CN109705189A - Tetraterpene derivatives and its preparation method and application with structure shown in Formulas I - Google Patents
Tetraterpene derivatives and its preparation method and application with structure shown in Formulas I Download PDFInfo
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Abstract
The present invention provides the tetraterpene derivatives with structure shown in Formulas I, belong to technical field of organic synthesis.Tetraterpene derivatives provided by the invention with structure shown in Formulas I have specific selective anti-HIV activity.
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly to tetraterpene derivatives and its system with structure shown in Formulas I
Preparation Method and application.
Background technique
AIDS (Acquired Immunodeficiency Syndrome, AIDS), also known as acquired immunodeficiency is comprehensive
Simulator sickness is due to a kind of serious prestige caused by aids infection malicious (Human Immunodeficiency Virus, HIV)
The major disease coerced human health, influence social development.The drug for capableing for the treatment of of AIDS is not still developed at present, so that
A large amount of patient dies of complication；Meanwhile this public health problem increases the pressure of state revenue and expenditure, has delayed economic hair
Exhibition.Therefore, the prevention and treatment problems demand of AIDS solves.
So far, it does not find the ideal medicament that can thoroughly cure HIV infection also, and mainly exists for the treatment of AIDS
In delay the course of disease and eliminate complication.Highly effective antiretroviral therapy (HAART), also known as " cocktail therapy " are a kind of
Administrated method is closed, i.e. two or more reverse transcriptase inhibitor is combined with one or more kinds of protease inhibitors and answered
With to inhibit HIV in the intracorporal duplication of people.And there is the secondary work of many poison in clinical application in the drug of HAART combination
With: efabirenz can may cause neuromuscular by blocking dna polymerase inducing mitochondrial toxicity
The serious side effect such as toxicity, pancreatitis, hyperlactacidemia, anaemia and Neutrophilic granulocytopenia；Non-nucleoside reverse transcriptase suppression
Preparation has hepatotoxicity wind agitation, can cause hepatic injury, and serious fash and Central neurotoxicity may occur in use
Adverse reaction；Protease inhibitors prolonged application will will lead to disorders of lipid metabolism, then induce atherosclerosis, cardiac muscle stalk
It waits indefinitely cardiovascular and cerebrovascular disease.During drug combination, adverse reaction caused by these drug interactions may more dash forward
Out, and because of long-term administration, the incidence of drug resistance is higher, generally requires the pharmaceutical composition more renewed after a period of time continuation
Treatment.
China's traditional Chinese medicine theory system is with a long history, treatment of the people in long-term clinical practice, to all kinds of Chinese medicines
Effect, toxicity etc. have accumulated experience abundant.By modern science and technology means, the material base of Chinese medicine effect is gradually dug
It excavates and, then use organic synthesis, the structure of lead compound is modified, to improve the activity of effective component, reduce poison
Side effect improves its absorption,distribution,metabolism,excretion, improves stability, and then obtain the monomer medicine that can be used for producing.According to
Document report, natural cycloartane triterpene compound Astragaloside IV and cycloastragenol can pass through the work of the upper Telomerase of adjusting
Property promotes CD8+T lymphopoiesis (Yung LY, Lam WS, Ho MK, et al. the Astragaloside IV of HIV patient
and cycloastragenol stimulate the phosphorylation of extracellular signal-
regulated protein kinase in multiple cell types.Planta Med, 2012,78(2):115-
121.)；Had also discovered from Schisandraceae Plant it is a series of can HIV-resistant activity cycloartane triterpenoids class compound [gold and silver
Duckweed, here stone, Liu Junxia waits Schisandraceae Plant middle ring Ah 's alkane type triterpenoid constituents and its Advance on Pharmacological Activities medium-height grass
Medicine, 2014,45 (4): 582-589].
Summary of the invention
In consideration of it, the purpose of the present invention is to provide tetraterpene derivatives with structure shown in Formulas I and preparation method thereof and
Using.Tetraterpene derivatives provided by the invention with structure shown in Formulas I have specific selective anti-HIV activity.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
Tetraterpene derivatives with structure shown in Formulas I.
The present invention also provides the preparation methods of the tetraterpene derivatives described in above-mentioned technical proposal, comprising the following steps:
By triterpene saponin componds beesioside I, hydrolase molsin and disodium hydrogen phosphate-citrate buffer solution
Mixing is reacted, and the aglycon of Beesioside I is obtained；
By the aglycon of the Beesioside I respectively with 2,2- dimethyl succinic anhydride, 2,2- dimethylated pentanedioic acid acid anhydride and
Diglycolic anhydride mixing carries out microwave reaction, obtains the tetraterpene derivatives with structure shown in Formulas I.
Preferably, the mass ratio of the triterpene saponin componds beesioside I and hydrolase molsin be 1:1~
1:10。
Preferably, the pH value of the disodium hydrogen phosphate-citrate buffer solution is 4.0.
Preferably, the temperature of the microwave reaction is 150~160 DEG C, and the time of the microwave reaction is 1~3h.
The present invention also provides the tetraterpene derivatives with structure shown in Formulas I described in above-mentioned technical proposal to prepare anti-Chinese mugwort
Grow the application in medicine.
Preferably, the anti-AIDS drug includes the tetraterpene derivatives with structure shown in Formulas I of effective dose, it spreads out
Biology, its stereoisomer, officinal salt and pharmaceutically acceptable carrier, auxiliary material, excipient and diluent.
Preferably, the dosage form of the anti-AIDS drug include tablet, injection, capsule, granule, pill, powder,
Oral solution, sustained release preparation, controlled release preparation or the pharmaceutically acceptable dosage form of nanometer formulation.
Preferably, when the R is 1 group, the tetraterpene derivatives with structure shown in Formulas I have significant external
Anti-HIV-1 effect, in HIV-1NL4-3In the MT-4 cell of virus infection, HIV virus is significantly inhibited, half
Effective inhibition concentration EC50It is 0.025 μM, and therapeutic index TI is greater than 800.
The present invention provides the tetraterpene derivatives with structure shown in Formulas I, have specific selective anti AIDS virus living
Property.
Detailed description of the invention
Fig. 1 is the schematic diagram of the preparation method for the tetraterpene derivatives that the present invention has structure shown in Formulas I.
Specific embodiment
The present invention provides the tetraterpene derivatives with structure shown in Formulas I,
In the present invention, when R is 1, the chemical name of the tetraterpene derivatives with structure shown in Formulas I are as follows: (20S,
24S)-15β,16β-diacetoxy-18,24,20,24-diepoxy-9,19-cyclolanostane -3β,25-diol 3-
O-3 ', 3 '-dimethylsuccinate, when R is 2, the chemical name of the tetraterpene derivatives with structure shown in Formulas I
Are as follows: (20S, 24S) -15 β, 16 β-diacetoxy-18,24；20,24- diepoxy-9,19-cyclolanostane-3β,
25-diol 3-O-4 ', 4 '-dimethylglutarate, when R is 3, the tetraterpene derivatives with structure shown in Formulas I
Chemical name are as follows: (20S, 24S) -15 β, 16 β-diacetoxy-18,24；20,24-diepoxy-9,19-
cyclolanostane-3β,25- diol 3-O-diglycolate。
The present invention also provides the preparation methods of the tetraterpene derivatives described in above-mentioned technical proposal, comprising the following steps:
By triterpene saponin componds beesioside I, hydrolase molsin and disodium hydrogen phosphate-citrate buffer solution
Mixing is reacted, and the aglycon of Beesioside I is obtained；
By the aglycon of the Beesioside I, respectively with 2,2- dimethyl succinic anhydride, 2,2- dimethylated pentanedioic acid acid anhydride
It is mixed with diglycolic anhydride and carries out microwave reaction, obtain the tetraterpene derivatives with structure shown in Formulas I.
The present invention is by triterpene saponin componds beesioside I, hydrolase molsin and disodium hydrogen phosphate-citric acid
Buffer mixing is reacted, and the aglycon of Beesioside I is obtained.
In the present invention, the triterpene saponin componds beesioside I has structure shown in Formula II:
The present invention does not have special restriction to the source of the triterpene saponin componds beesioside I, using ability
Preparation method known to field technique personnel is made.In an embodiment of the present invention, the triterpene saponin componds
Beesioside I is preferably obtained by following steps:
Take Rhizoma soulieae vaginatae Souliea vaginata (Maxim.) Franch.10Kg, after drying and crushing, using different times of amounts,
Different proportion ethanol/water, methanol/water or acetone/water reflux or cold soaking extract, and solvent is recovered under reduced pressure and obtains extract 220g, mentions
It takes object to be dissolved in water, successively passes through petroleum ether, chloroform, ethyl acetate and extracting n-butyl alcohol, Ethyl acetate fraction
35g through silica gel (100~200 mesh) column chromatograph, petrol ether/ethyl acetate (100:0~1:1), methylene chloride/methanol (50:1~
It 1:1) elutes, obtains the different fraction of polarity, moderately polar fraction 8g is taken, through silica gel column chromatography (200~300 mesh) petroleum
Ether/ethyl acetate (10:1~1:1), methylene chloride/methanol (20:1~5:1) elution, and inverted column chromatography methanol/water (50:
50~100:0) elution, and active precursor compounds crude product is eluted to obtain through gel LH-20 methanol, most obtained afterwards through recrystallizing methanol
Triterpene saponin componds beesioside I.
In the present invention, the mass ratio of the triterpene saponin componds beesioside I and hydrolase molsin is preferred
For 1:1~1:10.
In the present invention, the pH value of the disodium hydrogen phosphate-citrate buffer solution is preferably 4.0.
In the present invention, the mixing carries out preferably in dehydrated alcohol.In the present invention, the mixing is preferably first by three
Terpene saponins compound beesioside I is dissolved with dehydrated alcohol, and the hydrolase for being dissolved in pure water is added into the solution
Molsin (Aspergillus saitoi) and 0.2M disodium hydrogen phosphate -0.1M citrate buffer solution (pH 4.0).
In the present invention, the temperature of the reaction is preferably 37 DEG C, and the time of the reaction is preferably 2 days.
After reaction, the present invention preferably extracts the isometric ethyl acetate of gained reaction solution 3 times, ethyl acetate portion
Division simultaneously, after being dried over anhydrous sodium sulfate, being concentrated, through silicagel column (200~300 mesh) chromatograph, with n-hexane/acetone (10:1~
It 1:1) elutes, and through recrystallizing methanol, obtains the aglycon of Beesioside I.
In the present invention, the structure of the aglycon of the Beesioside I is as shown in formula III:
After obtaining the aglycon of Beesioside I, the present invention by the aglycon of the Beesioside I respectively with 2,2- bis-
Methyl succinic acid anhydrides, 2,2- dimethylated pentanedioic acid acid anhydride and diglycolic anhydride mixing carry out microwave reaction, obtain with structure shown in Formulas I
Tetraterpene derivatives.
When the aglycon and 2 of the Beesioside I, when 2- dimethyl succinic anhydride carries out microwave reaction, obtaining R is 1
Group the tetraterpene derivatives with structure shown in Formulas I；When the aglycon and 2,2- dimethyl-penten two of the Beesioside I
When acid anhydrides carries out microwave reaction, the tetraterpene derivatives with structure shown in Formulas I for the group that R is 2 are obtained；When described
When the aglycon of Beesioside I and diglycolic anhydride carry out microwave reaction, obtain the group that R is 3 with structure shown in Formulas I
Tetraterpene derivatives.
In the present invention, the microwave reaction preferably carries out in anhydrous pyridine and 4-dimethylaminopyridine (DMAP).
In the present invention, the aglycon and 2 of the Beesioside I, 2- dimethyl succinic anhydride, 2,2- dimethyl-penten two
The molar ratio of acid anhydrides and diglycolic anhydride is preferably all 1:1~1:10.
In the present invention, the temperature of the microwave reaction is preferably 150~160 DEG C, and the time of the microwave reaction is preferred
For 1~3h.
After the completion of microwave reaction.Reaction solution is preferably added 1N hydrochloric acid and neutralized by the present invention, and ethyl acetate extraction 3 is then added
Secondary, ethyl acetate portion is washed 3 times with brine, and anhydrous magnesium sulfate drying is added, chromatographs through silicagel column (200~300 mesh), just
Hexane/acetone gradient elution (10:1~1:1), obtains the tetraterpene derivatives with structure shown in Formulas I.
The present invention also provides the tetraterpene derivatives with structure shown in Formulas I described in above-mentioned technical proposal to prepare anti-Chinese mugwort
Grow the application in medicine.
In the present invention, the triterpene with structure shown in Formulas I that the anti-AIDS drug preferably comprises effective dose spreads out
Biology, its derivative, its stereoisomer, officinal salt and pharmaceutically acceptable carrier, auxiliary material, excipient and diluent.
In the present invention, the dosage form of the anti-AIDS drug preferably includes tablet, injection, capsule, granule, ball
Agent, powder, oral solution, sustained release preparation, controlled release preparation or the pharmaceutically acceptable dosage form of nanometer formulation.
In the present invention, when the R is 1 group, the tetraterpene derivatives with structure shown in Formulas I have significant
External anti-HIV-1 effect, in HIV-1NL4-3In the MT-4 cell of virus infection, inhibition of HIV is significantly inhibited, half
The effective inhibition concentration EC of number50It is 0.025 μM, and therapeutic index TI is greater than 800.
Below with reference to embodiment to tetraterpene derivatives provided by the invention with structure shown in Formulas I and preparation method thereof and
Using being described in detail, but they cannot be interpreted as limiting the scope of the present invention.
Fig. 1 is the schematic diagram of the preparation method for the tetraterpene derivatives that the present invention has structure shown in Formulas I.
Embodiment 1
The preparation of triterpene saponin componds beesioside I
Rhizoma soulieae vaginatae Souliea vaginata (Maxim.) Franch. medicinal material 10Kg is taken, after drying and crushing, using different times
Amount, different proportion ethanol/water, methanol/water or acetone/water reflux or cold soaking extract, and solvent is recovered under reduced pressure and obtains extract 220g,
Extract is dissolved in water, successively passes through petroleum ether, chloroform, ethyl acetate and extracting n-butyl alcohol, ethyl acetate extraction portion
Position 35g is chromatographed through silica gel (100~200 mesh, 200g) column, petrol ether/ethyl acetate (100:0~1:1), methylene chloride/methanol
(50:1~1:1) elution obtains the different fraction of polarity, moderately polar fraction 8g is taken, through silica gel column chromatography (200~300
Mesh, 150g) petrol ether/ethyl acetate (10:1~1:1), methylene chloride/methanol (20:1~5:1) elution, and inverted column layer
Methanol/water (50:50~100:0) elution is analysed, and elutes to obtain active precursor compounds crude product through gel LH-20 methanol, is most passed through afterwards
Recrystallizing methanol obtains monomeric compound 1.1g, through NMR spectrum and mass spectrum, and with bibliography (N.Sakurai,
M.Nagai,T.Goto,T.Inoue, P.G.Xiao,Studies on the constituents ofBeesia
calthaefolia and Souliea vaginata. IV.1)Beesioside I,a cyclolanostanol
xyloside from the rhizomes of Beesia calthaefolia,Chem.Pharm.Bull.,1993,41,
It 272-275) compares, is determined as triterpene saponin componds beesioside I.
Beesioside I, white powder, ESI-MS:m/z 743 [M+Na]+；1H-NMR(pyridine-d5,
600MHz)δH:1.16(1H,m,H-1),1.58(1H,m,H-1),2.06(1H,m,H-2),2.75(1H, m,H-2),3.50
(2H, dd, J=4.2,12.0Hz, H-3), 1.28 (1H, m, H-5), 0.57 (1H, dd, H-6a), 1.36 (1H, m, H-6b),
1.05 (1H, H-7a), 1.26 (1H, H-7b), 1.60 (1H, dd, J=12.0,4.8Hz, H-8), 1.16 (1H, m, H-11),
2.00 (1H, m, H-11), 1.54 (1H, m, H-12a), 2.94 (1H, m, H-12b), 5.65 (1H, d, J=9.0Hz, H-15),
5.90 (1H, dd, J=10.2,8.4 Hz, H-16), 2.69 (1H, d, J=11.4Hz, H-17), 4.45 (1H, d, J=
13.2Hz, H-18), 4.56 (1H, d, J=13.2Hz, H-18), 0.15 (1H, d, J=4.2Hz, H-19), 0.48 (1H, d, J
=3.6 Hz, H-19), 1.31 (3H, s, H-21), 3.65 (1H, d, J=10.5Hz, H-22), 2.40 (1H, m, H-23a),
1.90(1H,m,H-23b),1.53(3H,s,H-26),1.64(3H,s,H-27),1.25(3H,s, H-28),1.17(3H,s,
), H-29 1.00 (3H, s, H-30), 4.86 (1H, d, J=7.8Hz, H-1 '), 4.02 (1H, m, H-2 '), 4.15 (1H, t, J=
1H, t, J=10.8Hz, H-5 ' a), 4.34 8.4Hz, H-3 '), 4.22 (1H, m, H-4 '), 3.70 ((1H, dd, J=11.4,
5.4Hz,H-5′b),2.12(3H,COCH3),2.09 (3H,COCH3)；13C-NMR(pyridine-d5,150MHz)δC:32.7
(C-1),31.2(C-2),88.6 (C-3),41.7(C-4),47.5(C-5),20.8(C-6),26.4(C-7),47.6(C-8),
19.5(C-9),28.0 (C-10),26.6(C-11),28.4(C-12),46.2(C-13),51.9(C-14),82.4(C-15),
75.5 (C-16),56.6(C-17),66.8(C-18),31.8(C-19),87.2(C-20),32.8(C-21),38.6 (C-
22),30.4(C-23),114.6(C-24),73.1(C-25),26.0(C-26),26.1(C-27,28),15.8 (C-29),
15.7(C-30),108.0(C-1′),76.0(C-2′),79.0(C-3′),71.6(C-4′),67.5(C-5′), 21.6
(COCH3),171.3(COCH3),21.6(COCH3),171.0(COCH3).
Embodiment 2
1) aglycon of beesioside I is prepared
Beesioside I (1.1g, 1.53mmol) is dissolved with 100mL dehydrated alcohol, is added and is dissolved in into the solution
Hydrolase molsin (Aspergillus saitoi) 2.2g and 0.2M disodium hydrogen phosphate -0.1M citric acid of 100mL pure water is slow
Fliud flushing (pH 4.0) 1000mL, this solution system are stirred to react 2 days at 37 DEG C.Reaction solution is extracted with isometric ethyl acetate
3 times, ethyl acetate portion merge, after being dried over anhydrous sodium sulfate, be concentrated, through silicagel column (200~300 mesh) chromatography, use just oneself
Alkane/acetone (10:1~1:1) elution, and through recrystallizing methanol, monomeric compound is obtained, through NMR spectrum and mass spectrum, and
With bibliography (N.Sakurai, M.Nagai, T.Goto, T.Inoue, P.G.Xiao, Studies on the
constituents ofBeesia calthaefolia and Souliea vaginata.IV.1)Beesioside I,a
cyclolanostanol xyloside from the rhizomes ofBeesia calthaefolia,Chem.Pharm.
Bull., it 1993,41,272-275) compares, is determined as the aglycon of Beesioside I, clear crystal；ESIMS m/z 589[M+
H]+；1H NMR(400MHz,pyridine-d5)δH0.23 (1H, d, J=4.0Hz, H-19), 0.56 (1H, d, J=4.0Hz,
), H-19 0.66 (1H, q, J=12.0Hz, H-6a), 1.06 (3H, s, H3-30),1.23(6H,s,H3-28,29),1.27(3H,
m,H-1,7a,11a),1.30(3H,s,H3-21), 1.36(1H,m,H-5),1.47(1H,m,H-6b),1.56(3H,m,H-8,
11b,12a),1.57(3H,s, H3-27),1.58(1H,m,H-1b),1.68(3H,s,H3-26),1.85(1H,m,H-2a),
1.97(1H, m,H-22a),2.01(1H,m,H-2b),2.05(1H,m,H-7b),2.08(1H,m,H-23a),2.13 (3H,
s,COCH3),2.14(3H,s,COCH3), 2.73 (1H, d, J=11.2Hz, H-17), 2.79 (1H, m, H-23b), 2.96 (1H,
M, H-12b), 2.99 (1H, m, H-22b), 3.54 (1H, dd, J=11.2,4.0 Hz, H-3), 4.52 (1H, d, J=13.2Hz,
), H-18a 4.64 (1H, d, J=13.2Hz, H-18b), 5.71 (1H, d, J=8.8Hz, H-15), 5.94 (1H, dd, J=
11.2,8.8Hz,H-16)；13C NMR (pyridine-d5,100MHz)δC 15.2(C-30),15.9(C-29),19.5(C-
9),21.1(C-6),21.6 (COCH3),21.7(COCH3),26.0(C-27),26.2(C-26),26.5(C-11),26.6(C-
28), 26.7(C-7),28.3(C-10),28.4(C-12),31.3(C-23),31.6(C-2),32.0(C-19),32.9 (C-
1,21),38.6(C-22),41.5(C-4),46.2(C-13),47.4(C-5),47.6(C-8),51.9 (C-14),56.6(C-
17),66.8(C-18),73.1(C-25),75.6(C-16),78.2(C-3),82.4 (C-15),87.2(C-20),114.7
(C-24),171.0(COCH3),171.3(COCH3).
2) prepare compound 1~3
In 10mL anhydrous pyridine, the beesioside I aglycon (0.06 mmol) that above-mentioned steps obtain, equivalent is added
4-dimethylaminopyridine (DMAP), be separately added into 2, the 2- dimethyl succinic anhydride, 2,2- diformazan of 10 times of equivalents
Base glutaric anhydride and diglycolic anhydride, 155 DEG C of microwave reaction 2h, after reaction stops, reaction solution is added 1mL 1N hydrochloric acid and neutralizes, then
10mL ethyl acetate is added to extract 3 times, ethyl acetate extract is washed 3 times with brine, anhydrous magnesium sulfate drying is added, through silica gel
Column (200~300 mesh) chromatography, n-hexane/acetone gradient elution (10:1~1:1) obtain (20S, 24S) -15 β, 16 β -
diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3β,25-di ol 3-O-3′,3′-
Dimethylsuccinate (1, yield 37.2%), (20S, 24S) -15 β, 16 β-diacetoxy-18,24；20,24-
Diepoxy-9,19-cyclolanostane-3 β, 25-diol 3-O-4 ', 4 '-dimethylglutarate (2, yield
And (20S, 24S) -15 β, 16 β-diacetoxy-18,24 35.7%)；20,24 -diepoxy-9,19-
Cyclolanostane-3 β, 25-diol 3-O-diglycolate (3, yield 42.6%).
3) structure determination of compound
Compound 1, clear crystal, 221-223 DEG C of fusing point (MeOH)；[α]20D–12.0(c 0.10, MeOH)；ESIMS:
m/z 717[M+H]+,739[M+Na]+；1H NMR(400MHz, pyridine-d5)δH0.17 (1H, d, J=4.0Hz, H-
19), 0.48 (1H, d, J=4.0Hz, H-19), 0.55 (1H, q, J=12.0Hz, H-6a), 0.97 (6H, s, H3-28,29),
1.11(1H,m,H-7a),1.12 (1H,m,H-1a),1.16(1H,m,H-11a),1.18(3H,s,H3-30),1.23(1H,m,
H-5),1.28 (3H,s,H3-21),1.31(2H,m,H-6b,7b),1.47(1H,m,H-1b),1.54(1H,m,H-12a),
1.55(3H,s,H3-27),1.56(6H,s,H3-3'),1.59(1H,m,H-8),1.66(3H,s,H3-26), 1.69(1H,m,
H-2a),1.96(1H,m,H-11b),1.97(2H,m,H-2b,22a),2.08(1H,m, H-23a),2.12(3H,s,
COCH3),2.14(3H,s,COCH3), 2.73 (1H, d, J=11.2Hz, H-17), 2.79 (1H, m, H-23b), 2.89 (1H, d,
J=15.6Hz, H-2'a), 2.96 (1H, m, H-12b), 2.98 (1H, d, J=15.6Hz, H-2'b), 2.99 (1H, m, H-
22b), 4.49 (1H, d, J=13.2Hz, H-18a), 4.58 (1H, d, J=13.2Hz, H-18b), 4.86 (1H, dd, J=
12.0,4.0Hz, H-3), 5.67 (1H, d, J=8.8Hz, H-15), 5.94 (1H, dd, J=11.2,8.8Hz, H-16)；13C
NMR(pyridine-d5,100MHz)δC 15.8(C-29,30),19.6(C-9),20.6(C-6),21.6 (2×COCH3),
26.0(3'-2×CH3),26.2(C-26,27),26.3(C-11),26.6(C-7,28),27.5 (C-2),27.8(C-10),
28.3(C-12),31.2(C-23),31.7(C-19),32.2(C-1),32.8(C-21), 38.6(C-22),40.0(C-4),
41.2(C-3'),45.6(C-2'),46.1(C-13),47.2(C-5),47.4 (C-8),51.8(C-14),56.5(C-17),
66.7(C-18),73.1(C-25),75.5(C-16),80.8(C-3), 82.4(C-15),87.2(C-20),114.7(C-
24),171.0(COCH3),171.3(COCH3),171.9 (C-1'),179.7(C-4').
Compound 2, clear crystal, m.p.228-230 DEG C (MeOH)；[α]20D–13.6(c 0.15, MeOH)；ESIMS:
m/z 731[M+H]+,753[M+Na]+；1H NMR(400MHz, pyridine-d5)δH: 0.18 (1H, d, J=3.2Hz, H-
19), 0.49 (1H, d, J=3.2Hz, H-19), 0.60 (1H, q, J=12.0Hz, H-6a), 0.91 (6H, s, H3-28,29),
1.11(1H,m,H-7a),1.12 (1H,m,H-1a),1.16(1H,m,H-11a),1.18(3H,s,H3-30),1.23(1H,m,
H-5),1.29 (3H,s,H3-21),1.30(2H,m,H-7b),1.38(6H,s,H3-3'),1.43(1H,m,H-1b),1.47
(1H,m,H-6b),1.54(3H,s,H3-27),1.55(1H,m,H-12a),1.59(1H,m,H-8),1.65 (3H,s,H3-
26),1.69(1H,m,H-2a),1.96(1H,m,H-11b),1.97(2H,m,H-2b,22a), 2.08(1H,m,H-23a),
2.13(3H,s,COCH3),2.14(3H,s,COCH3),2.27(2H,m, H-3'),2.72(2H,m,H-2'),2.73(1H,d,J
=11.2Hz, H-17), 2.74 (2H, s, H-4'), 2.79 (1H, m, H-23b), 2.96 (1H, m, H-12b), 2.99 (1H, m,
), H-22b 4.50 (1H, d, J=13.2Hz, H-18a), 4.59 (1H, d, J=13.2Hz, H-18b), 4.83 (1H, dd, J=
11.2,4.0Hz, H-3), 5.67 (1H, d, J=8.8Hz, H-15), 5.94 (1H, dd, J=11.2,8.8Hz, H-16)；13C
NMR(pyridine-d5,100MHz)δC 15.9(C-29,30),19.7(C-9),20.8(C-6),21.8 (2×COCH3),
26.0(4'-2×CH3),26.1(C-26,27),26.3(C-11),26.4(C-28),27.6 (C-2),27.9(C-10),
28.4(C-12),31.4(C-23),31.8(C-19,2'),32.3(C-1),33.0 (C-21),36.6(C-3'),38.7(C-
22),40.2(C-4),42.4(C-4'),46.2(C-13),47.3(C-5), 47.5(C-8),52.0(C-14),56.7(C-
17),66.9(C-18),73.3(C-25),75.6(C-16),80.8 (C-3),82.5(C-15),87.3(C-20),114.8
(C-24),171.2(COCH3),171.6(COCH3), 174.0(C-1'),180.4(C-5').
Compound 3, clear crystal, m.p.197-199 DEG C (MeOH)；[α]20D–1.9(c 0.16, MeOH)；ESIMS:
m/z 727[M+Na]+；1H NMR(400MHz,pyridine-d5)δH0.19 (1H, d, J=4.0Hz, H-19), 0.52 (1H,
D, J=4.0Hz, H-19), 0.55 (1H, q, J=12.0 Hz, H-6a), 0.90 (3H, s, H3-29),0.92(3H,s,H3-28),
1.11(1H,m,H-7a),1.12(1H, m,H-1a),1.16(1H,m,H-11a),1.21(3H,s,H3-30),1.23(1H,m,
H-5),1.29(3H, s,H3-21),1.31(2H,m,H-6b,7b),1.47(1H,m,H-1b),1.54(1H,m,H-12a),
1.56 (3H,s,H3-27),1.59(1H,m,H-8),1.68(3H,s,H3-26),1.69(1H,m,H-2a),1.96 (1H,m,
H-11b),1.97(2H,m,H-2b,22a),2.08(1H,m,H-23a),2.13(3H,s, COCH3),2.15(3H,s,
COCH3), 2.73 (1H, d, J=11.6Hz, H-17), 2.79 (1H, m, H-23b), 2.96 (1H, m, H-12b), 2.99 (1H,
M, H-22b), 4.49 (1H, d, J=13.2Hz, H-18a), 4.58 (1H, d, J=13.2Hz, H-18b), 4.70 (2H, s, H-
3'), 4.71 (2H, s, H-2'), 4.90 (1H, dd, J=12.0,4.0Hz, H-3), 5.69 (1H, d, J=8.8Hz, H-15),
5.94 (1H, dd, J=11.6,8.8Hz, H-16)；13C NMR(pyridine-d5,100MHz)δC 15.8(C-29,30),
19.7(C-9),20.6(C-6),21.6(2×COCH3),26.0(C-26,27),26.2(C-11,28),26.6 (C-7),
27.5(C-2),27.9(C-10),28.3(C-12),31.2(C-23),31.6(C-19),32.1(C-1), 32.8(C-21),
38.6(C-22),40.1(C-4),46.1(C-13),47.1(C-5),47.3(C-8),51.7 (C-14),56.6(C-17),
66.8(C-18),68.9(C-2'),69.0(C-3'),73.0(C-25),75.5 (C-16),81.3(C-3),82.3(C-15),
87.2(C-20),114.7(C-24),170.7(C-1'),171.0 (COCH3),171.3(COCH3),173.2(C-4').
Embodiment 3
Compound of formula I is in HIV-1NL4-3Inhibit HIV activity test in the MT-4 cell of infection
Active drug to be tested:
(20S,24S)-15β,16β-diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3
β, 25-diol 3-O-3′,3′-dimethylsuccinate(1)
(20S,24S)-15β,16β-diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3
β, 25-diol 3-O-4′,4′-dimethylglutarate(2)
(20S,24S)-15β,16β-diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3
β, 25-diol 3-O-diglycolate(3)
Test method:
Sample carries out Z.Dang, L.Zhu, W. Lai to the in-vitro evaluation test reference literature of HIV-1 inhibiting effect,
H.Bogerd,K.H.Lee,L.Huang,C.H.Chen,Aloperine and its derivatives as a new
class ofHIV-1entry inhibitors.ACS Med.Chem.Lett.7(2016)240-244. HIV-1NL4-
The untested compound of various concentration, HIV-1 is added in 9 orifice plates in the MT4 cell culture of 3Nanoluc-sec virus infectionNL4- 3Nanoluc-sec virus is a kind of reporter virus, has secNluc as reporter gene, after compound is dissolved with DMSO, adopts
Virus is detected by detecting the activity of fluorescein kinases with Promega Nano-Glo LuciferaseAssay System
Duplication.Measurement result is shown in Table 1.As can be seen from Table 1, (20S, 24S) -15 β, 16 β-diacetoxy-18,24；20,24-
Diepoxy-9,19-cyclolanostane-3 β, 25-diol 3-O-3 ', 3 '-dimethylsuccinate (1) are considered as
Most effective AntiHIV1 RT activity substance, half effectively inhibit HIV concentration EC50Value is 0.025 μM, and therapeutic index TI value is greater than 800,
With the first HIV maturation phase inhibitor 3-O- (3 ', 3 '-dimethylsuccinyl)-into II clinical trial phase
Betulinic acid (DSB) is very nearly the same, it is possible to develop into natural anti-HIV-1 medicines.
1 sample of table and positive drug inhibit HIV-1 activity test result on MT-4 cella
aThe inhibition to HIV-1 virus is tested using the method for multicycle virus replication
b EC50: half effectively inhibits HIV concentration (mean+/- SD of3tests)
c CC50: half effectively inhibits cell concentration
d*-: without selectivity (CC50/EC50<5).
e TI:CC50/EC50.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. the tetraterpene derivatives with structure shown in Formulas I,
2. the preparation method of tetraterpene derivatives described in claim 1, which comprises the following steps:
Triterpene saponin componds beesioside I, hydrolase molsin and disodium hydrogen phosphate-citrate buffer solution are mixed
It is reacted, obtains the aglycon of Beesioside I；
The aglycon of the Beesioside I is sweet with 2,2- dimethyl succinic anhydride, 2,2- dimethylated pentanedioic acid acid anhydride and two respectively
The mixing of alcohol acid anhydride carries out microwave reaction, obtains the tetraterpene derivatives with structure shown in Formulas I.
3. preparation method according to claim 2, which is characterized in that the triterpene saponin componds beesioside I
Mass ratio with hydrolase molsin is 1:1~1:10.
4. preparation method according to claim 2 or 3, which is characterized in that the disodium hydrogen phosphate-citrate buffer solution
PH value is 4.0.
5. preparation method according to claim 1, which is characterized in that the temperature of the microwave reaction is 150~160 DEG C,
The time of the microwave reaction is 1~3h.
6. the preparation of any one of the tetraterpene derivatives or claim 2~5 described in claim 1 with structure shown in Formulas I
The method tetraterpene derivatives obtained with structure shown in Formulas I are preparing the application in anti-AIDS drug.
7. application according to claim 6, which is characterized in that the anti-AIDS drug includes effective dose with formula
It is the tetraterpene derivatives of structure shown in I, its derivative, its stereoisomer, officinal salt and pharmaceutically acceptable carrier, auxiliary
Material, excipient and diluent.
8. application according to claim 6 or 7, which is characterized in that the dosage form of the anti-AIDS drug includes tablet, note
It is pharmaceutically acceptable to penetrate agent, capsule, granule, pill, powder, oral solution, sustained release preparation, controlled release preparation or nanometer formulation
Dosage form.
9. application according to claim 6 or 7, which is characterized in that described to have shown in Formulas I when the R is 1 group
The tetraterpene derivatives of structure have significant external anti-HIV-1 effect, in HIV-1NL4-3It is right in the MT-4 cell of virus infection
Inhibition of HIV significantly inhibits, half effective inhibition concentration EC50It is 0.025 μM, and therapeutic index TI is greater than 800.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1958597A (en) * | 2006-06-07 | 2007-05-09 | 肖培根 | Triterpene saponin compound of cycro jackfruit alkyl, and effect for anti tumor |
| CN104540844A (en) * | 2012-05-07 | 2015-04-22 | 百时美施贵宝公司 | C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity |
| CN106046106A (en) * | 2012-02-15 | 2016-10-26 | 百时美施贵宝公司 | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
| CN106604909A (en) * | 2014-04-11 | 2017-04-26 | Viiv保健英国第四有限公司 | Triterpenoids with HIV maturation inhibitory activity, substituted in position 3 by a non-aromatic ring carrying a haloalkyl substituent |
| CN107428797A (en) * | 2015-02-09 | 2017-12-01 | 海特洛实验室有限公司 | The new triterpene ketenes of C 3 with 28 reverse amide derivatives of C as hiv inhibitor |
-
2018
- 2018-12-29 CN CN201811640954.3A patent/CN109705189B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1958597A (en) * | 2006-06-07 | 2007-05-09 | 肖培根 | Triterpene saponin compound of cycro jackfruit alkyl, and effect for anti tumor |
| CN106046106A (en) * | 2012-02-15 | 2016-10-26 | 百时美施贵宝公司 | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
| CN104540844A (en) * | 2012-05-07 | 2015-04-22 | 百时美施贵宝公司 | C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity |
| CN106604909A (en) * | 2014-04-11 | 2017-04-26 | Viiv保健英国第四有限公司 | Triterpenoids with HIV maturation inhibitory activity, substituted in position 3 by a non-aromatic ring carrying a haloalkyl substituent |
| CN107428797A (en) * | 2015-02-09 | 2017-12-01 | 海特洛实验室有限公司 | The new triterpene ketenes of C 3 with 28 reverse amide derivatives of C as hiv inhibitor |
Non-Patent Citations (4)
| Title |
|---|
| CHAO-MEI MA等: "Inhibitory Effects on HIV-1 Protease of Constituents from the Wood of Xanthoceras sorbifolia", 《J. NAT. PROD.》 * |
| NOBUKO SAKURAI等: "Studies on the Constituents of Beesia calthaefolia and Souliea vaginata. IV. Beesioside I, a Cyclolanostanoyl Xyloside from the Rhizomes of Beesia calthaefolia", 《CHEM.PHARM.BULL.》 * |
| 彭宗根等: "几种抑制HIV-1 复制酶的植物成分", 《药学学报》 * |
| 陈进汝等: "天然产物中抗ＨＩＶ萜类化合物研究进展", 《亚太传统医药》 * |
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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