CN115611839B - Preparation and application of sesquiterpene lactone compounds in elephantopus scaber - Google Patents
Preparation and application of sesquiterpene lactone compounds in elephantopus scaber Download PDFInfo
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- 229930009674 sesquiterpene lactone Natural products 0.000 title claims abstract description 21
- 244000110343 Elephantopus scaber Species 0.000 title claims abstract description 18
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 title claims abstract description 17
- -1 sesquiterpene lactone compounds Chemical class 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 201000007270 liver cancer Diseases 0.000 claims abstract description 19
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 11
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 claims abstract description 6
- 241000208838 Asteraceae Species 0.000 claims abstract description 5
- 238000004458 analytical method Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 241001317575 Elephantopus Species 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 claims description 3
- 241000196324 Embryophyta Species 0.000 claims description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
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- 238000004007 reversed phase HPLC Methods 0.000 claims description 3
- 239000003560 cancer drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 241001317582 Elephantopus mollis Species 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 21
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- 239000013078 crystal Substances 0.000 description 15
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 11
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- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 10
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- 210000004027 cell Anatomy 0.000 description 6
- 238000001211 electron capture detection Methods 0.000 description 5
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- 229960003787 sorafenib Drugs 0.000 description 1
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- 238000001356 surgical procedure Methods 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C67/00—Preparation of carboxylic acid esters
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- C07C2602/14—All rings being cycloaliphatic
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Abstract
The preparation and application of sesquiterpene lactone compounds in elephantopus scaber belongs to the technical field of medicines, and relates to 10 novel sesquiterpene lactone compounds extracted and separated from elephantopus scaber (Elephantopus tomentosus L.) of elephantfoot of Compositae, wherein 1-7 are germacrane-type sesquiterpene lactones, and 8-10 are eucalyptol-type sesquiterpene lactones. The invention also relates to novel compounds and novel medical application of the novel compounds in preparing medicines for resisting liver cancer. The preparation method is simple and easy to implement, and has better reproducibility and higher purity. The obtained compound has good anti-liver cancer activity.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for preparing novel sesquiterpene lactone compounds from a plant elephantopus scaber and application of the compounds in resisting liver cancer.
Background
Primary liver cancer (abbreviated as "liver cancer") is the third largest malignant tumor in the world, and more than 80 tens of thousands of patients are newly increased each year. Because the occurrence and development mechanisms of liver cancer are very complex, cancer cells proliferate rapidly and have a complex molecular stress network for resisting drug intervention, and most liver cancer patients miss the opportunity of surgical treatment. The traditional Chinese medicine has a long history in China for treating liver cancer, and the traditional Chinese medicine and the active ingredients thereof can play a role in treating liver cancer through participating in various mechanisms, so that the novel medicine for treating liver cancer is developed from the traditional Chinese medicine, and the traditional Chinese medicine has a wide application prospect.
The elephantopus scaber (Elephantopus tomentosus L.) is a plant of the genus elephantopus of the family Compositae, and is widely distributed in coastal areas in south China, generally in hillside fields, roadsides and bushes, and has very rich medicinal resources. Herba Hedyotidis Diffusae is commonly used for treating hepatitis, abdominal pain, tonsillitis, and sore. Modern pharmacological studies show that sesquiterpene lactone components contained in elephantopus are the pharmacodynamic substance basis for exerting anti-tumor effect.
Disclosure of Invention
The invention aims to provide 10 sesquiterpene lactone compounds separated from a elephantopus scaber [ Elephantopus tomentosus L ] of the genus elephantfoot of the family Compositae, and the structures are shown as follows:
the preparation technical scheme of the sesquiterpene lactone compound comprises the following steps:
extracting dried whole herb of elephantopus scaber with 70-80% industrial ethanol, mixing the extractive solutions, concentrating to obtain extract, extracting the extract with ethyl acetate, subjecting the obtained components to silica gel column chromatography, performing isocratic gradient elution with dichloromethane-methanol system 100:0-0:100, and collecting 5 fractions A-E;
performing gradient elution on the component B through HP20 column chromatography by using an ethanol-water system 0:100-100:0 to obtain four components B1, B2, B3 and B4, and performing gradient elution on the component B2 by using ODS column chromatography by using an ethanol-water system 10:90-90:10 to obtain five components a-e;
subjecting the component b to silica gel column chromatography with petroleum ether-ethyl acetate system 100:1-10:1 to obtain five sub-components b1-b5 on the basis of TLC analysis;
separating b2 and b3 on preparative reverse phase high performance liquid chromatography using a mobile phase of methanol-water (60:40, v/v) gives compounds 1-10.
The preparation method of the sesquiterpene lactone compound comprises the following steps:
the extraction is reflux extraction for 2-3 times, each for 2-3 hours.
The elephantopus scaber is a plant of the genus elephantfoot of the family Compositae [ Elephantopus tomentosus L ].
The results of the system structure identification of the obtained compound are as follows:
the structural identification of compounds 1-10 was carried out by high resolution mass spectrometry, one-dimensional NMR, two-dimensional NMR, ECD calculation and X single crystal diffraction methods, and the correlation maps are shown in FIGS. 1-12.
Tomentosusol A (1) is a white block crystal.(c 0.11,MeOH)，HRESIMS m/z 383.1475[M+Na] + (calcd for C 20 H 24 O 6 Na, 383.1465), molecular formula C 20 H 24 O 6 By analysis of tomtotosusol A 1 H NMR、 13 C NMR, HMQC, HMBC and X-ray single crystal diffraction, the structure of tomotosusol A is determined, and the compound is 5R,6S,7R,8S in absolute configuration.
Tomentosusol B (2) white setting powder.(c 0.28,MeOH)，HRESIMS m/z 415.1738[M+Na] + (calcd for C 21 H 28 O 7 Na, 415.1733), molecular formula C 21 H 28 O 7 By analysis of tomtotosusol B 1 H NMR、 13 C NMR, HMQC, HMBC and ECD calculation, the structure of tomotosusol B is determined as a new compound, absolute structureThe patterns are 5R,6S,7R,8S and 11R.
Tomentosusol C (3) white setting powder.(c 0.16,MeOH)，HRESIMS m/z 401.1590[M+Na] + (calcd for C 20 H 26 O 7 Na, 401.1591), molecular formula C 20 H 26 O 7 By analysis of tomtosol C 1 H NMR、 13 C NMR, HMQC, HMBC and ECD calculation, the structure of tomotosusol C is determined, and the compound is a new compound, and the absolute configuration is 5R,6S,7R,8S and 11R.
Tomentosusol D (4) white bulk crystals.(c 0.12,MeOH)，HRESIMS m/z 385.1620[M+Na] + (calcd for C 20 H 26 O 6 Na, 385.1622), molecular formula C 20 H 26 O 6 By analysis of tomtosol D 1 H NMR、 13 C NMR, HMQC, HMBC and X-ray single crystal diffraction, the structure of tomotosusol D is determined, and the compound is 5R,6S,7R,8S,11S in absolute configuration.
Tomentosusol E (5) white setting powder.(c 0.14,MeOH)，HRESIMS m/z 419.1678[M+Na] + (calcd for C 20 H 28 O 8 Na, 419.1682), molecular formula C 20 H 28 O 8 By analysis of tomtosol E 1 H NMR、 13 C NMR, HMQC, HMBC and ECD calculation, the structure of tomotosusol E is determined, and the compound is a new compound, and the absolute configuration is 4S,5S,6S,7R,8S,10R.
Tomentosusol F (6) white bulk crystals.(c 0.35,MeOH)，HRESIMS m/z 369.1307[M+Na] + (calcd for C 19 H 22 O 6 Na, 369.1309), molecular formula C 19 H 22 O 6 By analysis of tomtosol F 1 H NMR、 13 C NMR, HMQC, HMBC and X-ray single crystal diffraction, the structure of tomotosusol F is determined, and the compound is 5R,6S,7R and 8S in absolute configuration.
Tomentosusol G (7) white bulk crystals.(c 0.39,MeOH)，HRESIMS m/z 383.1474[M+Na] + (calcd for C 20 H 24 O 6 Na, 383.1465), molecular formula C 20 H 24 O 6 By analysis of tomtosol G 1 H NMR、 13 C NMR, HMQC, HMBC and X-ray single crystal diffraction, the structure of tomotosusol G is determined, and the compound is 5R,6S,7R and 8S in absolute configuration.
Tomentosusol H (8) white bulk crystals.(c 0.32,MeOH)，HRESIMS m/z 401.1588[M+Na] + (calcd for C 20 H 26 O 7 Na, 401.1591), molecular formula C 20 H 26 O 7 By analysis of tomtotosusol H 1 H NMR、 13 C NMR, HMQC, HMBC and X-ray single crystal diffraction, the structure of tomotosusol H is determined, and the compound is 5S,6S,7S,8S and 10S in absolute configuration.
Tomentosusol I (9) white bulk crystals.(c 0.27,MeOH)，HRESIMS m/z 415.1720[M+Na] + (calcd for C 21 H 28 O 7 Na, 415.1727), molecular formula C 21 H 28 O 7 By analysis of tomtosol I 1 H NMR、 13 C NMR, HMQC, HMBC and X-ray single crystal diffraction, the junction of tomotosusol I was determinedThe structure is a new compound, and the absolute configuration is 5S,6S,7S,8S and 10S.
Tomentosusol J (10) white shaped powder.(c 0.34,MeOH)，HRESIMS m/z 367.1156[M+Na] + (calcd for C 19 H 20 O 6 Na, 367.1152), molecular formula C 19 H 20 O 6 By analysis of tomtotosuol J 1 H NMR、 13 C NMR, HMQC, HMBC and ECD calculation, the structure of tomotosusol J is determined, and the structure is a novel compound, and the absolute configuration is 5R,6S,7R and 8S.
The anti-liver cancer activity of the 10 novel compounds is examined, wherein the compounds 1,5-8 and 10 all show good anti-liver cancer activity, so that the novel sesquiterpene lactone has the prospect of further developing medicaments for preventing and treating liver cancer.
A pharmaceutical composition comprising the novel sesquiterpene lactone compound or a pharmaceutically acceptable salt thereof prepared from elephantopus scaber and a pharmaceutically acceptable carrier or excipient.
An extract of herba Elephantopi scaberis contains the above novel sesquiterpene lactone compound prepared from herba Elephantopi scaberis.
The invention also provides application of the novel sesquiterpene lactone compound prepared from the elephantopus scaber or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound in preparation of anti-liver cancer drugs.
The invention has the advantages that the compounds are novel compounds, have novel structures, are optical pure compounds with determined three-dimensional configuration, have strong anti-liver cancer activity and have further development value.
Drawings
HRESIMS of Compound 1 of FIG. 1, 1 H、 13 C-NMR and HMBC spectra;
HRESIMS of Compound 2, 1 H、 13 C-NMR and HMBC spectra;
FIG. 3 HRESIMS of Compound 3, 1 H、 13 C-NMR and HMBC spectra;
HRESIMS of Compound 4, 1 H、 13 C-NMR and HMBC spectra;
HRESIMS of Compound 5, 1 H、 13 C-NMR and HMBC spectra;
FIG. 6 HRESIMS of Compound 6, 1 H、 13 C-NMR and HMBC spectra;
HRESIMS of Compound 7, 1 H、 13 C-NMR and HMBC spectra;
HRESIMS of Compound 8, 1 H、 13 C-NMR and HMBC spectra;
FIG. 9 HRESIMS of Compound 9, 1 H、 13 C-NMR and HMBC spectra;
HRESIMS of Compound 10, 1 H、 13 C-NMR and HMBC spectra;
FIG. 11 graphs of single crystal data for X of compounds 1, 4, 6, 7, 8, 9;
FIG. 12 HMBC and of Compounds 1-10 1 H- 1 H COSY-related.
Detailed Description
The examples set forth below are presented to aid one skilled in the art in a better understanding of the present invention and are not intended to limit the invention in any way.
Example 1: preparation of Compounds 1-10.
Reflux-extracting dried whole herb of elephantopus scaber with 70% industrial ethanol for 2 times and 2 hours each time, mixing the extracting solutions, concentrating to obtain extract, extracting the extract with ethyl acetate, subjecting the obtained components to silica gel column chromatography, performing isocratic gradient elution with dichloromethane-methanol system 100:0-0:100, and collecting 5 fractions A-E.
And (3) performing gradient elution on the fraction B through HP20 column chromatography by using an ethanol-water system of 0:100-100:0 to obtain four components B1, B2, B3 and B4. And (3) performing gradient elution on the component B2 by using an ODS column chromatography in an ethanol-water system of 10:90-90:10 to obtain five components a-f.
The component b obtained was subjected to silica gel column chromatography with a petroleum ether-ethyl acetate system of 100:1-10:1 to give five subfractions b1-b5 on the basis of TLC analysis.
Separating b2 and b3 on preparative reverse phase high performance liquid chromatography using a mobile phase of methanol-water (60:40, v/v) gives compounds 1-10.
Table 1 Nuclear magnetic data for Compounds 1-5 (δin ppm, J in Hz, CDCl) 3 )
a in DMSO-d 6 .
Table 2 Nuclear magnetic data for Compounds 6-10 (δin ppm, J in Hz, CDCl) 3 )
a in DMSO-d 6 .
Example 2: investigation of anti-liver cancer Activity of Compounds 1-10.
Human hepatoma cells (HepG 2, hep 3B) in logarithmic growth phase were taken and digested with pancreatin to form a cell suspension. The cells were seeded at a density of 5000 cells per well, 100. Mu.L/well on 96 well plates. The inoculated 96-well plate is cultured at 37 ℃ and 5% CO 2 Culturing in an incubator under the condition. After 12 hours, 100. Mu.L of test compound at different concentrations was added to each well and incubated at 37℃with 5% CO 2 The reaction was carried out in an incubator under the conditions for 48 hours. The control group was added with the same volume of blank medium, 3 duplicate wells were set per group, and no cell wells were used as background. After 48 hours, 20. Mu.L/well tetrazolium blue (MTT) was added, and the culture was continued under the same conditions for 4 hours, and the culture supernatant in 96 wells was carefully aspirated off, 150. Mu.L DMSO was added to each well, and the mixture was properly shaken at room temperature to dissolve the crystals formed.
TABLE 3 inhibition of two liver cancer cells by Compounds 1-10
a Sorafenib was used as a positive control.
Claims (7)
1. A sesquiterpene lactone compound in elephantopus scaber, which is characterized by being any one of the following compounds;
2. a pharmaceutical composition comprising a sesquiterpene lactone compound of elephantopus scaber of claim 1 and a pharmaceutically acceptable carrier.
3. A method for preparing sesquiterpene lactones in elephantopus scaber as claimed in claim 1, comprising the steps of:
extracting dried whole herb of elephantopus scaber with 70-80% industrial ethanol, mixing the extractive solutions, concentrating to obtain extract, extracting the extract with ethyl acetate, subjecting the obtained components to silica gel column chromatography, performing isocratic gradient elution with dichloromethane-methanol system 100:0-0:100, and collecting 5 fractions A-E;
performing gradient elution on the component B through HP20 column chromatography by using an ethanol-water system 0:100-100:0 to obtain four components B1, B2, B3 and B4, and performing gradient elution on the component B2 by using ODS column chromatography by using an ethanol-water system 10:90-90:10 to obtain five components a-e;
subjecting the component b to silica gel column chromatography with petroleum ether-ethyl acetate system 100:1-10:1 to obtain five sub-components b1-b5 on the basis of TLC analysis;
the mobile phase of methanol-water 60:40 was used to separate b2 and b3 on preparative reverse phase high performance liquid chromatography to give compounds 5-8, 10.
4. The method for preparing sesquiterpene lactones in elephantopus scaber according to claim 3, wherein the extraction is reflux extraction for 2-3 times each for 2-3 hours.
5. The method for producing a sesquiterpene lactone compound in elephantopus scaber as claimed in claim 3, wherein the elephantfoot scaber is a plant of the genus elephantfoot of the family Compositae [ Elephantopus tomentosus L ].
6. An application of sesquiterpene lactone compounds in herba elephantopi Alternifolia in preparing anti-liver cancer drugs according to claim 1.
7. Use of the pharmaceutical composition of claim 2 in the preparation of an anti-liver cancer medicament.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211135150.4A CN115611839B (en) | 2022-09-19 | 2022-09-19 | Preparation and application of sesquiterpene lactone compounds in elephantopus scaber |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211135150.4A CN115611839B (en) | 2022-09-19 | 2022-09-19 | Preparation and application of sesquiterpene lactone compounds in elephantopus scaber |
Publications (2)
| Publication Number | Publication Date |
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