CN106674231A - Diterpenoid alkaloid compounds in Aconitum naviculare as well as preparation method and application of diterpenoid alkaloid compounds - Google Patents
Diterpenoid alkaloid compounds in Aconitum naviculare as well as preparation method and application of diterpenoid alkaloid compounds Download PDFInfo
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- CN106674231A CN106674231A CN201611230639.4A CN201611230639A CN106674231A CN 106674231 A CN106674231 A CN 106674231A CN 201611230639 A CN201611230639 A CN 201611230639A CN 106674231 A CN106674231 A CN 106674231A
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- aconitum
- naviculare
- aconitum naviculare
- diterpene
- alkaloid compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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- Medicines Containing Plant Substances (AREA)
Abstract
The invention relates to diterpenoid alkaloid compounds in Aconitum naviculare as well as a preparation method and an application of the diterpenoid alkaloid compounds. According to the method, crude Aconitum naviculare medicine is taken as a raw material and is extracted with a solvent, an extract is subjected to acid dissolution and alkali precipitation, a product is processed with gel Sephadex LH-20 chromatography and reversed-phase RP-18 column chromatography separation, three diterpenoid alkaloid compounds including C40H50N2O4 (1), C47H56N2O5 (2) and C29H37NO3 (3) are obtained after analysis with thin-layer chromatography, in-vitro cytotoxic activity of the three compounds is determined, and test results prove that C47H56N2O5 (2) has anti-tumor activity in human promyelocytic leukemia cells, human hepatoma cells, human lung cancer cells, human breast cancer cells and human colon cancer cells, and can be used for preparing anti-tumor drugs.
Description
Technical field
The present invention relates to field of phytochemistry, and in particular to from extracting and developing diterpene alkaloid in Aconitum naviculare medical material
Compound.
Background technology
Aconitum naviculare (Aconitum naviculare.Stapf), Tibetan medicine name list loud, high-pitched sound, the beginning is loaded in the ancient books and records of Tibetan medicine《Month king
Medicine is examined》, belong to Ranunculaceae (Ranunculaceae) Aconitum (Aconitum.) plant.Aconitum naviculare nature and flavor are bitter, tremble with fear, and have little
Poison, enters ball more and dissipates, and has functions that heat-clearing and toxic substances removing.This kind of plant mostly is compound preparation in the application of Tibetan medicine, and such as ten simply
Golden ball, 12 taste wings head umbrellas, 13 taste list loud, high-pitched sounds dissipate.2010 editions《Chinese Pharmacopoeia》Contain ship helmet in 41 Tibetan medicine prescribed preparations
Aconitum carmichjaelii Debx., accounts for the 20% of Tibetan medicine prescription, it can be seen that the popularity of its application.Modern pharmacology research shows that Aconitum naviculare has
There are antiinflammatory, analgesic effect.
Aconitum naviculare application is relatively broad, at present for the chemical composition of the Tibetan medicine is available for the systematic study of pharmacological action
With reference to data it is less, therefore for extracting with the diterpene alkaloid chemical composition of anti-tumor activity in Aconitum naviculare
Separation Research is necessary, probing into very big learning value to Aconitum naviculare anti-tumor activity.
The content of the invention
It is an object of the present invention to provide in a kind of Aconitum naviculare diterpene alkaloid compound and preparation method thereof and use
On the way.The compound 1 is Aconitum naviculare element A (1)；Compound 2 is Aconitum naviculare element B (2)；Compound 3 is Aconitum naviculare element C (3).
Wherein, Aconitum naviculare element A (1) is double diterpene alkaloids, and its molecular formula is C40H50N2O4；Aconitum naviculare element B (2) is
Double diterpene alkaloids, its molecular formula is C47H56N2O5；Aconitum naviculare element C (3) molecular formula is C29H37NO3。
Wherein, Aconitum naviculare element A (1) structural formula is
Wherein, Aconitum naviculare element B (2) structural formula is
Wherein, Aconitum naviculare element C (3) structural formula is
Wherein, the preparation method of diterpene alkaloid compound follow these steps to carry out in Aconitum naviculare：
A, Aconitum naviculare aerial partss are taken, after drying and crushing, using industrial methanol merceration 3 times, industrial acetone merceration 1 time,
Merceration time 72h, concentrating under reduced pressure recycling design obtains extractum；
B, adopt hydrochloric acid adjust extractum PH for 2-3, successively using petroleum ether, ethyl acetate, n-butanol extraction, regulation sour water
PH is 10, is then used again, ethyl acetate, n-butanol extraction, and concentrating under reduced pressure reclaims the total alkaloidss for obtaining n-butanol portion；
C, by the total alkaloidss Jing gel Sephadex LH-20 chromatographs in step B, anti-phase RP-18 pillar layer separations are adopted
It is analyzed with thin layer chromatography, that is, obtains diterpene alkaloid compound Aconitum naviculare element A (1), Aconitum naviculare element B (2), ship helmet
Aconitum carmichjaelii Debx. element C (3).
Wherein, application of Aconitum naviculare element B (2) in the medicine for the treatment of or prophylaxis of cancer disease is prepared, the cancer is
Leukemia, hepatocarcinoma, pulmonary carcinoma, breast carcinoma, colon cancer.
Description of the drawings
Fig. 1 obtains the configuration for determining after being compared with experiment value by the Structure Calculation value using setting configuration of the present embodiment
Schematic diagram.
Specific embodiment
Aconitum naviculare ground position 10kg is taken, is dried, crushed, industrial methanol merceration 3 times, industrial acetone merceration 1 time, every time
72h.Recycling design, obtains extractum, then adjusts PH=2-3 with sour water, successively using petroleum ether, ethyl acetate, and n-butanol extraction.
Sour water part adjusts PH=10, then uses again, ethyl acetate, n-butanol extraction, then obtains total biology of n-butanol portion
Alkali 18g.Total alkaloidss adopt successively gel Sephadex LH-20 chromatographs, anti-phase RP-18 pillar layer separations and analysis.
Diterpene alkaloid compound in the Aconitum naviculare that obtains is analyzed, wherein Aconitum naviculare element A (1) passes through13C
NMR (table 2) and ESIMS (m/z [M+H]+=623), it may be determined that its molecular formula is C40H50N2O4Degree of unsaturation is 15, is passed through
2D NMR determine its planar structure.Its relative configuration, H-11 (J=11.0Hz) and H-9 (J=are determined by ROESY and document
9.0Hz), show that both dihedral angles are zero degree, determine H-11 as beta comfiguration with this.Shown according to 1H-1H COSY, H-11 and H-13
There is the coupling of W types, thus infer that H-13 is beta comfiguration, its nuclear magnetic data (table 1) and two-dimensional correlation are as follows：
The crucial HMBC of Aconitum naviculare A (1) and1H-1H COSY are related：
In terms of quantum chemistry calculation, VCD collection of illustrative plates is calculated, then using the Structure Calculation value and experiment value ratio of setting configuration
Compared with the configuration that acquisition determines.
Diterpene alkaloid compound in Aconitum naviculare obtained by the present invention, wherein Aconitum naviculare element B (2), pass through13C
NMR and ESIMS (m/z [M+H]+=729), it may be determined that its molecular formula is C47H56N2O5, by infared spectrum 3429,1719cm-1Presence absorbs more by force, it can be determined that molecule contains hydroxyl and carbonyl.Pass through13C NMR (table 2) compare with compound 1, ten split-phases
Seemingly, the benzoyl of compound more than 2 is in 2 replacements.Then by 2D NMR (HMBC and1H-1H COSY) determine its plane
Structure.Its relative configuration is determined by ROESY and document, H-2 a brs peak (w1/2=10.8Hz) occurs, shows H-2 and H-
1 β or H-3 β do not have axial bond (a-a) to couple, then H-2 is used as equatorial bond (beta comfiguration).H-11 (J=8.8Hz) and H-9, table
Both dihedral angles bright are zero degree, determine H-11 as beta comfiguration [5] with this.Shown according to 1H-1H COSY, H-11 and H-13 has W
Type is coupled, and thus infers that H-13 is beta comfiguration.Its nuclear magnetic data (table 2) and two-dimensional correlation are as follows:
The crucial HMBC of Aconitum naviculare B (2) and1H-1H COSY are related：
Diterpene alkaloid compound in Aconitum naviculare obtained by of the invention, wherein Aconitum naviculare element C (3) is white powder,
According to (the calcd for C of HREIMS m/z 447.277929H37NO3,447.2773[M]+), determine Aconitum naviculare C (3) molecule
Formula is C29H37NO3, with 11 degrees of unsaturation.Infared spectrum 3441 and 1641cm-1Place is strong to be absorbed and determines in molecule hydroxyl and double
The presence of key.By analysis13C NMR (table 2) and DEPT are composed, and Aconitum naviculare element C (3) are determined with 29 carbon atoms, wherein wrapping
Include 2 methyl, 10 methylene, 10 methines and 7 quaternary carbons.Analyzed according to 2D NMR spectras, determine its planar structure.
The crucial HMBC and 1H-1H COSY of Aconitum naviculare element C (3) are related
The Aconitum naviculare A (1) of table 1, Aconitum naviculare B (2), the hydrogen modal data of Aconitum naviculare C (3)
Wherein：Aconitum naviculare A (1), Aconitum naviculare B (2)：400MHz
Aconitum naviculare C (3)：600MHz
Solvent：pyridine-d5
The Aconitum naviculare A (1) of table 2, Aconitum naviculare B (2), Aconitum naviculare C (3) carbon modal data
Wherein, Aconitum naviculare A (1), Aconitum naviculare B (2)：100MHz
Aconitum naviculare C (3)：150MHz
Solvent：pyridine-d5
To the Aconitum naviculare A (1), Aconitum naviculare B (2), the Aconitum naviculare C (3) that extract five plants of tumor cell people's morning
Young grain leukaemia (HL-60), human liver cancer cell (SMMC-7721), human lung carcinoma cell (A549), human breast carcinoma (MCF-7),
Human colon cancer cell (SW480) carries out cytotoxic activity screening and finds that Aconitum naviculare B (2) is with preferable anti-tumor activity (table
3) in, can be used for the medicine for treat and prevent cancer.
Table 3, Aconitum naviculare A (1), Aconitum naviculare B (2), Aconitum naviculare C (3) cytotoxic activity the selection result
Diterpene alkaloid compound in Aconitum naviculare prepared by the Jing present invention, the compound 1 is Aconitum naviculare element A (1)；Change
Compound 2 is Aconitum naviculare element B (2)；Compound 3 is Aconitum naviculare element C (3), and compound 2 has preferable anti-tumor activity.Can
For preparing antitumor drug.
Claims (7)
1. diterpene alkaloid compound in a kind of Aconitum naviculare, it is characterised in that the compound 1 is Aconitum naviculare element A (1)；Chemical combination
Thing 2 is Aconitum naviculare element B (2)；Compound 3 is Aconitum naviculare element C (3)；Aconitum naviculare element A (1) is double diterpene alkaloids, its point
Minor is C40H50N2O4；Aconitum naviculare element B (2) is double diterpene alkaloids, and its molecular formula is C47H56N2O5；Aconitum naviculare element C (3)
Molecular formula is C29H37NO3。
2. diterpene alkaloid compound in a kind of Aconitum naviculare as claimed in claim 1, it is characterised in that the Aconitum naviculare
Plain A (1) structural formula is
。
3. diterpene alkaloid compound in a kind of Aconitum naviculare described in claim 1, it is characterised in that the Aconitum naviculare element
B (2) structural formula is
。
4. diterpene alkaloid compound in a kind of Aconitum naviculare described in claim 1, it is characterised in that the Aconitum naviculare element
C (3) structural formula is
。
5. in a kind of Aconitum naviculare as claimed in claim 1 diterpene alkaloid compound preparation method, it is characterised in that tool
Gymnastics follow these steps to carry out：
A, Aconitum naviculare aerial partss are taken, after drying and crushing, using industrial methanol merceration 3 times, industrial acetone merceration 1 time, merceration
Time 72h, concentrating under reduced pressure recycling design obtains extractum；
B, adopt hydrochloric acid adjust extractum PH for 2-3, successively using petroleum ether, ethyl acetate, n-butanol extraction, regulation sour water PH be
10, then use ethyl acetate, n-butanol extraction, concentrating under reduced pressure to reclaim the total alkaloidss for obtaining n-butanol portion again；
C, by the total alkaloidss Jing gel Sephadex LH-20 chromatographs in step B, anti-phase RP-18 pillar layer separations, using thin
Layer chromatography is analyzed, that is, obtain diterpene alkaloid compound Aconitum naviculare element A (1)；Aconitum naviculare element B (2)；Aconitum naviculare
Plain C (3).
6. diterpene alkaloid compound in a kind of Aconitum naviculare as claimed in claim 1, it is characterised in that the Aconitum naviculare
Application of the plain B (2) in the medicine for the treatment of or prophylaxis of cancer disease is prepared.
7. diterpene alkaloid compound in a kind of Aconitum naviculare as claimed in claim 6, the cancer be leukemia, hepatocarcinoma,
Pulmonary carcinoma, breast carcinoma, colon cancer.
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| CN201611230639.4A CN106674231A (en) | 2016-12-27 | 2016-12-27 | Diterpenoid alkaloid compounds in Aconitum naviculare as well as preparation method and application of diterpenoid alkaloid compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112500422A (en) * | 2020-11-19 | 2021-03-16 | 江西中医药大学 | Novel benzo-cycloheptatrienone alkaloid separated from radix Aconiti lateralis Preparata and its neuroprotective application |
| CN112694441A (en) * | 2019-10-22 | 2021-04-23 | 中国医学科学院药物研究所 | C20Diterpenoid alkaloids, their preparation and use for treating pain related diseases |
Citations (3)
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| CN102140079A (en) * | 2011-02-18 | 2011-08-03 | 四川大学 | Novel yunaconitine and preparation method thereof as well as pharmaceutical composition based on compound as active ingredient and application of novel yunaconitine |
| CN103749456A (en) * | 2013-12-25 | 2014-04-30 | 贵州大学 | Application of diterpene alkaloid compound and preparation to prevention of crop virus diseases |
| CN105837506A (en) * | 2016-04-29 | 2016-08-10 | 中国科学院新疆理化技术研究所 | Preparation method and application of diterpene alkaloid in soongaricum var .pubescens |
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2016
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Patent Citations (3)
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| CN102140079A (en) * | 2011-02-18 | 2011-08-03 | 四川大学 | Novel yunaconitine and preparation method thereof as well as pharmaceutical composition based on compound as active ingredient and application of novel yunaconitine |
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| S. WILLIAM PELLETIER: ""Research in the chemistry of diterpenoid alkaloids"", 《PURE & APPL.CHEM》 * |
| ZHONG-TANG ZHANG ET AL.: ""Bis-Diterpenoid Alkaloids from Aconitum tanguticum var.trichocarpum"", 《HELVETICA CHIMICA ACTA》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112694441A (en) * | 2019-10-22 | 2021-04-23 | 中国医学科学院药物研究所 | C20Diterpenoid alkaloids, their preparation and use for treating pain related diseases |
| CN112694441B (en) * | 2019-10-22 | 2023-03-21 | 中国医学科学院药物研究所 | C 20 Diterpenoid alkaloids, their preparation and use for treating pain related diseases |
| CN112500422A (en) * | 2020-11-19 | 2021-03-16 | 江西中医药大学 | Novel benzo-cycloheptatrienone alkaloid separated from radix Aconiti lateralis Preparata and its neuroprotective application |
| CN112500422B (en) * | 2020-11-19 | 2021-10-26 | 江西中医药大学 | Novel benzo-cycloheptatrienone alkaloid separated from radix Aconiti lateralis Preparata and its neuroprotective application |
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