CN101366719A - Triterpenes anti-AIDS drugs - Google Patents
Triterpenes anti-AIDS drugs Download PDFInfo
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- CN101366719A CN101366719A CNA2008101990130A CN200810199013A CN101366719A CN 101366719 A CN101366719 A CN 101366719A CN A2008101990130 A CNA2008101990130 A CN A2008101990130A CN 200810199013 A CN200810199013 A CN 200810199013A CN 101366719 A CN101366719 A CN 101366719A
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Abstract
The invention discloses a natural medicine having the function of resisting AIDS virus HIV-1. The medicine is a triterpene compound and can be prepared into a medicinal preparation for treating HIV-1 infected persons and AIDS patients.
Description
Technical field
The present invention relates to have a kind of triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ' of new chemical constitution, 3 '-dimethyl succinic acid monoesters is used to make anti-AIDS drug.
Background technology
Acquired immune deficiency syndrome (AIDS) is " acquired immune deficiency syndrome (AIDS) " (Acquired Immunodeficiency Syndrome, AIDS), it is by HIV (human immunodeficiency virus) (Human Immunodeficiency Virus), i.e. " HIV (human immunodeficiency virus) " (Human Immunodeficiency Virus, HIV) infect and a kind of serious harm human health that causes and the infectiousness major disease that produces serious social problem are the pernicious infectious disease that still can't cure so far.Quan Qiu HIV the infected surpasses 7,000 ten thousand so far, and existing more than 3,000 ten thousand people die from acquired immune deficiency syndrome (AIDS).Surpassed 800,000 China HIV the infected, it is popular to have entered quick propagation stage, and it is very severe to spread situation.If can not get effective control, will the social stability and the economic development generation of China be had a strong impact on.
Highly active antiretroviral therapy (HAART), i.e. reverse transcriptase inhibitors combination, perhaps reverse transcriptase inhibitors adds the protease inhibitor combination, and the method for administering drug combinations treatment is the most effective at present etiological treatment method.Long-term treatment can make Most patients reach and not detect viral curative effect in the blood plasma.Use the chemicals of HAART combination, control case fatality rate, prolongation life and minimizing HIV are propagated played important function.But these medicines can only be killed the free virus that exists in the blood, can't remove and be incorporated into intragenic virus; Part patient's (as merging patient lungy) is not suitable for the combination medicine treatment of HAART; Virus might produce drug resistance again because of gene mutation in therapeutic process, has been found that " the super strain " that present all antiviral drugs all showed resistance in clinical treatment.In addition, the medication combined administration of number of chemical, consumption is big, and toxic and side effects is obvious, and patient dependence is poor, adds factors such as the medicine is expensive, has all limited the application of HAART.The research and development of novel anti-hiv agent are the focuses of domestic and international the world of medicine work always.
Bio-diversity makes animal, plant, microorganism and marine organisms produce the extremely abundant secondary metabolite of structure type, therefrom excavate out quantity and structure kind extremely abundant natural product or lead compound, natural product is the important source that modern new drug is found.In anti-HIV/AIDS natural drug, the different phase that the pharmaceutically active natural product of some plant origins duplicates HIV can produce inhibitory action [De Clercq E. (2000) Current lead natural products for thechemotherapy of human immunodeficiency virus (HIV) infection.Med.Res.Rev., 20 (5): 323-349].The semi-synthetic derivant of some natural triterpene can become efficient AIDS virus resisting lead compound.For example, betulic acid (Betulinic acid) is present in Betula platyphylla Suk. genus (Betula) plant and other various plants.The dicarboxylic acid monoesters of betulic acid derivant, especially ad hoc structure (or claiming half ester) often shows the anti-HIV effect stronger than prototype.Studies show that of American scholar, medium effective concentration and therapeutic index that betulic acid inhibition HIV duplicates are respectively EC
50=1.4 μ M and TI=9.3, after the C-3 bit architecture is modified, can obtain 3-O-(3 ', 3 '-dimethylsuccinyl)-and betulinic acid (TI〉20000, stronger 2150 times than betulic acid), 3-O-(3 ', 3 '-dimethyl glutaryl)-highly active tetraterpene derivatives [Sun such as dihydrobetulinic acid (TI〉14000), IC, Wang H K, KashiwadaY, Shen, J K, Cosentino L M, Chen C H, Yang L M, Lee K H. (1998) AntiAIDS agents.34 Synthesis and structure-activity relationships of betulin derivatives as anti HIVagents[J] .J Med Chem, 41 (23): 4648-4657].
Summary of the invention
The chemical constitution 3 beta-hydroxy feather fans-20 of the new drug with specific triterpene compound structure (29)-alkene 3-O-3 ' all inequality that the purpose of this invention is to provide a kind of and known anti-AIDS drug, 3 '-dimethyl succinic acid monoesters has the chemical constitution shown in the structural formula I;
Structural formula I
Described chemical compound discloses new triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ' first, and the remarkable inhibition HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) that 3 '-dimethyl succinic acid monoesters has is duplicated effect.
Described triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', 3 '-dimethyl succinic acid monoesters has stronger external anti-HIV-1 effect, and the half-inhibition concentration that on the H9 cell HIV-1 is duplicated is 0.04 μ M, and therapeutic index reaches 2375.
Described have new triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', 3 '-dimethyl succinic acid monoesters has remarkable inhibition HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) and duplicates effect, can be used as active component and makes any pharmaceutically acceptable dosage forms such as tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, nanometer formulation, injection.
Triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ' of the present invention, 3 '-dimethyl succinic acid monoesters has new chemical constitution, can be made into pharmaceutical preparation, is used for treating HIV-1 the infected and HIV sufferers.
Description of drawings
Fig. 1 is the said two kinds of structural formulas with triterpenoid compound of external potent anti-HIV-1 virus function of the present invention
The specific embodiment
Below by drawings and Examples content of the present invention is described in further detail: those skilled in the art can understand the new triterpenoid compound 3 beta-hydroxy feather fans-20 of the present invention (29)-alkene 3-O-3 ', the acquisition methods of 3 '-dimethyl succinic acid monoesters and pharmacological action thereof; But these embodiment must not be interpreted as the restriction to claim of the present invention.
The preparation method of active precursor chemical compound is got flavor Radix Achyranthis Bidentatae Strubilanthes forrestii medical material 10Kg, and the industrial alcohol room temperature with 95% is extracted 3 times, and each 48 hours, extracting solution merged after concentrating under reduced pressure gets dry extract 700g.Extractum precipitation in a large number occurs with 80% methanol stir process, and precipitation must be measured 200g through filtering drying.Petroleum ether extraction 3 times of above-mentioned supernatant get petroleum ether part 20g.Mother solution after the above-mentioned extraction adds low amounts of water and becomes suspension after removing most of methanol, use chloroform, ethyl acetate and n-butanol extraction successively, each several part is respectively chloroform extract 50g, ethyl acetate extract 15g, n-butyl alcohol 60g and water-soluble position 200g through weakening must measure after concentrating.(the 100-200 order 3Kg), with petroleum ether-acetone gradient elution (98:2-4:1, volume ratio), instructs the merging that washes out fraction with TLC, obtains F will to precipitate the last silicagel column of part 180g
1-F
7Totally 7 positions.F
1(150g) find to have a main constituent, get pure substance HBS-0821, be defined as triterpenoid compound Lupeol through mass spectrum and nuclear magnetic resonance spectrometry through recrystallization through TLC.
Lupeol, numbering HBS-0821, white, needle-shaped crystals is soluble in chloroform, 215 ℃ of fusing points.[α]
D+26.8(c0.2，CHCl
3)。Molecular formula is C
30H
50O.ESI-MS?m/z：425.1[M-H]
-；
1HNMR(400MHz，CDCl
3)δ：4.67(1H，s，H-29a)，4.56(1H，s，H-29b)，3.15(1H，dd，J＝8.2，4.5Hz，H-3)，2.36(1H，m，H-19)，1.80(1H，m，H-29)，1.60(3H，s，H-30)，1.05(3H，s，H-26)，0.98(3H，s，H-27)，0.95(3H，s，H-24)，0.80(3H，s，H-23)，0.78(3H，s，H-25)，0.75(3H，s，H-28)。
13C-NMR(125MHz?in?CDCl
3)δ：38.7(C-1)，27.4(C-2)，78.8(C-3)，38.8(C-4)，55.2(C-5)，18.3(C-6)，34.2(C-7)，40.8(C-8)，50.4(C-9)，37.2(C-10)，20.9(C-11)，25.0(C-12)，38.1(C-13)，42.5(C-14)，27.5(C-15)，35.6(C-16)，43.0(C-17)，48.5(C-18)，48.0(C-19)，151.0(C-20)，29.9(C-21)，40.0(C-22)，28.0(C-23)，15.5(C-24)，16.2(C-25)，16.0(C-26)，14.5(C-27)，18.1(C-28)，109.5(C-29)，19.5(C-30)。
Embodiment 2
Compound H BS-0827 preparation
In the 100mL round-bottomed flask, add 214.9mg (0.50mmol) Lupeol, 107.2mg (0.51mmol) ferulic acid, 105.1mg (0.51mmol) DCC, 14.2mg (0.12mmol) DMAP and 15mL dichloromethane, at room temperature stir 48h.Reactant liquor concentrates, and through silica gel column chromatography, with petroleum ether-acetone (4:1) (volume ratio) eluting, steaming desolventizes, and gets white solid 278.8mg, and yield is 89.61%.
Compound H BS-0827-3A preparation:
Add 1067.0mg (2.5mmol) Lupeol in the 100mL there-necked flask, the 30mL dichloromethane stirs down and splashes into 2 of 326.7mg (2.55mmol), and the solution of 2-dimethyl succinic acid acid anhydride and 20mL dichloromethane after dripping off, at room temperature stirs 72h.Reactant liquor concentrates, and column chromatography (silica gel 200～300 orders, eluant petroleum ether-acetone (4:1) (volume ratio) eluting removes solvent under reduced pressure, gets white solid 1378.1mg, and productive rate is 94.15%.
The structure of chemical compound is determined
Infrared spectrum U.S. ANALECT RFX65A type spectrophotometer; Mass spectrum QP5000 mass spectrograph or U.S. API2000LC/MS/MS system measurement; Nuclear magnetic resoance spectrum is measured with DRX-400 type 400,000,000 NMR spectrometer with superconducting magnet of Germany-Switzerland Bruker company, and TMS does interior mark.
HBS-0827, clear crystal, 112 ℃ of fusing points, [α]
D+ 102.5 (c=0.05in CHCl
3), molecular formula C
40H
58O
4ESI-MSm/z:601[M-H]
-,
1HNMR (400MHz, CDCl
3) δ: 7.48 (1H, d, J=10.8, H-1 '), 7.05 (1H, d, J=1.2Hz, H-2, phenyl ring), (7.00 1H, dd, J=6.4,1.2Hz, H-6, phenyl ring), 6.75 (1H, d, J=6.4Hz, H-5, phenyl ring), 6.27 (1H, d, J=10.8Hz, H-2), 3.70 (3H, s, 3-OCH
3, phenyl ring), 4.68 (1H, s, H-29a), 4.55 (1H, s, H-29b), 4.59 (1H, dd, J=8.5,4.5Hz, H-3), 1.06 (3H, s, H-26), 0.98 (3H, s, H-27), 0.96 (3H, s, H-24), 0.82 (3H, s, H-23), 0.79 (3H, s, H-25), 0.77 (3H, s, H-28).
HBS-0827-3A, clear crystal, 258 ℃ of fusing points.[α]
D+40.8(c0.5in?CHCl
3)。Molecular formula C
30H
48O
4ESI-MS，m/z：553[M-H]
-，
1HNMR(400MHz，CDCl
3)δ：2.85，2.90(each?1H，d，J＝15.5Hz，-CH
2-，acyl?group)，1.50(6H，s，-CH
3×2，acyl?group)，4.66(1H，s，H-29a)，4.59(1H，s，H-29b)，4.49(1H，dd，J＝8.2，4.5Hz，H-3)，1.56(3H，s，H-30)，1.12(3H，s，H-26)，0.96(3H，s，H-27)，0.99(3H，s，H-24)，0.82(3H，s，H-23)，0.79(3H，s，H-25)，0.78(3H，s，H-28)。
13C-NMR(125Hz，CDCl
3)：171.0(C-1’)，45.0(C-2’)，40.9(C-3’)，179.5(C-4’)，25.5and26.0(CH
3×2，acyl?group)，38.6(C-1)，23.4(C-2)，81.1(C-3)，37.8(C-4)，55.1(C-5)，18.3(C-6)，34.4(C-7)，40.6(C-8)，50.4(C-9)，37.0(C-10)，20.6(C-11)，25.0(C-12)，38.4(C-13)，42.8(C-14)，27.7(C-15)，35.4(C-16)，43.0(C-17)，48.7(C-18)，48.0(C-19)，150.8(C-20)，29.7(C-21)，40.2(C-22)，28.2(C-23)，15.8(C-24)，16.0(C-25)，16.1(C-26)，14.7(C-27)，18.3(C-28)，109.0(C-29)，19.6(C-30)。
Embodiment 3
The external AIDS virus resisting effect of triterpenoid compound
Active medicine to be tested:
3 beta-hydroxy feather fans-20 (29)-alkene 3-O-4-hydroxyl-3-methoxy cinnamic acid monoesters (HSB-0827)
3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', 3 '-dimethyl succinic acid monoesters (HSB-0827-3A)
Assay method
Sample is to the inhibiting in-vitro evaluation test of HIV-1, and institute of oncology (NCI) carries out according to its conventional method in NIH (NIH).Use the H9T lymphocyte in the experiment, containing 10% hyclone, be added with among the complete medium RPMI1640 of L-glutamic acid, in 5% CO
2, 37 ℃ of following continuous passages are cultivated.The cell of trophophase of taking the logarithm is used for this experiment.
Medicine to be measured is dissolved in dimethyl sulfoxide earlier, becomes following ultimate density commonly used with the culture medium dilution: 100,20,4 and 0.8 μ g/mL, high-activity drug sample be further dilution then.Finally obtain one accurately to the half-inhibition concentration IC of virus
50
When sample is got all the ready, get the H9 cell and infect, get the H9 cell in addition with culture medium simulated infection (being made as viral negative control group) simultaneously, be used for the toxicity (IC of working sample pair cell with HIV-1 (IIIB type separated strain)
50).Research generally should reach 10 with virus
4The TCID of IU (infectious unit)/mL
50Value.The 1st group of cell of an amount of virus adding that virulence is equivalent to every cell 0.1 to 0.01IU will be infected; 1 group of cell that only adds culture medium uses the condition identical with infected group to hatch in addition.At 37 ℃ and 5% CO
2After hatching 4h, two groups of cells are all washed 3 times with fresh culture, are added in the 24-orifice plate that contains variable concentrations medicine or culture medium and (form positive infect contrast or the contrast of negative medicine), and each test all contrasts as positive drug with zidovudine AZT.With plate at 37 ℃, 5% CO
2Under hatched 4 days.Collect not celliferous culture medium supernatant at the 4th day, measure the p24 antigen of virus with the ELISA method.
P24 is the cAg of HIV, its existence existence of indicator virus in cell conditioned medium indirectly.Measure the toxicity of various samples on not by the H9 cell of viral infection with the Coulter enumerator.
The following term description of experimental result: TC
50, be meant the concentration when specimen produces 50% toxicity to the H9 cell; IC
50, be meant the concentration when specimen suppresses 50% virus; Therapeutic index (TI), TI=TC
50/ IC
50
Measurement result sees Table 2.
Table 2 triterpene sample and positive drug on the H9 cell to HIV-1 inhibitory action result of the test
Conclusion noval chemical compound HSB-0827-3A i.e. 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', and 3 '-dimethyl succinic acid monoesters has very strong external anti-HIV-1 effect, and therapeutic index reaches 2375, might develop into the anti-HIV-1 medicine of natural origin.
Claims (3)
1. triterpenes anti-AIDS drugs, it is characterized in that: described triterpenoid compound is 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', 3 '-dimethyl succinic acid monoesters, English name is 3-O-(3 ', 3 '-dimethylsuccinyl)-lupeol has the chemical constitution shown in the structural formula I;
Structural formula I
2. a kind of triterpenes anti-AIDS drugs according to claim 1, it is characterized in that described triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', 3 '-dimethyl succinic acid monoesters has stronger external anti-HIV-1 effect, the half-inhibition concentration that on the H9 cell HIV-1 is duplicated is 0.04 μ M, and therapeutic index reaches 2375.
3. a kind of triterpenes anti-AIDS drugs according to claim 1, it is characterized in that prepared anti-AIDS drug is with described triterpenoid compound 3 beta-hydroxy feather fans-20 (29)-alkene 3-O-3 ', 3 '-dimethyl succinic acid monoesters is as active constituents of medicine, acceptable forms on any pharmaceuticss such as the tablet of making, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, nanometer formulation, injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113956323A (en) * | 2021-11-12 | 2022-01-21 | 中国医学科学院药用植物研究所 | Tetracyclic triterpene derivative and preparation method and application thereof |
-
2008
- 2008-10-09 CN CNA2008101990130A patent/CN101366719A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113956323A (en) * | 2021-11-12 | 2022-01-21 | 中国医学科学院药用植物研究所 | Tetracyclic triterpene derivative and preparation method and application thereof |
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