CN102786562A - Pyrrolizidine alkaloids and purpose thereof - Google Patents
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- CN102786562A CN102786562A CN2012102921933A CN201210292193A CN102786562A CN 102786562 A CN102786562 A CN 102786562A CN 2012102921933 A CN2012102921933 A CN 2012102921933A CN 201210292193 A CN201210292193 A CN 201210292193A CN 102786562 A CN102786562 A CN 102786562A
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Abstract
The invention discloses pyrrolizidine alkaloids (PAs) and application thereof in anti-inflammatory drugs. The structural formula of the pyrrolizidine alkaloids is shown as the accompanying drawing. The pyrrolizidine alkaloids can be used as anti-inflammatory drugs to be applied in prevention or treatment of inflammation caused by release of NO, tumor necrosis factor-alpha, interleukin-6 and other inflammatory mediators.
Description
Technical field
The present invention relates to western pyridine vegeto-alkali and uses thereof in one group of pyrroles.
Background technology
Inflammation is a biological tissue with vascular system to the defensive raction that damage factor took place; Be body for a kind of defensive raction that stimulates, common is characteristic with the white corpuscle number in heating, the blood increases and organs such as the heart, liver, kidney occur in various degree sex change, necrosis etc.That acute inflammation shows as is red, swollen, hot, pain and dysfunction.Chronic inflammatory diseases is obviously harmful to health, possibly cause cancer, mellitus, pulmonary disorder, the cardiovascular system neural disease etc. of unifying.
The lasting existence of pro-inflammatory cytokine and continuous damaged tissue are the basic reasons that chronic inflammatory diseases takes place.But some pro-inflammatory cytokine coup injury endothelium cause that vascular permeability raises, but many pro-inflammatory cytokines does not directly act on local organization, and mainly is that effect through the endogenous chemokines causes inflammation, so be referred to as chemical mediator or inflammatory mediator again.The release of inflammatory mediator and regulatory mechanism are the key subjects of inflammation research.The inflammatory mediator that cell discharges comprises NO (nitrogen protoxide), TNF-α (tumor necrosis factor-alpha) and, IL-α (interleukin--α); IL-β (interleukin--β); IL-2 (interleukin II), IL-6 (interleukin-6), IL-8 (interleukin 8) etc.
Through suppressing the release of pro-inflammatory cytokines such as NO, TNF-α, IL-6, can treat the multiple disease that causes by chronic inflammatory diseases, like rheumatoid arthritis, osteoarthritis, systemic inflammatory response syndrome, central nervous system injury, joint of vertebral column inflammation etc.Exploitation good effect, the inflammatory mediator inhibitory substance that toxicity is low have become the focus that people develop new anti-inflammatory drug.
Summary of the invention
First purpose of the present invention is to provide western pyridine vegeto-alkali in one type of pyrroles.
Second purpose of the present invention is to provide the purposes as the preparation anti-inflammatory drug of western pyridine vegeto-alkali in the above-mentioned pyrroles.
The present invention realizes its first goal of the invention, and the technical scheme that is adopted is: western pyridine vegeto-alkali in a kind of pyrroles, have as shown in the formula structure:
In the formula:
R
1Be α-H or β-H;
R
2Be α-H or β-H;
R
3Be H, OH, following structural formula (A), structural formula (B) or structural formula (C);
R
4Be H, OH, following structural formula (A), structural formula (B), structural formula (C) or structural formula (D);
R
5Be following structural formula (D), structural formula (E), structural formula (F), structural formula (G) or structural formula (H); R6 is O or nothing.
Western pyridine vegeto-alkali is following formula I in the above-mentioned pyrroles, formula II, formula III, formula IV, a kind of among formula V or the formula VI.
The present invention realizes its second goal of the invention, and the technical scheme that is adopted is:
The alkaloidal purposes of western pyridine is the preparation anti-inflammatory drug in the above-mentioned pyrroles, or uses as the precursor of anti-inflammatory drug or the lead compound of anti-inflammatory drug.
Above-mentioned anti-inflammatory drug is to be used for prevention or to treat by NO the inflammation that the release of tumor necrosis factor-alpha and interleukin-6 inflammatory mediator causes.
Above-mentioned anti-inflammatory drug contains western pyridine vegeto-alkali and pharmaceutically acceptable carrier in the described pyrroles who treats significant quantity.
Containing the alkaloidal anti-inflammatory drug of the present invention can be for being applicable to the form of oral application; For example, can be tablet, tablet, lozenge, moisture or contain oil suspension, dispersible powder or granula, emulsion, liquor, hard capsule or soft capsule, or sugar dress agent or make agent.
Compared with prior art, the invention has the beneficial effects as follows:
One, western pyridine vegeto-alkali in one group of new pyrroles is provided;
Two, utilization extracorporeal anti-inflammatory screening active ingredients system is carried out activity rating, finds that western pyridine vegeto-alkali can suppress mouse macrophage release nitrogen protoxide (IC effectively in the pyrroles of the present invention
50Be merely 2.16-38.25 μ M), tumor necrosis factor-alpha (IC
50Be merely 37.88-70.33 μ M) and interleukin-6 (IC
50Be merely 36.62-58.68 μ M) etc. the release of inflammatory mediator; And the mouse macrophage toxicity test shows, most of alkaloidal IC of the present invention
50All, show that vegeto-alkali of the present invention has the effect of prevention and treatment inflammation, and toxicity is low, has good research and development prospect greater than 100 μ M.
Below in conjunction with embodiment invention is specified further.
Embodiment
Embodiment
A kind of embodiment of the present invention is, western pyridine vegeto-alkali in a kind of pyrroles, have as shown in the formula structure:
In the formula:
R
1Be α-H or β-H;
R
2Be α-H or β-H;
R
3Be H, OH, following structural formula (A), structural formula (B) or structural formula (C);
R
4Be H, OH, following structural formula (A), structural formula (B), structural formula (C) or structural formula (D);
R
5Be OH, structural formula (D), structural formula (E), structural formula (F), structural formula (G) or structural formula (H);
R
6Be O or nothing.
More specifically, western pyridine vegeto-alkali is as shown in the formula I in this routine pyrroles, formula II, formula III, formula IV, a kind of among formula V or the formula VI.
Above formula I, formula II, formula III, formula IV, western pyridine vegeto-alkali in the pyrroles of formula V and formula VI, available following method makes:
Get orchid Liparis arteries and veins fen orchid Liparis nervosa (Thunb.ex A.Murray) Lindl. herb 10kg, at ambient temperature, the dry root of Nerved Twayblade with 95% extraction using alcohol three times, is soaked a week at every turn, obtain medicinal extract behind the concentrating under reduced pressure.Remainder is dipped in 50 ℃ of water, regulates pH to 2.8 with HCl, uses the extraction of chloroform (500mL * 3) and ETHYLE ACETATE (500mL * 3) respectively again.Water layer is used ethyl acetate extraction after regulating pH to 9.4 with ammoniacal liquor again, obtains the ETHYLE ACETATE medicinal extract crude extract (10g) of alkalescence after the vacuum-evaporation.The ETHYLE ACETATE crude extract of alkalescence is through silica gel column chromatography, by CH
2Cl
2: CH
3OH (1: 0 → 0: 1, carry out gradient elution, detect through thin-layer chromatography, merge stream part according to the order of sequence, obtain six parts: A (200mg) successively, B (344mg), C (243mg), D (229mg), E (1.1g) and F (300mg).
B partly passes through the further separation and purification of silica gel column chromatography, and moving phase is CH
2Cl
2: MeOH: NH
3H
2O (10: 1: 0.1) obtains two kinds of compounds respectively, identifies that through spectrographies such as NMR, HRMS, IR the two is respectively the compound with following formula V and formula VI, wherein:
The chinesization formal name used at school of the compound of formula V is called: [(1S; 7aS)-and six hydrogen-1H-double pyrrolizidine-1-yl] methyl-3-(3-hydroxy-3-methyl butane group) 4-O-(α-L-arabopyranose base)-5-(3-methyl-2-butene base)-benzoic ether, English chemical name is:
[(1S，7aS)-hexahydro-1H-pyrrolizin-1-yl]methyl-3-(3-hydroxy-3-methylbutyl)-4-O-(α-L-arabinosyl)-5-(3-methyl-2-butenyl)benzoate；
The chinesization formal name used at school of the compound of formula VI is called: [(1S, 7aS)-six hydrogen-1H-double pyrrolizidine-1-yl] methyl-2,2-dimethyl--8-(3-methyl-2-butene base)-2H-benzene pyrans-6-carboxylicesters, English chemical name is:
[(1S，7aS)-hexahydro-1H-pyrrolizin-1-yl]methyl-2，2-dimethyl-8-(3-methyl-2-butenyl)-2H-chromene-6-carboxylate；
The contriver is with compound difference called after Nervosine V and the Nervosine VI of formula V and formula VI.
The C part is also further passed through silica gel column chromatography, by CH
2Cl
2: MeOH: NH
3H
2O (10: 1: 0.1) carries out gradient elution, obtains two kinds of compounds respectively, identifies that through spectrographies such as NMR, HRMS, IR the two is respectively the compound with following formula I and formula II, wherein:
The chinesization formal name used at school of the compound of formula I is called: [(1S, 7aS)-six hydrogen-1H-double pyrrolizidine-1-yl] methyl-3,5-two (3-methyl-2-butene base)-4-O-(α-L-arabopyranose base)-benzoic ether, English chemical name is:
[(1S，7aS)-hexahydro-1H-pyrrolizin-1-yl]-methyl?3，5-bis(3-methylbut-2-enyl)-4-O-(α-L-arabinosyl)benzoate；
The chinesization formal name used at school of the compound of formula II is called: [(1R; 7aS)-and six hydrogen-1H-double pyrrolizidine-1-yl] methyl-3; 5-two (3-methyl-2-butene base)-4-O-(α-L-arabopyranose base)-benzoic ether; English chemical name is: [(1R, 7aS)-hexahydro-1H-pyrrolizin-1-yl] methyl-3,5-bis (3-methylbut-2-enyl)-4-O-(benzoate of α-L-arabinosyl);
The contriver is with compound difference called after Nervosine I and the NervosineII of formula I and formula II.
E partly passes through the silica gel column chromatography method, uses EtOAc: MeOH: NH
3H
2O (12: 1: 0.5 → 1: 1: 0.5) carries out gradient elution, obtains 4 parts of (E1-E4) bullions; The E3 part is further purified through silica gel column chromatography, and moving phase is EtOAc: MeOH: NH
3H
2O (7: 1: 0.5) obtains two kinds of compounds respectively, identifies that through spectrographies such as NMR, HRMS, IR the two is respectively the compound of following formula III and formula IV, wherein:
The chinesization formal name used at school of the compound of formula III is called: [(1S; 7aS)-and six hydrogen-1H-double pyrrolizidine-1-yl] methyl-3; 5-two (3-methyl-2-butene base)-4-O-[β-D-Glucopyranose-(1 → 4)-α-D-β-D-glucopyranosyl]-benzoic ether; English chemical name is: [(1S; 7aS)-and hexahydro-1H-pyrrolizin-1-yl] methyl 3,5-bis (3-methylbut-2-enyl)-4-O-[β-D-glucopyranosyl-(1 → 4)-β-D-glucopyranosyl] benzoate;
The chinesization formal name used at school of the compound of formula IV is called: [(1S; 7aS)-and six hydrogen-1H-double pyrrolizidine-1-yl] methyl-3; 5-two (3-methyl-2-butene base)-4-O-[β-D-Glucopyranose-(1 → 2)-α-L-arabopyranose base]-benzoic ether; English chemical name is: (1S, 7aS)-hexahydro-1H-pyrrolizin-1-yl] methyl-3,5-bis (3-methylbut-2-enyl)-4-O-[β-D-glucopyranosyl-(1 → 2)-α-L-arabinosyl] benzoate;
The contriver is with compound called after Nervosine III and the Nervosine IV of formula III and formula IV.
Above compound is western pyridine vegeto-alkali in the pyrroles, finds to be the new compound of not seeing bibliographical information through the Scifinder retrieval.
Western pyridine vegeto-alkali also is that the physicochemical constant of six compounds of contriver's called after Nervosine I-VI is following in the pyrroles of above structural formulas I-VI:
Nervosine I, colorless solid, the bismuth potassium iodide reaction shows positive.[α]
20 D＝+18.3(c?0.350MeOH)；UV(MeOH)λ
max(logε)，242(3.97)nm；IR(KBr)v
max?3387，2970，2967，2918，2858，1716，1600，1453，1384，1317，1284，1219，1182，1075，1014，950，774，651cm
-1。
1H with
13C NMR data are seen table 1.HR-ESI-MS?at?m/z?530.3116[M+H]
+(calcd.for?C
30H
44NO
7，530.3118)。
Nervosine II, colorless solid, the bismuth potassium iodide reaction shows positive.[α]
20 D=0 (c 0.250MeOH); UV (MeOH) λ
Max(log ε), 241 (3.59), 216 (3.10) nm; IR (KBr) v
Max3415,2964,2922,2854,1719,1631,1602,1436,1319,1287,1220,1181,1083,1027,951,774,651cm
-1 1H with
13C NMR data are seen table 1.HR-ESI-MS?at?m/z?530.3115[M+H]
+(calcd.for?C
30H
44NO
7，530.3118)。
Nervosine III, colorless solid, the bismuth potassium iodide reaction shows positive.[α]
20 D=+4.3 (c 0.035MeOH); UV (MeOH) λ
Max(log ε), 239 (4.04) nm; IR (KBr) v
Max3399,2967,2923,2730,1716,1600,1456,1383,1316,1285,1229,1185,1073,1044,901,771,640,612,570cm
-1 1H and
13C NMR data are seen table 2.HR-ESI-MS?atm/z?722.3765[M+H]
+(calcd.for?C
37H
56NO
13，722.3752)。
Nervosine IV, colorless solid, the bismuth potassium iodide reaction shows positive.[α]
20 D=+12.0 (c 0.035MeOH); UV (MeOH) λ
Max(log ε), 245 (4.12) nm; IR (KBr) v
Max3397,2965,2915,1716,1601,1454,1384,1316,1284,1219,1220,1183,1079,1032,1016,956,773,654,597cm
-1 1H with
13C NMR data are seen table 2.HR-ESI-MS?at?m/z?692.3639[M+H]
+(calcd.for?C
36H
54NO
12，692.3646)。
Nervosine V, colorless solid, the bismuth potassium iodide reaction shows positive.[α]
20 D=+19.2 (c 0.025MeOH); UV (MeOH) λ
Max(log ε), 245 (3.15), 220 (3.09) nm; Nm; IR (KBr) v
Max3396,2962,2923,2854,1716,1601,1457,1382,1314,1277,1217,1184,1076,1015,951,773,650cm
-1 1H with
13C NMR data are seen table 3.HR-ESI-MS?at?m/z?548.3221[M+H]
+(calcd.for?C
30H
46NO
8，548.3223)。
Nervosine VI, colorless solid, the bismuth potassium iodide reaction shows positive.[α]
20 D=+17.7 (c 0.030MeOH); UV (MeOH) λ
Max(log ε), 245 (3.27), 213 (2.7) nm; IR (KBr) v
Max3409,2969,2925,1713,1640,1602,1462,1376,1310,1286,1194,1124,1004,1049,989,954,930,769cm
-1 1H with
13C NMR data are seen table 3.HR-ESI-MS?at?m/z?396.2545[M+H]
+(calcd.for?C
25H
34NO
3，396.2539)。
Table 1: the hydrogen spectrum of compound N ervosine I and Nervosine II and carbon spectrum data
Annotate: solvent is CDCl
3,
1H NMR (400MHz),
13C NMR (100MHz).
Table 2: the hydrogen spectrum of compound N ervosine III and Nervosine IV and carbon spectrum data
Annotate: Nervosine III solvent is CD
3OD, Nervosine IV solvent is CDCl
3+ CD
3OD,
1H NMR (400MHz),
13C NMR (100MHz), " ov " are overlapping peaks.
Table 3: the hydrogen spectrum of compound N ervosine III and Nervosine IV and carbon spectrum data
Annotate: solvent is CDCl
3,
1H NMR (400MHz),
13C NMR (100MHz), " ov " are overlapping peaks.
Following biological activity test shows that western pyridine vegeto-alkali can be used to prepare anti-inflammatory drug in six kinds of above pyrroles, or as the precursor of anti-inflammatory drug or the lead compound of anti-inflammatory drug; The anti-inflammatory drug of preparation especially can be used for prevention or treats by NO the inflammation that the release of tumor necrosis factor-alpha and interleukin-6 inflammatory mediator causes.
Biological activity test
One, lipopolysaccharide-induced mouse macrophage RAW 264.7 is discharged the inhibition activity experiment of nitrogen protoxide (NO)
Mouse monokaryon scavenger cell RAW 264.7 (ATCC TIB-71) is incubated at and contains (56 ℃ of 10% hot deactivations; 30min) foetal calf serum (FBS), 100 μ/mL sistomycocin sodium (Gibco); In RPMI1640 (Gibco) nutrient solution of 100 μ/mL Streptomycin sulphate (Gibco), 37 ℃, 5%CO
2Constant incubator in hatch growth.
Because NO is extremely unstable, in cell culture supernatant, is rapidly metabolized to oxynitroso NO
2 -So, adopt NO in the Griess rule working sample
2 -Concentration as the index of weighing the NO level.
Use the RPMI RPMI-1640, with RAW 264.7 cell dilutions to 5 * 10
4The concentration of cells/well is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.At CO
2After cultivating 30min in the incubator, every hole adds 0.4 μ L intestinal bacteria, serotype O111: B4 respectively, the mixture of LPS and by DMSO dissolved specimen 0.4 μ L; Establish the LPS group simultaneously; (add LPS, but do not add specimen, the inhibiting rate that NO is discharged is 0%) and blank group (do not add LPS and specimen; The DMSO that only adds 0.4 μ L, the inhibiting rate that NO is discharged is 100%).Each sample is established 4 parallel holes, at 37 ℃, and 5%CO
2Cultivate 24h in the constant incubator, draw 100 μ L nutrient solution supernatants to enzyme plate, centrifugal (1000 * g, 4 ℃, 3min), add Griess reagent, room temperature lucifuge reaction 10min measures its light absorption value at the 540nm place in ELIASA.Be respectively the NaNO of 1,5,10,50 μ mol/L with concentration
2The drawing standard curve is according to NaNO
2Typical curve calculates NO in the cell culture supernatant
2 -Concentration so that calculate the inhibiting rate that specimen discharges NO.Active result such as following table:
Two, to the inhibition activity experiment of lipopolysaccharide-induced mouse monokaryon scavenger cell RAW 264.7 release tumor necrosis factors-α (TNF-α)
Cell cultures discharges with NO and suppresses active testing.
Inhibition active testing to TNF--α uses mouse TNF-α ELISA kit test kit (R&D).With the RPMI RPMI-1640 with RAW 264.7 cell dilutions to 5 * 10
5Cells/mL concentration is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.CO
2After cultivating 1h in the incubator; Every hole adds LPS, and (lipopolysaccharide, the specimen 0.4 μ L of LPS) (Sigma) (final concentration 1 μ g/mL) and DMSO dissolved different concns establish the LPS group simultaneously and (add LPS; But do not add specimen; The inhibiting rate that TNF-α is discharged is 0%) and blank group (do not add LPS and specimen, only add 0.4 μ L DMSO, the inhibiting rate that TNF-α is discharged is 100%).Each sample is established 3 parallel holes.At 37 ℃, 5%CO
2Draw the nutrient solution supernatant after cultivating 6h in the constant incubator, carry out typical curve according to ELISA test kit specification sheets method and draw the mensuration with TNF-α, calculating inhibiting rate.Active result such as following table:
Three, lipopolysaccharide-induced mouse monokaryon scavenger cell RAW 264.7 is discharged the inhibition activity experiment of interleukin-6 (IL-6)
Cell cultures discharges with NO and suppresses active testing.
Inhibition active testing to IL-6 uses mouse IL-6ELISA kit test kit (R&D).
With the RPMI RPMI-1640 with RAW 264.7 cell dilutions to 5 * 10
5Cells/mL concentration is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.CO
2After cultivating 1h in the incubator, every hole adds LPS (lipopolysaccharide, the specimen 0.4 μ L of LPS) (Sigma) (final concentration 1 μ g/mL) and DMSO dissolved different concns; Establish the LPS group simultaneously and (add LPS; But do not add specimen, the inhibiting rate that IL-6 is discharged is 0%) and the blank group (do not add LPS and specimen, only add 0.4 μ L DMSO; The inhibiting rate that IL-6 is discharged is 100%), each sample is established 3 parallel holes.At 37 ℃, 5%CO
2Draw the nutrient solution supernatant after cultivating 6h in the constant incubator, carry out typical curve according to ELISA test kit specification sheets method and draw the mensuration with IL-6, calculating inhibiting rate, result such as following table.
Four, to the cell toxicity test of mouse monokaryon scavenger cell RAW 264.7
Cell cultures discharges with NO and suppresses active testing.
Mtt assay is measured cell viability: with the RPMI RPMI-1640 with RAW 264.7 cell dilutions to 5 * 10
5Cells/mL concentration is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.CO
2After cultivating 1h in the incubator, 1 * 10
5Individual/mL RAW 264.7 cell suspension inoculations are in 96 porocyte plates, and every hole 90 μ L cell suspensions are behind the cultivation 12h; Experimental group adds the specimen of different concns respectively; Control group adds isopyknic serum-free DMEM nutrient solution, is provided with blank zeroing group simultaneously, and every group has 5 multiple holes.After cell was cultivated 48h again, every hole added blue (MTT) solution of tetramethyl-azo azoles (5mg/mL, phosphate buffered saline buffer preparation) 10 μ L; Remove nutrient solution after hatching 2h; Add 150 μ L DMSO 99.8MIN.s (DMSO), vibration 15m in measures absorbancy with the full-automatic enzyme-linked immunologic detector in the 540nm wavelength; Computer writes down and preserves 3 batches of every group of experiment of data repetitions, result such as following table automatically.
It is thus clear that; Above material can be used to prepare anti-inflammatory drug; Or as the precursor of anti-inflammatory drug or the lead compound of anti-inflammatory drug, said anti-inflammatory drug can be used for prevention or treats by NO the inflammation that the release of tumor necrosis factor-alpha and interleukin-6 inflammatory mediator causes.Anti-inflammatory drug contains western pyridine vegeto-alkali and pharmaceutically acceptable carrier in the described pyrroles who treats significant quantity.
Claims (5)
1. western pyridine vegeto-alkali in the pyrroles, have as shown in the formula structure:
In the formula:
R
1Be α-H or β-H;
R
2Be α-H or β-H;
R
3Be H, OH, following structural formula (A), structural formula (B) or structural formula (C);
R
4Be H, OH, following structural formula (A), structural formula (B), structural formula (C) or structural formula (D);
R
5Be OH, structural formula (D), structural formula (E), structural formula (F), structural formula (G) or structural formula (H);
R
6Be O or nothing.
2. western pyridine vegeto-alkali in a kind of pyrroles according to claim 1 is characterized in that: western pyridine vegeto-alkali is as shown in the formula I in the described pyrroles, formula II, formula III, formula IV, a kind of among formula V or the formula VI.
3. the alkaloidal purposes of western pyridine is the preparation anti-inflammatory drug in claim 1 or the 2 described a kind of pyrroles, or uses as the precursor of anti-inflammatory drug or the lead compound of anti-inflammatory drug.
4. purposes according to claim 3 is characterized in that: said anti-inflammatory drug is to be used for prevention or to treat by NO the inflammation that the release of tumor necrosis factor-alpha and interleukin-6 inflammatory mediator causes.
5. purposes according to claim 4 is characterized in that: said anti-inflammatory drug contains western pyridine vegeto-alkali and pharmaceutically acceptable carrier in the described pyrroles who treats significant quantity.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214447A (en) * | 2013-05-08 | 2013-07-24 | 重庆理工大学 | Liparis nervosa extract monomeric compound as well as preparation method and application thereof |
| CN104610396A (en) * | 2014-06-24 | 2015-05-13 | 江西中医药大学 | Oxidized pyrrolizidine alkaloid glycoside compound and application thereof |
| CN106389425A (en) * | 2016-10-30 | 2017-02-15 | 徐州诺克非医药科技有限公司 | PenibruguieramineA-containing pharmaceutical composition for treating chronic nephritis |
| CN110294763A (en) * | 2019-02-28 | 2019-10-01 | 西南交通大学 | A kind of preparation method and applications of pyrrolizidine alkaloids |
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