CN1153779C - Acylated derivative of dioscin and its producing process and use - Google Patents
Acylated derivative of dioscin and its producing process and use Download PDFInfo
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- CN1153779C CN1153779C CNB011128704A CN01112870A CN1153779C CN 1153779 C CN1153779 C CN 1153779C CN B011128704 A CNB011128704 A CN B011128704A CN 01112870 A CN01112870 A CN 01112870A CN 1153779 C CN1153779 C CN 1153779C
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Abstract
The present invention relates to a mono-acylated and bis-acylated dioscin derivative prepared by using lipase to catalyze a dioscin derivative and ester in an organic solvent. The structure of the mono-acylated and bis-acylated dioscin derivative is identified by mass spectra nuclear magnetic resonance spectra, element analysis, etc. The derivative has physiological activity, and can be used for anti-tumor medicine.
Description
The present invention relates to the dioscin derivative.A kind of specifically monoacylation and two acylations dioscin derivatives, this derivative is to utilize this compounds of lipase-catalyzed preparation in organic solvent, and with mass spectrum, NMR (Nuclear Magnetic Resonance) spectrum and ultimate analysis etc. its structure is identified.This derivative has physiologically active, can be used for anti-tumor drug.
Saponin is a kind of glycoconjugate with multiple physiologically active, is present in widely in the root, stem, leaf of plant.All contain a large amount of saponins in herbal medicine that China is traditional such as genseng, polygala root, the Radix Astragali etc.According to the difference of glucoside unit in its molecule, saponin is divided into triterpenoid saponin and steroid saponin two big classes usually.At occurring in nature, the free hydroxyl on many triterpenoid saponin sugar chains is modified by acyl group functional group, as: ethanoyl, butyryl radicals, benzoyl etc.But seldom have the report steroid saponin in free hydroxyl by the situation of acyl group modified with functional group.Modify its bioactive variation of back in order to further investigate natural steroid saponin through acyl group, for drug screening provides the compound with physiologically active, we study the synthetic of this compounds.Because partly there is the approaching hydroxy functional group of a plurality of reactive behavioies in sugar chain in the saponin molecule; and the formation of sugar chain is complicated and changeable; replace or disubstituted saponin acyl derivative deficiencies such as to have a synthesis step many, and synthesis cycle is long with the preparation of traditional chemical synthesis process is single.Enzymic catalytic reaction has the stereoselectivity height, and advantages such as the strong and reaction conditions gentleness of regioselectivity split and the fields such as preparation of natural product have obtained many application at asymmetric synthesis, optically active compound.In recent years, people such as Riva have reported and utilized lipase-catalyzed a kind of triterpenoid saponin that synthesized in tertiary amyl alcohols---acyl derivative (Danieli, the B. of ginsenoside; Luisetti, M; Riva, S.; Bertinotti, A.; Ragg, E.; Scaglioni, L.; Bombardel1i, E.J.Org.Chem, 1995,60,3637-3642.).But up to the present also do not use lipase synthesizing steroid saponin---the report of dioscin acyl derivative.Therefore, providing monoacylation and the various acyl derivatives that two acylations dioscin derivatives and use enzyme process prepare dioscin easily is highly significant.
The objective of the invention is the chemosynthesis of a series of dioscins have been carried out on the systematic research basis the contriver; the a series of different monoacylations and two acylations dioscin derivative, the i.e. disaccharides of monoacylation or two acylations and trisaccharide dioscin derivatives of acquisition are provided.
Another object of the present invention provides a kind of enzymatic synthesis method for preparing acylations dioscin derivative.
Purpose of the present invention also provides a kind of purposes of above-mentioned acylations dioscin derivative, is drug screening the compound with physiologically active is provided.
A kind of monoacylation provided by the invention is as follows with two acylations dioscin derivant structure formulas:
In the structural formula, R=C
1-8Acyl group or enoyl-.As ethanoyl (Ac), butyryl radicals [CH
3(CH
2)
2C (O)], caproyl [CH
3(CH
2)
4C (O)] or vinyl adipyl [CH
2=CHOC (O) (CH
2)
4C (O)] etc.; R, p, q=0,1 or 2, and, 0＜r+p+q≤2; The M=glucosyl group
N, the U=rhamanopyranosyl
Or Arabic glycosyl
N or u=0 or 1.
Above-mentioned monoacylation of the present invention and two acylations dioscin derivatives can be the compounds in the following structural formula:
In the said structure formula: R
1, R
2Or R
3=H or R, R=C
1-8Acyl group or enoyl-, R wherein
1, R
2Or R
3Can not equal H simultaneously.
The lipase-catalyzed method of synthetic method system's employing of the present invention; with different dioscins is that raw material is through a step enzymic catalytic reaction; synthetic monoacylation of the present invention or the disaccharides of two acylations or the dioscin derivative of trisaccharide; and use mass spectrum; one-dimensional nuclear magnetic resonance and two dimensional NMR wave spectrum, ultimate analysis etc. are identified its structure.These NMR (Nuclear Magnetic Resonance) spectrum comprise
1H-NMR (proton nmr spectra),
13C-NMR (carbon-13 nmr spectra),
1H-
1HCOSY (with the relevant spectrum of nuclear chemistry displacement), TOCSY (total correlation spectrum), HSQC (the relevant spectrum of the single quantum of heteronuclear) etc.The structure of this compounds can be as mentioned above.
It is raw material that the inventive method adopts dioscin, and its structural formula is as follows:
In the structural formula, the M=glucosyl group
N, the U=rhamanopyranosyl
Or Arabic glycosyl
N, u=0 or 1.
Can Chinese yam glucoside unit-β-D-glycoside (1) in the method for the present invention; Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-β-D-glycoside (2); Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 4)-β-D-glycoside (3); Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[α-L-rhamanopyranosyl-(1 → 4)]-β-D-glycoside (4); Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[α-L-arabinose base-(1 → 4)]-β-D-glycoside (5) or Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 6)-β-D-glycoside dioscins such as (6) are raw material; in organic solvent and lipase be catalyzer; with the transesterification reaction of different esters, obtained the disaccharides and the trisaccharide dioscin derivative of various monoacylations or two acylations.
Method of the present invention also can further describe as follows:
Acyl group gives body ROR ' and above-mentioned acyl acceptor dioscin in polar organic solvent; and under the catalysis of lipase transesterification reaction takes place; in enzymatic reaction, described acyl acceptor, acyl group are followed successively by 1-7 for the mol ratio of body and lipase: 100-210: 0.02-0.4.Above-claimed cpd is in polar solvent, and temperature of reaction is a room temperature-100 ℃, reacts the dioscin derivative that obtained monoacylation or two acylations in 1 hour-120 hours.Described acyl group is given among the body ROR ', and R is C
1-8Acyl group or enoyl-.As: ethanoyl, butyryl radicals, caproyl, benzoyl, crotonoyl, vinyl adipyl etc.R ' is vinyl or trifluoroethyl.Described polar solvent is tetrahydrofuran (THF) (THF), trichloromethane, N, dinethylformamide (DMF), dioxane or water etc.Catalyst system therefor lipase is any one in the following various lipase: lipase CRL (lipase from Candida rugosa), lipase PPL (lipase from Porcine Pancreas), lipase MJL (lipase from Mucor javanicus), lipase WGL (lipase from Wheat Germ), lipase PFL (Amano lipase from Pseudomonasfluorescens), lipase Novozyme 435 (Lipase B from Candida antarctica immobilized onacrylic resin) etc.The dioscin derivative of reaction product monoacylation or two acylations can be through silica gel column chromatography separating purification.
With lipase-catalyzed preparation 6-O-ethanoyl trillin 1a and 4,6-O-diacetyl trillin 1b is an example, and method of the present invention can be represented with following reaction formula:
The dioscin derivative and the saponin library of monoacylation of the present invention or two acylations have physiologically actives such as antitumor.Can be used for anti-tumor drug.
The present invention provides first and has prepared a series of the have monoacylation of physiologically active or the dioscin derivatives of two acylations.Utilize the enzymatic reaction to prepare acylations dioscin derivative, the regioselectivity height, method is easy, has improved the efficient of synthetic this compounds greatly, for find and screen new saponin provide a kind of efficiently, method easily.Compare with chemical method is synthetic, enzyme process prepares acylations dioscin derivative and has industrial prospect.
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited:
Embodiment 1 experiment reagent and analytical instrument
Various lipase are available from Sigma or Aldrich.Various vinyl acetate and trifluoro ethyl ester change into or make by oneself available from Tokyo.Reaction solvent THF, DMF, dioxane are analytical reagent.Column chromatography silica gel H (10-40 μ) is homemade silica gel.The specific rotation light value records through Pekin-Elmer 241MC polarimeter, and probe temperature is generally 17 ℃ without indicating especially.Various peacekeeping two dimensional NMR (NMR) wave spectrum Bruker AM300, Bruker DPX300 or Bruker DPX400 nuclear magnetic resonance spectrometer record, and test is a deuterated pyridine with solvent.The used mass spectrograph model of electrospray ionization mass spectrum (ESI-MS) is PE Mariner API-TOF.The elemental analyser model is Elementar Vario EL.
The general step of embodiment 2 lipase-catalyzed reactions
Get dioscin 30mg in 1-5mlTHF, add vinyl acetate or trifluoro ethyl ester 0.1-2ml and lipase 10-200mg.After 40 ℃ of oscillatory reaction 1-3 days, remove solvent under reduced pressure, resistates is used the silica gel H column chromatography purification with thick silica gel mixed sample upper prop.Use CH
2Cl
2→ CH
2Cl
2-CH
3OH (30: 1) → CH
2Cl
2-CH
3OH (20: 1) → CH
2Cl
2-CH
3OH (10: 1) gradient elution detects the elutriant of collecting with TLC, and the part concentrating under reduced pressure that will contain product gets white solid.
Embodiment 3 experimental results
The productive rate of table 1 reaction conditions and various acetylize dioscin derivatives
Saponin lipase reaction solvent reaction time product productive rate %
1 PPL，MJL or WGL THF 1-2 1a 10
1
a CRL THF 4 1a 17
1
b CRL DMF 2 1a 15
1
c PFL THF 4 1a 43
1 Novozyme 435 THF 1 1a，1b 75，17
1 Novozyme 435 THF 2 1a，1b 64，35
1 Novozyme, 435 dioxane, 3 1a, 1b 62,32
2 Novozyme 435 THF 2 2a，2b 53，31
3 Novozyme 435 THF 2 3a 91
4 Novozyme 435 THF 2 4a 86
5 Novozyme 435 THF 3 5a，5b 55，26
6 Novozyme 435 THF 2 6a 70e
A adds phosphate buffered saline buffer (pH 7.4) in reaction system, and the water content that makes THF is 0.8% (V/V).
B adds phosphate buffered saline buffer (pH 7.4) in reaction system, and the water content that makes DMF is 10.0% (V/V).
C adds phosphate buffered saline buffer (pH 8.0) in reaction system, and the water content that makes THF is 0.8% (V/V).
Embodiment 4 experimental results
Table 2 utilizes the reaction yield of the various acylations saponin of Novozyme 435 catalytic preparation in THF 4a-4d
Acyl group is given body acyl acceptor product productive rate %
AcOCH＝CH
2 4 4a 86
AcOCH
2CF
3 4 4a 76
CH
3(CH
2)
2C(O)OCH＝CH
2 4 4b 63
CH
3(CH
2)
2C(O)OCH
2CF
3 4 4b 60
CH
3(CH
2)
4C(O)OCH＝CH
2 4 4c 40
CH
3CH＝CHC(O)OCH＝CH
2 4 / 10
PhC(O)OCH＝CH
2 4 / 5
CH
2＝CHOC(O)(CH
2)
4C(O)OCH＝CH
2 4 4d 72
The physical constant and the spectral data of embodiment 5 various acylations dioscin derivatives
(the 1a of Diosgenyl 6-O-acetyl-β-D-glucopyranoside) of Chinese yam glucoside unit-6-O-ethanoyl-β-D-glycoside
R
f：0.52[CH
2Cl
2-CH
3OH(10∶1)]；[α]
D＝-94.6°(c 0.56，THF)；ESI-MS：641.6(M+Na)，657.6(M+K)；
1H-NMR(400MHz)5.26(d，1H，J＝4.8Hz)，4.94(d，1H，J＝7.6Hz)，4.87(d，1H，J＝10.0Hz)，4.75(dd，1H，J＝11.6，5.6Hz)，4.48(m，1H)，4.20(t，1H，J＝8.8Hz)，4.05(t，1H，J＝9.2Hz)，3.98(m，2H)，3.86(m，1H)，3.54-3.41(m，2H)，1.90(s，3H)，1.07(d，3H，J＝6.8Hz)，0.84(s，3H)，0.77(s，3H)，0.62(d，3H，J＝5.2Hz)；
13C-NMR(100MHz)：171.0(C＝O)，141.1，121.9，109.4，103.0，81.3，78.8，78.5，75.4，75.3，71.6，67.0，65.0，63.1，56.8，50.4，42.1，40.6，40.0，39.5，37.7，37.2，32.4(2×C)，32.0，31.8，30.8，30.4，29.4，21.3，21.0，19.6，17.5，16.6，15.2.Anal.Calcd.for C
35H
54O
9·H
2O：C，66.01；H，8.86.Found：C，66.41；H8.87.
Chinese yam glucoside unit-4, (Diosgenyl 4, the 1b of 6-O-di-acetyl-β-D-glucopyranoside) for 6-O-diacetyl-β-D-glycoside
R
f：0.72[CH
2Cl
2-CH
3OH(10∶1)]；[α]
D＝-64.1°(c，0.30，THF)；ESI-MS：661.6(M+1)，683.6(M+Na)，699.6(M+K)；
1H-NMR(400MHz)5.80(t，1H，J＝9.4Hz)，5.23(d，1H，J＝4.8Hz)，4.94(d，1H，J＝7.6Hz)，4.84(dd，1H，J＝11.8，1.8Hz)，4.72(dd，1H，J＝11.8，5.4Hz)，4.48(m，1H)，4.09(t，1H，J＝9.4Hz)，4.03-3.97(m，2H)，3.82(m，1H)，3.54-3.40(m，2H)，1.93(s，3H)，1.07(d，3H，J＝6.8Hz)，0.80(s，3H)，0.76(s，3H)，0.62(d，3H，J＝5.6Hz)；
13C-NMR(100MHz)：171.0(2×C＝O)，141.0，122.0，109.4，102.7，81.3，79.2，78.9，75.0，73.2，69.7，67.0，64.5，63.1，56.8，50.4，42.1，40.6，40.0，39.3，37.6，37.2，32.4(2×C)，32.0，31.8，30.8，30.3，29.4，21.4，21.3，20.9，19.5，17.5，16.5，15.2.Anal.Calcd.for C
37H
56O
10·H
2O；C，65.46；H，8.61.Found：C，65.82；H，8.32.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-6-O-ethanoyl-β-D-glycoside (2a of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-6-O-acetyl-β-D-glucopyranoside)
R
f：0.15[CH
2Cl
2-CH
3OH(8∶1)]；[α]
D＝-99.8°(c，0.29，THF)；ESI-MS：765.7(M+1)，787.7(M+Na)；
1H-NMR(400MHz)：6.37(s，1H)，5.25(d，1H，J＝4.8Hz)，4.96-4.91(m，2H)，4.81(d，1H，J＝10.8Hz)，4.75-4.68(m，2H)，4.57(dd，1H，J＝9.2，3.2Hz)，4.49(m，1H)，4.30(t，1H，J＝9.5Hz)，4.25-4.17(m，2H)，3.97-3.89(m，3H)，3.54-3.41(m，2H)，1.88(s，3H)，1.71(d，3H，J＝6.4Hz)，1.07(d，3H，6.8Hz)，0.98(s，3H)，0.76(s，3H)，0.63(d，3H，J＝5.2Hz)；
13C-NMR(100MHz)：171.0(C＝O)， 41.0，121.9，109.4，102.3，100.8，81.3，79.5，78.7，77.8，75.0，74.3，73.0，72.7，71.7，69.8，67.0，64.7，63.1，56.8，50.4，42.1，40.6，40.0，39.2，37.7，37.3，32.5，32.4，32.0，31.9，30.8，30.4，29.4，21.3，20.9，19.6，18.9，17.5，16.5，15.2.Anal.Calcd.for C
41H
64O
13·2H
2O：C，61.48；H，8.56；.Found：C，61.20；H，8.48.
(the 2b of Diosgenyl 4-O-acetyl-α-L-rhamnopyranosyl-(1 → 2)-6-O-acetyl-β-D-glucopyranoside) of Chinese yam glucoside unit-4-O-ethanoyl-α-L-rhamanopyranosyl-(1 → 2)-6-O-ethanoyl-β-D-glycoside
R
f：0.37[CH
2Cl
2-CH
3OH(8∶1)]；[α]
D＝-80.4°(c 0.28，THF)；ESI-MS：807.7(M+1)，829.7(M+Na)，845.7(M+K)；
1H-NMR(400MHz)6.36(s，1H)，5.83(t，1H，J＝9.8Hz)，5.33(d，1H，J＝4.8Hz)，5.01-4.94(m，2H)，4.81(d，1H，J＝10.4Hz)，4.72-4.68(m，2H)，4.61(dd，1H，J＝9.6，3.2Hz)，4.51(m，1H)，4.22-4.15(m，2H)，3.97-3.88(m，3H)，3.54-3.41(m，2H)，2.04(s，3H)，1.86(s，3H)，1.44(d，3H，J＝6.0Hz)，1.09(d，3H，6.8Hz)，1.04(s，3H)，0.81(s，3H)，0.63(d，3H，J＝5.2Hz)；
13C-NMR(100MHz)：171.0(C＝O)，170.9(C＝O)，140.9，122.2，109.5，101.7，100.2，81.3，79.4，78.2，76.9，76.3，75.1，72.6，71.6，70.4，67.0(2×C)，64.6，63.1，56.8，50.5，42.1，40.7，40.0，39.2，37.6，37.3，32.5，32.4，32.0，31.9，30.8，30.3，29.4，21.4，21.3，20.9，19.6，18.2，17.5，16.6，15.2.Anal.Calcd.for C
43H
66O
14：C，64.00；H，8.24.Found：C，64.06；H，8.54.
Chinese yam glucoside unit-4-O-ethanoyl-α-L-rhamanopyranosyl-(1 → 4)-β-D-glycoside (3a of Diosgenyl 4-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranoside)
R
f：0.27[CH
2Cl
2-CH
3OH(10∶1)]；[α]
D＝-95.8°(c，0.16，THF)；ESI-MS：765.7(M+1)，787.7(M+Na)，803.6(M+K)；
1H-NMR(400MHz)：5.90(s，1H)，5.80(t，1H，J＝9.6Hz)，5.25(d，1H，J＝5.2Hz)，5.07(m，1H)，4.92(d，1H，J＝7.6Hz)，4.63(brs，1H)，4.56(dd，1H，J＝9.6，3.2Hz)，4.50-4.44(m，2H)，4.23-4.18(m，2H)，4.06(brd，1H)，3.92(t，1H，J＝8.4Hz)，3.82(m，1H)，3.66(brd，1H)，3.53-3.40(m，2H)，1.96(s，3H)，1.40(d，3H，J＝6.0Hz)，1.07(d，3H，J＝6.8Hz)，0.84(s，3H)，0.76(s，3H)，0.62(d，3H，J＝5.2Hz)；
13C-NMR(100MHz)：170.9(C＝O)，141.0，122.0，109.4，102.7，102.3，81.3，78.4，77.6，77.4，76.8，76.2，75.9，72.7，70.5，67.6，67.0，63.0，61.5，56.8，50.4，42.1，40.6，40.0，39.5，37.6，37.2，32.4(2×C)，32.0，31.8，30.8，30.4，29.4，21.3(2×C)，19.6，18.1，17.5.16.5，15.2.Anal.Calcd.for C
41H
64O
13：C，64.38；H，8.43.Found：C，64.60；H，8.83.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[4-O-ethanoyl-α-L-rhamanopyranosyl-(1 → 4)]-β-D-glycoside (4a of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-[4-O-acetyl-α-L-rhamnopyranosyl-(1 → 4)]-β-D-glucopyranoside)
R
f：0.48[CH
2Cl
2-CH
3OH(6∶1)]；[α]
D＝-100.8°(c，0.39，THF)；ESI-MS：911.9(M+1)，933.8(M+Na)，949.8(M+K)；
1H-NMR(400MHz)：6.40(s，1H)，5.87(s，1H)，5.79(t，1H，J＝9.8Hz)，5.24(d，1H，J＝4.4Hz)，4.98-4.90(m，3H)，4.80(brs，1H)，4.62-4.47(m，4H)，4.40(t，1H，J＝9.0Hz)，4.33(t，1H，J＝9.4Hz)，4.21-4.17(m，3H)，4.02(brd，1H)，3.82(m，1H)，3.58(brd，1H)，3.53-3.43(m，2H)，1.96(s，3H)，1.71(d，3H，J＝6.4Hz)，1.31(d，3H，J＝6.0Hz)，1.07(d，3H，J＝6.8Hz)，0.98(s，3H)，0.75(s，3H)，0.62(d，3H，J＝4.8Hz)；
13C-NMR(100MHz)：170.9(C＝O)，140.9，122.0，109.4，102.5，102.2，100.5，81.3，78.2，78.1(3×C)，77.2，76.0，74.3，73.0，72.8，72.6，70.4，69.7，67.7，67.0，63.0，61.3，56.8，50.4，42.1，40.6，40.0，39.1，37.7，37.3，32.5，32.4，32.0，31.9，30.8，30.3，29.4，21.3(2×C)，19.6，18.8，18.0，17.5，16.5，15.3.Anal.Calcd.for C
47H
74O
17：C，61.96；H，8.19.Found：C，61.68；H，8.50.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[4-O-butyryl radicals-α-L-rhamanopyranosyl-(1 → 4)]-β-D-glycoside (4b of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-[4-O-butyryl-α-L-rhamnopyranosyl-(1 → 4)]-β-D-glucopyranoside)
R
f：0.27[CH
2Cl
2-CH
3OH(8∶1)]；[α]
D＝-102.0°(c，0.36，THF)；ESI-MS：961.8(M+Na)，978.1(M+K)；
1H-NMR(400MHz)：6.37(s，1H)，5.84(s，1H)，5.79(t，1H，J＝9.7Hz)，5.25(d，1H，J＝4.3Hz)，4.95-4.89(m，3H)，4.76(d，1H，J＝1.1Hz)，4.60-4.45(m，4H)，4.38(t，1H，J＝8.8Hz)，4.30(t-like，1H，J＝9.9，9.0Hz)，4.20-4.14(m，3H)，4.02(brd，1H)，3.82(m，1H)，3.58(brd，1H)，3.53-3.41(m，2H)，2.28(t，2H，J＝7.4Hz)，1.70(d，3H，J＝5.9Hz)，1.32(d，3H，J＝6.1Hz)，1.07(d，3H，J＝6.9Hz)，0.99(s，3H)，0.78(t，3H，J＝7.6Hz)，0.77(s，3H)，0.63(d，3H，J＝4.7Hz).Anal.Calcd.for C
49H
78O
17·1.5H
2O：C，60.91；H，8.45；.Found：C，60.77；H，8.52.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[4-O-caproyl-α-L-rhamanopyranosyl-(1 → 4)]-β-D-glycoside (4c of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-[4-O-caproyl-α-L-rhamnopyranosyl-(1 → 4)]-β-D-glucopyranoside)
R
f：0.29[CH
2Cl
2-CH
3OH(8∶1)]；[α]
D 21＝-92.8°(c，0.40，THF)；ESI-MS：989.9(M+Na)；
1H-NMR(400MHz)：6.37(s，1H)，5.84(s，1H)，5.80(t，1H，J＝9.9Hz)，5.26(d，1H，J＝4.0Hz)，4.97-4.89(m，3H)，4.76(m，1H)，4.60-4.45(m，4H)，4.38(t，1H，J＝8.9Hz)，4.30(t，1H，J＝9.4Hz)，4.20-4.14(m，3H)，4.02(brd，1H)，3.82(m，1H)，3.58(brd，1H)，3.54-3.41(m，2H)，2.32(m，2H)，1.70(d，3H，J＝6.0Hz)，1.34(d，3H，J＝6.2Hz)，1.07(d，3H，J＝6.9Hz)，0.99(s，3H)，0.77(s，3H)，0.69(t，3H，J＝7.0Hz)，0.63(d，3H，J＝4.7Hz)Anal.Calcd.for C
51H
82O
17：C，63.33；H，8.55.Found：C，63.08；H，8.63.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[4-O-vinyl adipyl-c-L-rhamanopyranosyl-(1 → 4)]-β-D-glycoside (4d of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-[4-O-vinyladipyl-α-L-rhamnopyranosyl-(1 → 4)]-β-D-glucopyranoside)
R
f：0.40[CH
2Cl
2-CH
3OH(8∶1)]；[α]
D 21＝-99.7°(c，0.19，THF)；ESI-MS：1045.7(M+Na)；
1H-NMR(400MHz)：7.36(dd，1H，J＝14.0，6.3Hz)，6.36(s，1H)，5.84(s，1H)，5.78(t，1H，J＝9.8Hz)，5.26(d，1H，J＝5.1Hz)，4.95-4.88(m，3H)，4.84(dd，1H，J＝14.0，1.5Hz)，4.76(m，1H)，4.60-4.46(m，5H)，4.37(t，1H，J＝9.0Hz)，4.30(t，1H，J＝9.4Hz)，4.20-4.14(m，2H)，4.02(dd，1H，J＝12.2，3.0Hz)，3.82(m，1H)，3.58(brd，1H)，3.54-3.41(m，2H)，2.34-2.26(m，4H)，1.70(d，3H，J＝6.2Hz)，1.31(d，3H，J＝6.2Hz)，1.07(d，3H，J＝7.0Hz)，0.99(s，3H)，0.77(s，3H)，0.63(t，3H，J＝5.6Hz).Anal.Calcd.forC
53H
82O
19·2H
2O：C，60.10；H，8.18.Found：C，60.24；H，7.86.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[3; 5-O-diacetyl-α-L-arabinose base-(1 → 4)]-β-D-glycoside (5a of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-[3,5-O-di-acetyl-α-L-arabinofuranosyl-(1 → 4)]-β-D-glucopyranoside)
R
f：0.28[CH
2Cl
2-CH
3OH(10∶1)]；[α]
D＝-92.7°(c，0.19，THF)；ESI-MS：961.8(M+Na)，977.8(M+K)；
1H-NMR(400MHz)：6.30(s，1H)，6.07(s，1H)，5.45(dd，1H，J＝5.0，1.8Hz)，5.24(d，1H，J＝4.8Hz)，4.98(m，1H)，4.93-4.86(m，3H)，4.73(brd，1H)，4.69(dd，1H，J＝11.6，4.0Hz)，4.57-4.47(m，3H)，4.35-4.12(m，6H)，3.81(m，1H)，3.65(brd，1H)，3.53-3.41(m，2H)，1.89(s，3H)，1.81(s，3H)，1.71(d，3H，J＝6.0Hz)，1.07(d，3H，J＝6.8Hz)，0.99(s，3H)，0.76(s，3H)，0.62(d，3H，5.2Hz)；
13C-NMR(100MHz)：170.8(2×C＝O)，140.9，122.0，109.8，109.4，102.2，100.4，81.4，81.3(2×C)，80.4，78.2，77.9(2×C)，76.8(2×C)，74.3，73.0，72.7，69.7，67.0，64.7，63.1，61.2，56.8，50.5，42.1，40.6，40.0，39.1，37.7，37.3，32.5，32.4，32.0，31.8，30.8，30.3，29.4，21.3，20.9，20.8，19.6，18.8，17.5，16.5，15.2.Anal.Calcd.for C
48H
74O
18：C，61.39；H，7.94.Found：C，61.18；H，7.97.
Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[2; 5-O-diacetyl-α-L-arabinose base-(1 → 4)]-β-D-glycoside (5b of Diosgenyl α-L-rhamnopyranosyl-(1 → 2)-[2,5-O-di-acetyl-α-L-arabinofuranosyl-(1 → 4)]-β-D-glucopyranoside)
R
f：0.20[CH
2Cl
2-CH
3OH(10∶1)]；[α]
D＝-90.7°(c，0.18，THF)；ESI-MS：961.8(M+Na)，977.8(M+K)；
1H-NMR(400MHz)：6.32(s，1H)，5.88(s，1H)，5.60(d，1H，J＝2.4Hz)，5.23(d，1H，J＝4.4Hz)，5.09(m，1H)，4.93-4.86(m，2H)，4.75(brs，1H)，4.64(dd，1H，J＝12.0，3.6Hz)，4.57-4.54(m，2H)，4.49-4.39(m，3H)，4.33-4.25(m，3H)，4.17-4.15(m，2H)，3.80(m，1H)，3.63(brd，1H)，3.53-3.41(m，2H)，1.87(s，3H)，1.80(s，3H)，1.70(d，3H，J＝6.4Hz)，1.07(d，3H，J＝6.8Hz)，0.98(s，3H)，0.76(s，3H)，0.62(d，3H，5.2Hz)；
13C-NMR(100MHz)：170.8(C＝O)，170.6(C＝O)，140.9，122.0，109.4，106.6，102.1，100.5，85.8，82.5，81.3，78.2，77.7(2×C)，76.9，76.1(2×C)，74.3，73.0，72.7，69.7，67.0，64.3，63.0，61.2，56.8，50.4，42.1，40.6，40.0，39.1，37.6，37.3，32.5，32.4，32.0，31.8，30.8，30.2，29.4，23.1，20.8(2×C)，19.6，18.8，17.5，16.5，15.2.
Chinese yam glucoside unit-4-O-ethanoyl-α-L-rhamanopyranosyl-(1 → 6)-β-D-glycoside (6a of Diosgenyl 4-O-acetyl-α-L-rhamnopyranosyl-(1 → 6)-β-D-glucopyranoside)
R
f：0.51[CH
2Cl
2-CH
3OH(5∶1)]；[α]
D＝-75.3°(c，0.24，THF)；ESI-MS：765.7(M+1)，787.6(M+Na)，803.6(M+K)；
1H-NMR(300MHz)：5.67(t，1H，J＝9.5Hz)，5.41(s，1H)，5.24(d，1H，J＝4.9Hz)，4.92(d，1H，J＝7.7Hz)，4.53-4.43(m，4H)，4.20-3.84(m，6H)，3.52-3.42(m，2H)，1.95(s，3H)，1.28(d，3H，J＝6.3Hz)，1.06(d，3H，J＝6.9Hz)，0.84(s，3H)，0.75(s，3H)，0.62(d，3H，J＝5.5Hz)；
13C-NMR(100MHz)：170.9(C＝O)，141.2，121.8，109.5，103.2，102.5，81.3，79.1，78.7，76.9，75.9，75.4，72.4，71.9，70.4，68.5，67.2，67.0，64.6(CH
3OH)，63.0，56.8，50.4，42.1，40.6，40.0，39.7，37.7，37.2，32.4，32.3，32.0，31.8，30.8，30.6，29.4，21.3(2×C)，19.6，18.3，17.5，16.5，15.2.Anal.Calcd.forC
41H
64O
13·H
2O：C，62.90；H，8.50.Found：C，63.16；H，8.82.
Embodiment 6
Glycosyl part in the table 37 acidylate dioscin derivatives
13The chemical shift of C (δ)
a
1a 1b 2a 2b 3a 4a 5a 5b
C-1’ 103.0 102.7 100.8 100.2 102.3 100.5 100.4 100.5
C-2’ 75.3 75.0 79.5 79.4 75.9 78.1 77.9 77.7
C-3’ 78.8 69.7 77.8 76.9 76.8 78.1 77.9 77.7
C-4’ 71.6 79.2 71.7 71.6 77.6 78.1 76.8 76.0
C-5’ 75.4 73.2 75.0 75.1 77.4 77.2 76.8 76.9
C-6’ 65.0 64.5 64.7 64.6 61.5 61.3 61.2 61.2
C-1r 102.3 101.7 102.7 102.2 102.2 102.1
C-2r 72.7 72.6 72.7 72.8 72.7 72.7
C-3r 73.0 70.4 70.5 73.0 73.0 73.0
C-4r 74.3 76.3 76.2 74.3 74.3 74.3
C-5r 69.8 67.0 67.6 69.7 69.7 69.7
C-6r 18.9 18.2 18.1 18.8 18.8 18.8
C- 102.5 109.8 106.6
1r’(1a)
C- 72.6 80.4 85.8
2r’(2a)
C- 70.4 81.4 76.9
3r’(3a)
C- 76.0 81.3 82.5
4r’(4a)
C- 67.0 64.7 64.3
5r’(5a)
C-6r’ 18.1
A, the ownership of this chemical shift be through
1H-NMR,
13C-NMR,
1H-
1HCOSY, TOCSY, the result of hsqc spectrum analysis-by-synthesis
The experiment of embodiment 7 anti-tumor biological in-vitro screenings
Result evaluation: invalid: 10
-5Mol/l＜85%
The weak effect: 10
-5Mol/l 〉=85% or 10
-6Mol/l 〉=50%
Potent: 10
-6Mol/l 〉=85% or 10
-7Mol/l＞50%
Table 4
Screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method
Cell strain: A-549 human lung adenocarcinoma action time: 72h
Inhibiting rate % to growth of tumour cell
| Saponin | A-549 | Estimate | ||||
| 10 -4 | 10 -5 | 10 -6 | 10 -7 | 10 -8 | ||
| 2a | 100 | 3.6 | 8.1 | 4.3 | 4.2 | Invalid |
| 2b | 100 | 93.0 | 7.1 | 8.7 | 4.4 | The weak effect |
| 3a | 100 | 14.8 | 9.1 | 7.4 | 3.4 | Invalid |
| 4a | 100 | 99.0 | 4.7 | 8.3 | 7.8 | The weak effect |
| 5a | 100 | 100 | 26.4 | 5.2 | 5.0 | The weak effect |
| 5b | 99.8 | 100 | 5.9 | 1.3 | 0 | The weak effect |
Table 5
Screening method: tetrazolium (microculture tetrozolium, MTT) reduction method
Cell strain: P388 mouse leukemia action time: 48h
Inhibiting rate % to growth of tumour cell
| Saponin | P-388 | Estimate | ||||
| 10 -4 | 10 -5 | 10 -6 | 10 -7 | 10 -8 | ||
| 2a | 99.4 | 9.2 | 13.7 | 0 | 0 | Invalid |
| 2b | 99.2 | 37.5 | 2.3 | 0 | 0 | Invalid |
| 3a | 97.6 | 0 | 0 | 0 | 0 | Invalid |
| 4a | 99.3 | 97.8 | 0 | 0 | 0 | The weak effect |
| 5a | 98.7 | 98.6 | 24.9 | 11.0 | 10.7 | The weak effect |
| 5b | 99.3 | 98.2 | 0 | 0 | 0 | The weak effect |
Claims (10)
1, a kind of acyl derivative of dioscin is characterized in that its structural formula is as follows:
In the structural formula, R=C
1-8Acyl group or enoyl-; R, p, q=0,1 or 2, and, 0＜r+p+q≤2;
The M=glucosyl group
N, the U=rhamanopyranosyl
Or Arabic glycosyl
N, u=0 or 1
2, the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that described structural formula is as follows:
R wherein
1Or R
2=H or R, R
1And R
2Can not equal H, R such as claim 1 simultaneously
3, the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that described structural formula is as follows:
4, the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that described structural formula is as follows:
5, the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that described structural formula is as follows:
6, the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that described structural formula is as follows:
7, the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that described structural formula is as follows:
8, the enzymatic synthesis method of the acyl derivative of a kind of dioscin as claimed in claim 1; it is characterized in that when polar solvent neutralization reaction temperature is room temperature-100 ℃; acyl acceptor, acyl group are followed successively by 1-7 for the mol ratio of body and lipase: 100-210: 0.02-0.4; reacted 1 hour-120 hours, described acyl acceptor dioscin structural formula is as follows:
N, the U=rhamanopyranosyl
Or Arabic glycosyl
N, u=0 or 1,
Described acyl group donor molecule formula is ROR ', wherein R=C
1-8Acyl group or enoyl-, R ' is vinyl or trifluoroethyl, described lipase is lipase CRL, lipase PPL, lipase MJL, lipase WGL, lipase PFL or lipase Novozyme435.
9; the enzymatic synthesis method of the acyl derivative of a kind of dioscin as claimed in claim 3 is characterized in that described acyl acceptor dioscin is Chinese yam glucoside unit-β-D-glycoside; Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-β-D-glycoside; Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 4)-β-D-glycoside; Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[α-L-rhamanopyranosyl-(1 → 4)]-β-D-glycoside; Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 2)-[α-L-arabinose base-(1 → 4)]-β-D-glycoside or Chinese yam glucoside unit-α-L-rhamanopyranosyl-(1 → 6)-β-D-glycoside.
10, the purposes of the acyl derivative of a kind of dioscin as claimed in claim 1 is characterized in that being used to prepare anti-tumor drug.
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| CN104334571B (en) * | 2012-06-13 | 2016-08-31 | 杭州本生药业有限公司 | The acylated derivatives of Rhizoma Paridis saponin I, and its preparation method and application |
| US10925887B2 (en) | 2017-02-10 | 2021-02-23 | Oncology Research International Limited | Steroid saponins with anti-cancer activity |
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