions (position A-D), position A gets Compound P hysagilin A (135mg) and WithagulatinA (124mg) through ODS (C-18) column chromatography (methanol 85:15) and Sephadax LH-20 purification (chloroform/methanol); Position B is through ODS (C-18) column chromatography (methanol 78:22) and Sephadax LH-20 purification (chloroform/methanol), get Compound P hysagulins L (55mg), Physagulin B (27mg), PhysagulinC (23mg) and Physagulin I (31mg); Position C is through ODS (C-18) column chromatography (methanol 65:35) and Sephadax LH-20 purification (methanol), get Compound P hysagulins M (27mg), Physagulin J (12mg), Withaminimin (90mg) Pubesenolide (46mg) and Physagulin F (47mg); Position A gets Compound P hysagulins N (33mg), Physagulins O (32mg), Physagulin K (87mg) through ODS (C-18) column chromatography (methanol 50:50) and Sephadax LH-20 purification (methanol).
Above-mentioned separated product is the chemical compound of 14 classical withanolide skeletons, by
1H NMR and
13C-NMR determines its structure, and determination data and structural formula are as follows respectively:
Compound P hysagulins L
The unsetting powder of white is soluble in chloroform, acetone and methanol.According to its mass spectrum m/z 510.2637, obtain its molecular formula: C
30H
38O
7The infrared chromatography prompting has a α, β-unsaturated delta-lactone (1731cm
-1) and a α, alpha, beta-unsaturated ketone (1712cm
-1).By
1H-NMR and
13The C-NMR prompting is the Withanolides:Physagulin compounds of classics.By
1H,
13C-NMR spectrum (table 1 and table 2) prompting has the existence of six methyl, one of them methyl that links to each other with tertiary carbon [1.08 (d, J=6.9)], and other is five link to each other with quaternary carbon (1H, 1.72, s; 1H, 1.85, s; 1H, 1.92, s; 1H, 1.13, s; 1H, 1.28, s), from the DEPT spectrum as can be seen: four methylene [C (34.3), C (21.2), C (38.2), C (32.0)], the quaternary carbon [C (82.4)] of an O of company, three carbonyls [C (206.2), C (167.8), C (169.7)], the methine [C (72.8), C (83.6), C (78.2)] of three O of company.Compound P hysagulins L and chemical compound withaminimin compare, and the signal both on the C-E ring is very approaching, and prompting Compound P hysagulins L and withaminimin are the different of A, B ring.(6.0Hz) (d, J=6.0Hz) (d J=9.7Hz) is correlated with δ 5.92 with other pair key signals δ 6.12 for dd, J=9.7 from the two as can be known key signals δ 6.92 of coupling constant J value.From HMQC, HMQC compose as can be known δ 6.12 (d, J=6.0Hz) and C-2, C-6 relevant with C-10 (Fig. 1), (dd, J=9.7 6.0Hz) are H-C (4) to prompting δ 6.92; δ 6.92 (dd, J=9.7,6.0Hz) relevant with C-1 and C-5, prompting δ 6.92 (dd, J=9.7 6.0Hz) are H-C (3), thus from can infer and position of double bond at C-2 and C-4.NOE has determined the relative configuration of this chemical compound: Me (18) and H-C (8), Me (19) and H-C (8), and Me (19) and H-C (6) prompting H-C (8) and H-C (6) they are beta comfigurations.As can be known, if H-C (22) is α-configuration, then J (22,23) is respectively 0.5-4Hz and 9-13.8Hz from the document, if beta configuration, then J (22,23) is respectively 2.5-7Hz and 2-5Hz.Therefore (J=3.2,13.0Hz) prompting H-C (22) is a configuration; The words C (14 of 156-acetyl group-14 beta-hydroxy or hydroxyl-14 beta-hydroxies; 15) chemical displacement value is respectively 76-80 and 80-88ppm; 15 α-acetyl group-14 Alpha-hydroxy chemical displacement value is respectively 83-84 and 82-83ppm[3 on the other hand; 7; 11], from C-15 (δ 83.6) and C-14 (δ 82.4) as can be known chemical compound contain 15 α-acetyl group-14 beta-hydroxy.So the structure of chemical compound is confirmed as (22R)-15 α-acetoxy-6 α, 14a-dihydroxy-1-oxo-witha-2,4,16,24-tetraenolide is named as Physagulin L.
Table 1 Physagulins L, Physagulins M, the hydrogen spectrum data (400MHz) of Physagulins N and Physagulins O
a)Measured?in?CDCl
3.
b)Measured?in?CDCl
3/CD
3OD，95:5(v/v).
Table 2. Compound P hysagulin L, M, N, O, K, J and Withaminimin's
13C-NMR data (100MHz)
a)Measured?in?CDCl
3.
b)Measured?in?CDCl
3/CD
3OD，95:5(v/v).
Compound P hysagulins M
The white amorphous powder is soluble in chloroform, acetone and methanol.Determine that according to mass spectrometric data the molecular formula of Compound P hysagulinsM is C
30H
40O
8Compare with Compound P hysagulin K: the methylene among the Compound P hysagulin J (δ 36.8) and company's oxygen quaternary carbon (δ 77.3), the two keys (δ 117.8,157.4) among the combined thing Physagulins M replace.With Compound P hysagulins M relatively: chemical compound is many, and two keys have lacked a hydroxyl.From HMQC, HMBC as can be known H-C (4) (δ 6.12 (and d, J=5.9Hz) relevant with C-10 (δ 53.7) with C-6 (δ 73.6), C-5 (δ 157.4) and H-C (19) (δ 1.42 (s)) relevant (Fig. 2), the prompting C-4, C-5 two keys are arranged.Because Compound P hysagulins M and Compound P hysagulin J are very close at the signal of C-E ring, so hydroxyl on 14,17 and H-C (15) are β.C-15 (δ 87.0) and C-14 (δ 79.0) have also confirmed it is 15 α-acetyl group-14 beta-hydroxy.So Compound P hysagulinsM structure is confirmed as (22R)-15a-acetoxy-6a, 14 β, 17 β-trihydroxy-1-oxo-witha-2,4,24-trienolide is named as Physagulin M.
Compound P hysagulins N
The white amorphous powder is soluble in chloroform, acetone and methanol.Determine that according to mass spectrometric data the molecular formula of Compound P hysagulinsN is C
28H
40O
7As can be seen, 6 methyl are arranged, 6 methylene [C (34.6) from the spectrogram, C (35.9), C (23.2), C (42.7), C (29.3), C (27.4)], the quaternary carbon [C (76.6) of 2 O of company, C (84.3)], 2 carbonyls [C (205.4), C (167.9)], the methine [C (73.5) of 3 O of company, C (76.7), C (78.8)].Compare with Compound P hysagulinsN, the hydroxyl among the combined thing Physagulins M of C (15)-OAc signal (δ 170.3,21.4) that unique different place is a chemical compound replaces.Other hydrogen, carbon signal are determined (Fig. 3) by HMQC and HMBC.So the structure of Compound P hysagulins N be confirmed as (17R, 22R)-5 α, 6 β, 14 β, 15 α-tetrahydroxy-1-oxo-witha-2,24-dienolide is named as Physagulin N.
Compound P hysagulins O
The white amorphous powder is soluble in chloroform, acetone and methanol.With chemical compound Withaminimin relatively, chemical compound has 15 α-acetyl group equally, different places be the position of two keys and hydroxyl number.C-1 has moved 5.6ppm to low, and δ 5.61 (4.2Hz) relevant with C-5 (δ 77.7) with C-1 (δ 210.3), (d, J=9.5Hz) relevant with C-6 (δ 74.1), these have pointed out position of double bond at C-3 to δ 6.10, C-4 for dt, J=9.5.Compound P hysagulins O has been Duoed a hydroxyl than chemical compound Withaminimin, because many tertiary carbons (δ 70.7 (d)) of O even, and this tertiary carbon is relevant with H-18, and the tertiary carbon of the O of the company of prompting is C-12.Come H-19 relevant with H-12 as can be seen from NOE, prompting H-12 is a beta comfiguration.Therefore the structure of Compound P hysagulinsO is confirmed as (22R)-15 α-acetoxy-5 α, 6 β, 12 α, 14 α-tetrahydroxy-1-oxo-witha-3,16,24-trienolide, called after Physagulin O.
Chemical compound Withagulatin A
The unsetting powder of white is soluble in chloroform, acetone and methanol.EI-MS:526, molecular formula: C
30H
38O
8
1H-NMR(CDCl
3)：δ?6.14(1H，d，J＝10Hz，H-2)，6.96(1H，dd，J＝10，5.8Hz，H-3)，3.76(1H，dd，J＝5.8，2.0Hz，H-4)，3.33(1H，br?s，H-6)，5.19(1H，d，J＝2.7Hz，H-15)，5.62(1H，d，J＝2.7Hz，H-16)，1.05(3H，s，H-18)，1.40(3H，s，H-19)，1.07(3H，d，H-21)，4.21(1H，ddd，J＝12，7，3Hz，H-22)，1.80(3H，s，H-27)，1.90(3H，s，H-28)，1.91(3H，s，H-OAc)；
13C-NMR(CDCl
3)：δ?202.5(s，C-1)，131.5(d，C-2)，142.8(d，C-3)，69.6(d，C-4)，63.3(s，C-5)，63.3(d，C-6)，24.7(t，C-7)，34.8(t，C-8)，39.4(d，C-9)，47.7(s，C-10)，21.9(t，C-11)，37.6(t，C-12)，52.1(s，C-13)，81.6(d，C-14)，83.6(t，C-15)，120.9(t，C-16)，162.5(s，C-17)，17.7(q，C-18)，16.0(q，C-19)，35.5(d，C-20)，17.4(q，C-21)，79.5(d，C-22)，33.2(t，C-23)，148.5(s，C-24)，122.2(s，C-25)，166.4(s，C-26)，12.6(q，C-27)，20.3(q，C-28)，21.3(q，C-OAc)，170.0(s，C-0Ac)。
1H,
13Withagulatin A spectral data unanimity in (C.M.Chen, Z.T.Chen, C.H.Hsieh, W.S.Li, S.Y.Wen, Heterocycles 1990,31,1371.) of C-NMR spectrum and bibliographical information.
Compound P hysagulin K
The unsetting powder of white is soluble in chloroform, acetone and methanol.EI-MS:546, molecular formula: C
30H
42O
9
1H-NMR (CDCl
3): δ 6.13 (1H, dd, J=10,2Hz, H-2), 6.65 (1H, ddd, J=10,5,2Hz, H-3), 4.15 (1H, t, J=2Hz, H-6), 5.88 (1H, d, J=4Hz, H-15), 1.47 (3H, s, H-18), 1.66 (3H, s, H-19), 1.26 (3H, d, J=2Hz, H-21), 5.05 (1H, dt, J=13,2Hz, H-22), 1.95 (3H, s, H-27), 1.73 (3H, s, H-28), 2.23 (3H, s, H-OAc)
13C-NMR spectrum ownership sees Table 2.
Physagulin K spectral data unanimity in its hydrogen spectrum and carbon spectrum data and the document (S.Nagafuji, H.Okabe, H.Akahane, F.Abe, Biol.Pharm.Bull2004,27 (2), 193.).
Chemical compound With aminimin
The unsetting powder of white is soluble in chloroform, acetone and methanol.5% sulphuric acid adds colour developing and is aubergine.EI-MS:528, molecular formula: C
30H
40O
8
1H-NMR (CDCl
3): δ 5.86 (1H, dd, J=10,2.5Hz, H-2), 6.57 (1H, ddd, J=10,5,2Hz, H-3), 3.60 (1H, br t, J=2Hz, H-6), 5.32 (1H, d, J=2.5Hz, H-15), 5.59 (1H, br d, J=2.5Hz, H-16), 1.15 (3H, s, H-18), 1.20 (3H, s, H-19), 1.11 (3H, d, H-21), 4.34 (1H, ddd, J=12,7,4Hz, H-22), 4.36 (2H, q, J=14,2Hz, H-27), 3.98 (1H, m, H-3), 3.85 (1H, t, H-1), 1.86 (3H, s, H-27), 1.98 (3H, s, H-28)
13C-NMR spectrum ownership sees Table 2.
Its hydrogen spectrum and carbon are composed the Withaminimin spectral data unanimity in data and the document (H.E.Gottlieb, M.Cojocaru, S.C.Sinha, M.Saha, Phytochemistry 1987,26,1801.).
Compound P hysagulin J
The unsetting powder of white is soluble in chloroform, acetone and methanol.EI-MS:530, molecular formula: C
30H
42O
8
1H-NMR (CDCl
3): δ 6.11 (1H, dd, J=10,2Hz, H-2), 6.69 (1H, ddd, J=10,5,2Hz, H-3), 4.15 (1H, t, J=2Hz, H-6), 5.73 (1H, d, J=4Hz, H-15), 1.44 (3H, s, H-18), 1.65 (3H, s, H-19), 1.12 (3H, d, J=2Hz, H-21), 4.50 (1H, dt, J=13,2Hz, H-22), 1.92 (3H, s, H-27), 1.63 (3H, s, H-28), 2.19 (3H, s, H-OAc)
13C-NMR spectrum ownership sees Table 2.
Its hydrogen spectrum and carbon are composed the Physagulin J spectral data unanimity in data and the document (C.M.Chen, Z.T.Chen, C.H.Hsieh, W.S.Li, S.Y.Wen, Heterocycles 1990,31,1371.).
Compound P hysagulin B
The white amorphous powder is soluble in chloroform, acetone and methanol.EI-MS:546, molecular formula: C
30H
39ClO
7
1H?NMR(CDCl
3)：δ?5.89(1H，br?d，J＝10.3，2.6Hz，H-2)，6.61(1H，ddd，J＝10.3，5.1，3.0Hz，H-3)，3.95(1H，br?s，H-6)，5.28(1H，d，J＝2.6Hz，H-15)，5.64(1H，d，J＝2.6Hz，H-16)，1.14(3H，s，H-18)，1.27(3H，s，H-19)，1.11(3H，d，J＝6.5Hz，H-21)，1.85(3H，s，H-27)，2.00(3H，s，H-28)，2.05(3H，s，H-OAc)；
13C-NMR(CDCl
3)：δ?200.9(s，C-1)，128.2(d，C-2)，141.7(d，C-3)，36.9(t，C-4)，81.0(s，C-5)，73.9(d，C-6)，26.5(t，C-7)，35.2(t，C-8)，36.9(d，C-9)，52.7(s，C-10)，22.8(t，C-11)，38.5(t，C-12)，52.0(s，C-13)，82.0(d，C-14)，83.4(t，C-15)，120.5(t，C-16)，160.7(s，C-17)，16.7(q，C-18)，15.5(q，C-19)，35.3(d，C-20)，17.0(q，C-21)，78.3(d，C-22)，32.0(t，C-23)，150.5(s，C-24)，121.2(s，C-25)，167.5(s，C-26)，12.2(q，C-27)，20.6(q，C-28)，21.3(q，C-OAc)，170.4(s，C-OAc)。
Physagulin B spectral data unanimity in its hydrogen spectrum and carbon spectrum data and the document (K.Shingu, S.Yahara, T.Nohara, H.Okabe, Chem.Pharm.Bull.1992,40,2088.).
Compound P ubesenolide
The unsetting powder of white is soluble in chloroform, acetone and methanol.EI-MS:458, molecular formula: C
28H
42O
5
1H?NMR(CDCl3)：δ5.59(1H，brd，J＝5.4Hz，H-6)，4.45(1H，dt，J＝14.3，3.4Hz，H-22)，4.36(2H，q，J＝14，2Hz，H-27)，3.98(1H，m，H-3)，3.85(1H，t，H-1)，2.03(3H，s，H-28)，1.04(3H，s，H-19)，1.03(3H，d，J＝6.5Hz，H-21)，0.73(3H，s，H-18)；
13C-NMR(CDCl
3)：δ?72.7(d，C-1)，38.2(t，C-2)，66.0(d，C-3)，41.4(t，C-4)，137.7(s，C-5)，125.5(d，C-6)，31.9(t，C-7)，31.3(t，C-8)，41.5(d，C-9)，41.5(s，C-10)，22.3(t，C-11)，39.5(t，C-12)，42.8(s，C-13)，56.2(d，C-14)，24.5(t，C-15)，27.3(t，C-16)，52.0(d，C-17)，11.7(q，C-18)，15.4(q，C-19)，38.7(d，C-20)，13.4(q，C-21)，78.7(d，C-22)，29.8(t，C-23)，154.0(s，C-24)，124.8(s，C-25)，167.1(s，C-26)，56.9(t，C-27)，20.1(q，C-28)。
Pubesenolide spectral data unanimity in its hydrogen spectrum and carbon spectrum data and the document (M.Sahai, J.Nat.Prod.1985,48,474.) is so this chemical compound is confirmed as Pubesenolide.
Compound P hysagulin D
The unsetting powder of white is soluble in chloroform, acetone and methanol.EI-MS:620, molecular formula: C
34H
52O
10
1H?NMR(CDCl
3)：δ?5.59(1H，br?d，J＝5.4Hz，H-6)，4.45(1H，dt，J＝14.3，3.4Hz，H-22)，4.36(2H，q，J＝14，2Hz，H-27)，3.82(1H，m，H-3)，3.85(1H，t，H-1)，2.03(3H，s，H-28)，1.04(3H，s，H-19)，1.03(3H，d，J＝6.5Hz，H-21)，0.73(3H，s，H-18)，4.58(1H，d，J＝8Hz，H-1’)；
13C-NMR(C
5D
5N)：δ?72.4(d，C-1)，37.9(t，C-2)，74.0(d，C-3)，39.2(t，C-4)，139.3(s，C-5)，124.1(d，C-6)，32.2(t，C-7)，32.1(t，C-8)，41.5(d，C-9)，42.2(s，C-10)，20.6(t，C-11)，39.7(t，C-12)，42.8(s，C-13)，56.5(d，C-14)，24.7(t，C-15)，27.3(t，C-16)，52.0(d，C-17)，11.7(q，C-18)，19.7(q，C-19)，39.1(d，C-20)，13.6(q，C-21)，78.3(d，C-22)，29.8(t，C-23)，154.0(s，C-24)，127.4(s，C-25)，166.4(s，C-26)，56.1(t，C-27)，20.1(q，C-28)，102.8(d，C-glc-1)，75.3(d，C-glc-2)，78.5(d，C-glc-3)，71.5(d，C-glc-4)，78.4(d，C-glc-5)，62.6(t，C-glc-6)。
Physagulin D spectral data unanimity in its hydrogen spectrum and carbon spectrum data and the document (K.Shingu, S.Yahara, T.Nohara, H.Okabe, Chem.Pharm.Bull.1992,40,2088.).
Compound P hysagulin I
The white amorphous powder is soluble in chloroform, acetone and methanol.EI-MS:562, molecular formula: C
30H
39ClO
8
1H?NMR(CDCl
3)：δ?6.11(1H，dd，J＝10，2Hz，H-2)，6.69(1H，ddd，J＝10，5，2Hz，H-3)，4.27(1H，t，J＝3Hz，H-6)，5.47(1H，br?s，H-15)，3.76(1H，brs，H-16)，1.34(3H，s，H-18)，1.58(3H，s，H-19)，1.01(3H，d，J＝7Hz，H-21)，1.89(3H，s，H-27)，1.74(3H，s，H-28)，2.19(3H，s，H-OAc)；
13C-NMR(CDCl
3)：δ?201.5(s，C-1)，128.6(d，C-2)，142.9(d，C-3)，38.0(t，C-4)，83.2(s，C-5)，74.4(d，C-6)，29.1(t，C-7)，36.3(t，C-8)，37.1(d，C-9)，53.6(s，C-10)，22.6(t，C-11)，32.9(t，C-12)，47.2(s，C-13)，81.8(d，C-14)，77.8(t，C-15)，59.7(d，C-16)，76.3(s，C-17)，16.1(q，C-18)，16.3(q，C-19)，34.1(d，C-20)，14.2(q，C-21)，77.1(d，C-22)，32.9(t，C-23)，149.4(s，C-24)，121.9(s，C-25)，165.9(s，C-26)，12.7(q，C-27)，20.1(q，C-28)，21.3(q，C-OAc)，170.0(s，C-OAc)。
Its hydrogen spectrum and carbon are composed the Physagulin I spectral data unanimity in data and the document (C.M.Chen, Z.T.Chen, C.H.Hsieh, W.S.Li, S.Y.Wen, Heterocycles 1990,31,1371.).
Compound P hysagilin A
The white amorphous powder is soluble in chloroform, acetone and methanol.EI-MS:510, molecular formula: C
30H
38O
7
1H?NMR(CDCl
3)：δ?6.03(1H，br?d，J＝10.0，2.7Hz，H-2)，6.89(1H，ddd，J＝10.0，6.1，2.2Hz，H-3)，3.25(1H，d，J＝2.7Hz，H-6)，5.24(1H，d，J＝2.8Hz，H-15)，5.68(1H，d，J＝2.8Hz，H-16)，1.10(3H，s，H-18)，1.27(3H，s，H-19)，1.13(3H，d，J＝7.2Hz，H-21)，1.85(3H，s，H-27)，1.94(3H，s，H-28)，1.96(3H，s，H-OAc)；
13C-NMR(CDCl
3)：δ?203.8(s，C-1)，128.9(d，C-2)，145.0(d，C-3)，33.0(t，C-4)，61.7(s，C-5)，64.0(d，C-6)，25.0(t，C-7)，35.1(t，C-8)，36.4(d，C-9)，48.5(s，C-10)，23.5(t，C-11)，37.8(t，C-12)，52.2(s，C-13)，81.5(d，C-14)，83.8(t，C-15)，121.3(t，C-16)，162.0(s，C-17)，16.2(q，C-18)，15.3(q，C-19)，35.5(d，C-20)，17.6(q，C-21)，78.0(d，C-22)，32.8(t，C-23)，148.9(s，C-24)，122.2(s，C-25)，166.4(s，C-26)，12.6(q，C-27)，20.6(q，C-28)，21.3(q，C-OAc)，170.0(s，C-OAc)。
Physagulin A spectral data unanimity in its hydrogen spectrum and carbon spectrum data and the document (K.Shingu, S.Yahara, T.Nohara, H.Okabe, Chem.Pharm.Bull.1992,40,2088.).
Compound P hysagulin C
The white amorphous powder is soluble in chloroform, acetone and methanol.EI-MS:542, molecular formula: C
30H
38O
9
1H?NMR(CDCl
3)：δ?6.45(1H，d，J＝10Hz，H-2)，7.26(1H，dd，J＝10，6Hz，H-3)，4.01(1H，d，J＝6Hz，H-4)，3.26(1H，brs，H-6)，5.31(1H，brs，H-15)，3.75(1H，brs，H-16)，1.29(3H，s，H-18)，1.77(3H，s，H-19)，0.97(3H，d，J＝7Hz，H-21)，1.89(3H，s，H-27)，1.74(3H，s，H-28)，2.12(3H，s，H-OAc)；
13C-NMR(CDCl
3)：δ?202.9(s，C-1)，131.6(d，C-2)，146.0(d，C-3)，70.2(d，C-4)，63.8(s，C-5)，61.0(d，C-6)，26.3(t，C-7)，35.8(t，C-8)，40.1(d，C-9)，48.3(s，C-10)，20.4(t，C-11)，31.5(t，C-12)，46.9(s，C-13)，81.5(d，C-14)，78.4(t，C-15)，59.2(d，C-16)，76.3(s，C-17)，15.5(q，C-18)，17.1(q，C-19)，34.4(d，C-20)，14.0(q，C-21)，77.0(d，C-22)，33.0(t，C-23)，149.8(s，C-24)，122.0(s，C-25)，165.9(s，C-26)，12.7(q，C-27)，20.1(q，C-28)，20.9(q，C-OAc)，169.7(s，C-OAc)。
Its hydrogen spectrum and carbon are composed the Physagulin C spectral data unanimity in data and the document (C.M.Chen, Z.T.Chen, C.H.Hsieh, W.S.Li, S.Y.Wen, Heterocycles 1990,31,1371.).
Compound P hysagulin F
The white amorphous powder is soluble in chloroform, acetone and methanol.EI-MS:544, molecular formula: C
30H
40O
9
1H?NMR(CDCl
3)：δ?6.11(1H，dd，J＝10，2Hz，H-2)，6.67(1H，ddd，J＝10，5，2Hz，H-3)，4.11(1H，t，J＝3Hz，H-6)，5.60(1H，br?s，H-15)，3.70(1H，br?s，H-16)，1.39(3H，s，H-18)，1.60(3H，s，H-19)，1.01(3H，d，J＝7Hz，H-21)，1.89(3H，s，H-27)，1.74(3H，s，H-28)，2.22(3H，s，H-OAc)；
13C-NMR(CDCl
3)：δ?204.9(s，C-1)，129.0(d，C-2)，142.4(d，C-3)，36.9(t，C-4)，77.3(s，C-5)，74.9(d，C-6)，29.2(t，C-7)，36.5(t，C-8)，36.0(d，C-9)，52.6(s，C-10)，23.1(t，C-11)，33.5(t，C-12)，47.2(s，C-13)，82.5(d，C-14)，77.4(t，C-15)，59.7(d，C-16)，76.8(s，C-17)，16.1(q，C-18)，15.3(q，C-19)，33.7(d，C-20)，14.2(q，C-21)，77.1(d，C-22)，32.9(t，C-23)，149.4(s，C-24)，121.9(s，C-25)，165.9(s，C-26)，12.7(q，C-27)，20.1(q，C-28)，21.3(q，C-OAc)，170.4(s，C-OAc)。
Its hydrogen spectrum and carbon are composed the Physagulin F spectral data unanimity in data and the document (C.M.Chen, Z.T.Chen, C.H.Hsieh, W.S.Li, S.Y.Wen, Heterocycles 1990,31,1371.).
Embodiment 4 Withanolide type chemical compound immunobiologic activity screening experiment
The breeder reaction of model name: T, bone-marrow-derived lymphocyte and cytotoxicity experiment
Screening object: sample 1, sample 2 and 25 kind of Withanolide type chemical compound of embodiment 1-3 preparation.
Screening technique: the BALB/C mice spleen lymphocyte is at mitogen ConA, and under the stimulation of LPS, a series of variation can take place for the form of cell and metabolism, is converted into blast cell, and differentiation and proliferation.This experiment adds ConA (concanavalin A, Con A) 5ug/ml inducer T lymphocyte propagation.Add LPS (lipopolysaccharide) 10ug/ml and induce bone-marrow-derived lymphocyte propagation.Mix the propagation that standard measure is measured cell with 3H-TdR.Mitochondrial dehydrogenase can have MTT yellow to be reduced into blue first the part between the ribs and the hips in the living cells, and first the part between the ribs and the hips output is directly proportional with living cells.Behind organic solvent dissolution, available microplate reader detects the OD value.
Test system: external.
Testing result sees Table 3.
Table 3. separates the monomer that obtains and the inhibition T of sample 1 and sample 2, the activity of B cell proliferation from Calyx seu fructus physalis He the Herba Physalis pubescentis ethanol extraction
| Sample | IC 50(uM) suppressor T cell propagation | IC 50(uM) suppress B cell proliferation |
| Physalin?A | 0.86±0.03 | 0.93±0.05 |
| Physalin?B | 0.92±0.03 | 1.23±0.05 |
| Physalin?D | 1.16±0.09 | 1.71±0.08 |
| Physalin?H | 0.32±0.02 | 0.38±0.04 |
| 2，3-dihydrophysalin?D | >30 | >30 |
| 13-acetoxyphysalin?D | 5.86±0.33 | 7.93±0.56 |
| Physalin?L | >30 | >30 |
| Physalin?N | 4.86±0.33 | 5.93±0.65 |
| Physalin?O | 8.86±0.53 | 8.93±0.75 |
| Isophysalin?B | >30 | >30 |
| Isophysalin?G | >30 | >30 |
| Physagulin?L | 19.8±1.0 | 22.9±1.7 |
| Physagulin?M | 22.6±1.9 | 25.6±2.2 |
| Physagulin?N | 8.22±0.5 | 9.93±0.7 |
| Physagulin?J | 8.85±0.4 | 9.99±0.8 |
| Physagulin?O | >30 | >30 |
| Withagulatin?A | 2.74±0.13 | 3.94±0.25 |
| Physagulin?A | 1.78±0.12 | 1.98±0.25 |
| Withaminimin | 5.86±0.43 | 6.80±0.54 |
| Physagulin?B | 0.21±0.03 | 0.39±0.05 |
| Physagulin?C | 0.77±0.04 | 1.53±0.15 |
| Pubesenolide | >30 | >30 |
| Physagulin?I | 0.26±0.03 | 0.40±0.05 |
| Physagulin?F | 6.86±0.53 | 8.93±0.75 |
| Physagulin?K | 11.8.±0.9 | 15.3±1.3 |
| Sample 1 | 10.3±0.8 | 11.6±0.8 |
| Sample 2 | 7.81±0.6 | 8.56±0.7 |
| CsA | 0.34±0.02 | 0.47±0.03 |
As can be seen from Table 3, the active component that suppresses T, B cell proliferation is mainly the Withanolide constituents, comprising Physalin skeleton and two kinds of framework types of classical Withanolide skeleton.Especially Compound P hysalin H, Physagulin B and Physagulin I have the activity that is better than encircling luxuriant rhzomorph (CsA).
In sum, Withanolide type chemical compound of the present invention has stronger immunosuppressive action, excessive value-added T, bone-marrow-derived lymphocyte cycle is produced check effect, can be used for preparing immunosuppressant, with treatment autoimmune disease and relevant disease.
Need to prove, all quote in this application as a reference, just quoted as a reference separately as each piece document at all documents that the present invention mentions.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read above-mentioned teachings of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (8)
1. an immunosuppressant is characterized in that, described immunosuppressant comprises chemical compound or its optical isomer shown in following general formula I and/or the general formula I I:
Wherein, R1, R2, R3, R4, R5, R6, R7 are selected from H, OH, O-acyl, OMe, OEt, O
nPr, OiPr, F, Cl, Br, NH
2, NO
2Or CN, wherein 5,6 is epoxy or two key, and 14,27 ehter bonds connect or disconnection in the general formula I, and 14,15 and 16,17 is epoxy and two keys among the general formula I I.
Immunosuppressant as claimed in claim 1 is characterized in that, chemical compound comprises PhysalinA shown in the described general formula I, Physalin B, Physalin D, Physalin H, 2,3-Dihydrophysalin D, 13-Acetoxyphysalin D, Physalin L, Physalin N, Physalin O, one or more of Isophysalin B and Isophysalin G:
Chemical compound comprises Physagulin L shown in the described general formula I I, Physagulin M, Physagulin N, PhysagulinJ, Physagulin O, Withagulatin A, Physagulin A, Withaminimin, Physagulin B, PhysagulinC, Pubesenolide, Physagulin I, one or more of Physagulin F and Physagulin K:
2. immunosuppressant as claimed in claim 2 is characterized in that, chemical compound shown in the described general formula I is Physalin H, and chemical compound shown in the described general formula I I is Physagulin B and/or Physagulin I.
3. an immunosuppressant is characterized in that, described immunosuppressant comprises plant extract, and described plant extract contains the chemical compound shown in general formula I as claimed in claim 1 or the general formula I I or its optical isomer.
4. plant extract as claimed in claim 4 is characterized in that, described plant extract Wei Herba Physalis pubescentis overground part extract and/or Calyx seu fructus physalis overground part extract.
5. the application in the medicine of preparation treatment autoimmune disease as claim 1 or 4 described immunosuppressant.
6. application as claimed in claim 6, it is characterized in that described autoimmune disease is rheumatoid arthritis, autoimmune hepatitis, insulin-dependent diabetes, ulcerative colitis, multiple sclerosis, scleroderma, myasthenia gravis, multiple myositis, autoimmunity cytopenia, vasculitis syndrome or systemic lupus erythematosus (sle).
7. as exempt from service in preparation treatment inflammatory reaction, fibrosis or by self the application in the dysfunction that has tissue injury or infection due to disease and the relevant disease, anaphylactic disease, the medicine of graft versus host disease due to transplanting by bone marrow (hematopoietic stem cell) of claim 1 or 4 described immunosuppressant.
8. application as claimed in claim 8 is characterized in that, described anaphylactic disease is bronchial asthma, allergic rhinitis, atopic dermatitis or pollinosis.
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| CN103784435B (en) * | 2014-02-27 | 2015-10-28 | 富阳科兴生物化工有限公司 | The application of physalin A in preparation JAK2-STAT3 signal pathway inhibitor and antitumor drug |
| CN105949266A (en) * | 2016-05-20 | 2016-09-21 | 天津中医药大学 | Withana lactide compound, method for extracting same and application of withana lactide compound |
| CN106008641A (en) * | 2016-05-20 | 2016-10-12 | 天津中医药大学 | Withania somnifera lactide compound, method for extracting same and application of withania somnifera lactide compound |
| CN107056869A (en) * | 2016-05-20 | 2017-08-18 | 天津中医药大学 | A kind of withanolide class compound and extracting method and application |
| CN105949266B (en) * | 2016-05-20 | 2018-01-12 | 天津中医药大学 | Withanolide class compound and extracting method and application |
| CN106008641B (en) * | 2016-05-20 | 2018-11-06 | 天津中医药大学 | Withanolide class compound and extracting method and purposes |
| CN107056869B (en) * | 2016-05-20 | 2019-07-16 | 天津中医药大学 | A kind of withanolide class compound and extracting method and application |
| CN105968162A (en) * | 2016-07-01 | 2016-09-28 | 中国药科大学 | Withanolides type compound and use thereof |
| CN105968162B (en) * | 2016-07-01 | 2019-01-01 | 中国药科大学 | Withanolides type compound and application thereof |
| CN109776565A (en) * | 2019-01-28 | 2019-05-21 | 浙江省中医药研究院 | A kind of bitter taste chlorins compound and the preparation method and application thereof |
| CN112618539A (en) * | 2021-01-05 | 2021-04-09 | 广东药科大学 | Application of physalin B in preparation of medicine for treating acute lung injury |
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