CN116589474B - Artemisia reesei olefine lactone A-F and its medicine composition and its prepn and application - Google Patents
Artemisia reesei olefine lactone A-F and its medicine composition and its prepn and application Download PDFInfo
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
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- FYJROXRIVQPKRY-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 FYJROXRIVQPKRY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides 6 novel compounds shown in a structural formula, kui arte lactone A-F (artemiprincepsolides A-F, 1-6), a pharmaceutical composition thereof, a preparation method and application thereof, and belongs to the technical field of medicines. The compound has remarkable cytotoxic activity on human liver cancer cell strains HepG2, huh7 and SK-Hep-1, can form a pharmaceutical composition with a pharmaceutically acceptable carrier, and can be used for preparing anti-liver cancer drugs.
Description
Technical field:
The invention belongs to the technical field of medicines. In particular to kui haoenolide A-F (artemiprincepsolides A-F, 1-6), a preparation method and application thereof, a pharmaceutical composition and application thereof.
The background technology is as follows:
Because the signal transmission path for regulating and controlling liver cancer is extremely complex, a single-target targeting preparation is developed and marketed, and currently, products on the market of liver cancer targeting therapeutic drugs are mainly multi-target small molecule targeting preparations and immune checkpoint inhibitors. Liver cancer can be classified into hepatocellular carcinoma (HCC), cholangiocarcinoma, and mixed hepatocellular carcinoma and cholangiocarcinoma according to its pathological types, wherein HCC is the most common pathological type of liver cancer, accounting for 75% -85% of all primary liver cancers worldwide.
Currently, there are 7 clinical drugs for treating liver cancer patients: sorafenib (sorafenib), regorafenib (regorafenib), lenvatinib (lenvatinib), cabitinib (cabozantinib), nivolumab (nivolumab), pam mab (pembrolizumab) and Lei Molu mab (ramucirumab), but may develop resistance and some toxic side effects. Although autonomous research and development of medicines in China also rapidly develop, such as apatinib mesylate, carilizumab, tirelizumab and the like, enrich liver cancer treatment schemes, some problems still exist. Liver cancer is easy to relapse and transfer, has poor surgical treatment effect, lacks effective treatment drugs, and clinically has urgent need of developing novel drugs with high efficiency and low toxicity. Therefore, the research and development of liver cancer specific target drugs have important significance.
Artemisia (Artemisia L.) is a large genus in Asteraceae (Asteraceae) spring Huang Juzu (ANTHEMIDEAE), which is a perennial herb, with about 380 species worldwide, 186 species in China, 44 varieties, 82 unique species, and distributed across the country. A great deal of researches show that the plant has wide modern pharmacological activities, such as antimalarial, anti-inflammatory, anticancer, antifungal infection, antiviral and other functions, and such as artemisia annua, artemisia anomala, artemisia capillaris, artemisia argyi and the like are common traditional Chinese medicines and are taken as Chinese pharmacopoeia collection varieties. The representative sesquiterpene molecular artemisinin from the Artemisia annua of the genus plant creates a new generation of antimalarial drugs, is an excellent example of successful research and development from the treasury of traditional Chinese drugs, and has good antimalarial activity, and also has certain anti-tumor, antifungal and immunoregulatory effects. The plant is more and more focused by students at home and abroad because of its wide medicinal value, novel and diverse secondary metabolites and diverse biological activities.
The Artemisia princeps (ARTEMISIA PRINCEPS) is a perennial herb plant of Artemisia of Compositae, and is also called Artemisia rupestris, artemisia annua, distributed in northern, eastern and western provinces of China, and is mainly used at low altitude or on roadside, hillside, shrub, forest margin and ditch side of Zhonghai region. Researches show that the artemisia kui extract can be used for treating various diseases such as inflammation, diarrhea, circulatory disturbance and the like, and leaf oil has the effects of relieving cough, relieving asthma, diminishing inflammation and eliminating phlegm and is clinically used for treating the diseases such as chronic bronchitis, emphysema, bronchial asthma and the like.
To date, the prior art has no report on the artesenolide A-F (artemiprincepsolides A-F, 1-6), no report on a pharmaceutical composition taking the artesenolide A-F as an active ingredient, and no report on the application of the pharmaceutical composition in preparing or treating liver cancer drugs.
The invention comprises the following steps:
The invention aims to provide a novel kuhaoenolide A-F (artemiprincepsolides A-F, 1-6) with medicinal value shown in a formula (I), a preparation method and application thereof, a pharmaceutical composition and application thereof, and the compound has obvious cytotoxic activity on liver cancer cell lines and can be used for preparing anti-liver cancer drugs.
In order to achieve the above object of the present invention, the present invention provides the following technical solutions:
the invention provides a series of sesquiterpene dimer compounds, namely, kui artelactone A-F (artemiprincepsolides A-F, 1-6), which has a structure shown in the following structural formula:
The invention provides a preparation method of the compounds 1-6, crushing the dried overground part of artemisia kui, carrying out cold leaching extraction twice by using 90% ethanol with the amount of 10 times, combining ethanol extract, concentrating under reduced pressure until no ethanol smell exists, obtaining ethanol extract, dispersing the extract in water, extracting for 3 times by using ethyl acetate to obtain an ethyl acetate extract part, carrying out silica gel column chromatography on the ethyl acetate extract part, and carrying out gradient elution by using acetone-petroleum ether (10:90, 20:80,30:70,40:60, v/v) and acetone to obtain 5 fractions Fr.1-Fr.5; fr.2 is subjected to medium pressure MCI CHP 20P column chromatography, and water-methanol (50:50, 30:70,10:90, 0:100) gradient elution is carried out to obtain 4 components Fr.2-1-Fr.2-4; fr.2-3 was subjected to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80,30:70,40:60,100:0, v/v) to give 4 fractions Fr.2-3-1-Fr.2-3-4; fr.2-3-3 is subjected to medium pressure RP-C18 column chromatography and is subjected to gradient elution by water-methanol (40:60, 20:80, 0:100) to obtain 3 components Fr.2-3-3-1-Fr.2-3-3-3; fr.2-3-3-1 was purified by Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50) followed by preparative HPLC (water-acetonitrile, 47:53) to give compounds 2 and 3; fr.3 is subjected to medium pressure MCI CHP 20P column chromatography, and water-methanol (50:50, 30:70,10:90, 0:100) gradient elution is carried out to obtain 4 components Fr.3-1-Fr.3-4; fr.3-2 is subjected to medium pressure RP-C18 column chromatography and is subjected to gradient elution by water-methanol (50:50, 40:60, 30:70) to obtain 3 components Fr.3-2-1-Fr.3-2-3; fr.3-2-2 is subjected to medium pressure RP-C18 column chromatography and is subjected to gradient elution by water-acetonitrile (70:30, 65:35,60:40,55:45, 50:50) to obtain 5 components Fr.3-2-2-1-Fr.3-2-2-5; fr.3-2-2-2 was purified by preparative HPLC (water-acetonitrile, 60:40) to give 5 subfractions Fr.3-2-2-2a-3-2-2-2e; fr.3-2-2-2b was purified by semi-preparative HPLC (water-methanol, 42:58) to give compound 1; fr.3-2-2-2c was purified by semi-preparative HPLC (water-acetonitrile, 62:38) to give compound 4; fr.3-2-2-2d was purified by semi-preparative HPLC (water-acetonitrile, 62:38) to give 4 subfractions Fr.3-2-2-2d-1-Fr.3-2-2-2d-4; fr.3-2-2-2d-4 was purified by semi-preparative HPLC (water-acetonitrile, 58:42) to give compounds 5 and 6.
The invention provides application of the compounds 1-6 in preparing anti-liver cancer drugs. The method of the present invention is not particularly limited, and methods well known in the art may be used.
The invention also provides a pharmaceutical composition comprising at least one of the compounds 1-6 of formula (I) and a pharmaceutically acceptable carrier.
And also provides application of the pharmaceutical composition in preparing anti-liver cancer drugs.
When at least one of the compounds 1 to 6 is used for preparing an anti-liver cancer drug, the present invention preferably uses the compounds 1 to 6 directly or in the form of a pharmaceutical composition.
The invention provides a pharmaceutical composition comprising at least one of the above compounds 1-6 and a pharmaceutically acceptable carrier. In the present invention, the pharmaceutically acceptable carrier is preferably a solid, semi-solid or liquid diluent, filler and pharmaceutical preparation auxiliary. The pharmaceutically acceptable carrier is not particularly limited, and pharmaceutically acceptable carriers which are well known in the art, nontoxic and inert to human and animals can be selected.
The preparation method of the pharmaceutical composition is not particularly limited, at least one of the compounds 1-6 is directly mixed with a pharmaceutically acceptable carrier, the mixing process is not particularly limited, and the pharmaceutical composition can be obtained by adopting the processes well known in the art.
The invention provides application of the pharmaceutical composition in preparation of anti-liver cancer drugs. The method of the present invention is not particularly limited, and methods well known in the art may be used.
In the present invention, when the pharmaceutical composition is used for preparing an anti-liver cancer drug, the content of the composition in the drug is preferably 0.1 to 99%; in the pharmaceutical composition, the content of at least one of the compounds 1 to 6 in the pharmaceutical composition is preferably 0.5 to 90%. The pharmaceutical composition of the present invention is preferably used in the form of a unit weight dose. In the present invention, the prepared medicine may be preferably administered in both injection (intravenous injection, intramuscular injection) and oral administration.
Compared with the prior art, the invention has the following advantages:
1. the invention provides a series of novel sesquiterpene dimer compounds, namely, kuhaoenolactone A-F (artemiprincepsolides A-F, 1-6).
2. The invention provides a novel method for preparing novel compounds 1-6, which has the advantages of easily available raw materials, simple process and easy operation.
3. The invention provides a pharmaceutical composition with novel compounds 1-6 as active ingredients, and provides a novel drug with better medicinal effect for a novel anti-liver cancer drug.
4. The compound 1-6 has stronger cytotoxic activity on three liver cancer cells (HepG 2, SK-HEP-1 and Huh 7), and has stronger cytotoxic activity on the HepG2 cells, the IC 50 value is 9.9 mu M, and is better than the positive medicine sorafenib; compounds 2 and 3 showed a certain cytotoxic activity with IC 50 values of 26.4 and 24.9. Mu.M, respectively. For Huh7 cells, the compound 1 has stronger cytotoxic activity, and the IC 50 value is 9.2 mu M, which is better than that of a positive medicine sorafenib; compounds 3 and 5 also have a cytotoxic activity with IC 50 values of 20.1 and 24.6. Mu.M, respectively. For SK-Hep-1 cells, the compound 1 has stronger cytotoxic activity, and the IC 50 values of the compound are respectively 5.0 mu M, which is superior to the positive medicine sorafenib; compounds 2-4 also have a cytotoxic activity with IC 50 values of 18.8,19.7 and 28.1. Mu.M, respectively. Interestingly, compound 1 had strong cytotoxic activity against all three liver cancer cells, with IC 50 values of 9.9,9.2 and 5.0 μm, respectively.
5. Sesquiterpene dimer artetretene A-F (artemiprincepsolides A-F, 1-6) separated from Artemisia kui can be used as medicine for treating liver cancer related diseases.
Description of the drawings:
FIG. 1 is a schematic representation of the structural formula of compounds 1-6 of the present invention.
The specific embodiment is as follows:
In order to better understand the essence of the present invention, the sesquiterpene dimers of the present invention, the kuhaoenenolide A-F (artemiprincepsolides A-F, 1-6), and the preparation method, structure identification, pharmacological effects thereof will be further described with reference to the accompanying drawings, but the present invention is not limited by the examples and examples.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1:
Preparation of Compounds 1-6:
Pulverizing the dried aerial parts (49.5 kg) of Artemisia kui, cold-leaching with 90% ethanol of 10 times amount for two times, mixing ethanol extracts, concentrating under reduced pressure until no ethanol smell exists to obtain ethanol extract, dispersing the extract in water, extracting with ethyl acetate for 3 times to obtain ethyl acetate extract, subjecting the ethyl acetate extract to silica gel column chromatography, and gradient eluting with acetone-petroleum ether (10:90, 20:80,30:70,40:60, v/v) and acetone to obtain 5 fractions Fr.1-Fr.5; fr.2 is subjected to medium pressure MCI CHP 20P column chromatography, and water-methanol (50:50, 30:70,10:90, 0:100) gradient elution is carried out to obtain 4 components Fr.2-1-Fr.2-4; fr.2-3 was subjected to silica gel column chromatography (ethyl acetate-petroleum ether, 20:80,30:70,40:60,100:0, v/v) to give 4 fractions Fr.2-3-1-Fr.2-3-4; fr.2-3-3 is subjected to medium pressure RP-C18 column chromatography and is subjected to gradient elution by water-methanol (40:60, 20:80, 0:100) to obtain 3 components Fr.2-3-3-1-Fr.2-3-3-3; fr.2-3-3-1 was purified by Sephadex LH-20 gel column chromatography (methanol-chloroform, 50:50) followed by preparative HPLC (water-acetonitrile, 47:53) to give compounds 2 (22 mg) and 3 (25 mg); fr.3 is subjected to medium pressure MCI CHP 20P column chromatography, and water-methanol (50:50, 30:70,10:90, 0:100) gradient elution is carried out to obtain 4 components Fr.3-1-Fr.3-4; fr.3-2 is subjected to medium pressure RP-C18 column chromatography and is subjected to gradient elution by water-methanol (50:50, 40:60, 30:70) to obtain 3 components Fr.3-2-1-Fr.3-2-3; fr.3-2-2 is subjected to medium pressure RP-C18 column chromatography and is subjected to gradient elution by water-acetonitrile (70:30, 65:35,60:40,55:45, 50:50) to obtain 5 components Fr.3-2-2-1-Fr.3-2-2-5; fr.3-2-2-2 was purified by preparative HPLC (water-acetonitrile, 60:40) to give 5 subfractions Fr.3-2-2-2a-3-2-2-2e; fr.3-2-2-2b was purified by semi-preparative HPLC (water-methanol, 42:58) to give compound 1 (5 mg); fr.3-2-2-2c was purified by semi-preparative HPLC (water-acetonitrile, 62:38) to give compound 4 (5 mg); fr.3-2-2-2d was purified by semi-preparative HPLC (water-acetonitrile, 62:38) to give 4 subfractions Fr.3-2-2-2d-1-Fr.3-2-2-2d-4; fr.3-2-2-2d-4 was purified by semi-preparative HPLC (water-acetonitrile, 58:42) to give compounds 5 (10 mg) and 6 (3 mg).
Structural data for compounds 1-6:
nuclear magnetic resonance spectroscopy was performed using AVANCE III 600,600 (Bruker, Switzerland) or AVANCE III HD 400 (Bruker, bremerhaven, germany) as an internal standard. High resolution mass spectrometry was performed using Shimadzu LC-MS-IT-TOF (Shimadzu, kyoto, japan). Infrared spectroscopy (IR) was determined by KBr tabletting method by means of a NICOLET iS model 10 infrared spectrometer (Thermo FISHER SCIENTIFIC, madison, USA). ECD spectra were measured using a CHIRASCAN-type instrument (Applied Photophysics, surrey, UK). The optical rotation was determined by Autopol VI polarimeter (Rudolph RESEARCH ANALYTICAL, hackettstown, USA). Melting Point use/>The measurement was performed by an X-4B micro-melting point apparatus available from Shanghai precision scientific instruments Co. The thin layer chromatography silica gel plate HSGF254 is a product of Nicotiana tabacum Jiang you silica gel development Co., ltd; column chromatography silica gel (200-300 meshes) is produced by Yi Ling Shang Hai Xiang chemical industry Co., ltd; column chromatography Sephadex LH-20 is available from GE HEALTHCARE Bio-Sciences AB. The high performance liquid chromatograph is manufactured by Shimadzu corporation, the controller model is CBM-20A, the pump model is LC-20AR, the detector model is SPD-M20A, the column temperature box model is AT-350, and the used chromatographic column model is Agilent-Eclipse XDB-C18 (5 μm, 9.4X1250 mm). Chromatographic pure acetonitrile was purchased from merida, and deionized channel water was purified by MINGCHETM-D24 UV Merk Millipore system. The medium pressure liquid phase (Dr Flash-II) is the product of Shanghai Lisui company, mitsubishi corporation of Japan, MCI column, model CHP-20P (75-150 μm). Analytically pure methanol and acetonitrile were purchased from Tianjin metallocene chemical reagent plant. The color reagent was a 10% H 2SO4 -EtOH solution.
Artemisia princeps lactone A (1)
The molecular formula: c 30H38O6
Molecular weight: 494.26
Traits: white amorphous powder
Optical rotation:
HRESIMS (+) m/z Experimental values 495.2675[ M+H ] +, calculated 495.2741[ M+H ] +.
IR(KBr)νmax:3495,1764,1712,1632,1401,1290,1126cm-1。
ECD (methanol) lambda max (. DELTA.. Epsilon.) 203 (+0.11), 219 (+14.58), 244 (-0.41) nm.
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemisia princeps lactone B (2)
The molecular formula: c 32H40O7
Molecular weight: 536.27
Traits: white amorphous powder
Optical rotation: HRESIMS (+) m/z Experimental value 581.2734[ M+HCOO ] –, calculated 581.2756[ M+HCOO ] –.IRνmax:3436,1763,1630,1400,1298,1263,1077cm-1.
ECD (methanol) lambda max (. DELTA.. Epsilon.) 201 (-1.89), 219 (+8.52), 244 (-0.65) nm.
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemisia princeps lactone C (3)
The molecular formula: c 32H40O7
Molecular weight: 536.27
Traits: white amorphous powder
Optical rotation: HRESIMS (-) m/z experimental 581.2715[ M+HCOO ] –, calculated 581.2756[ M+HCOO ] –.IR(KBr)νmax:3436,1765,1631,1457,1386,1265,1155,1058cm-1.
ECD (methanol) lambda max (. DELTA.. Epsilon.) 200 (-4.92), 212 (+7.29), 232 (-4.09) nm.
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemisia princeps lactone D (4)
The molecular formula: c 30H38O7
Molecular weight: 510.26
Traits: white amorphous powder
Optical rotation: HRESIMS (-) m/z, experimental 555.2606[ M+HCOO ] –, calculated 555.2600[ M+HCOO ] –.IRνmax:3447,1766,1714,1643,1379,1356,1153cm-1.
ECD (methanol) lambda max (. DELTA.. Epsilon.) 196 (+11.32), 240 (-0.75), 289 (+0.98) nm.
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemisia princeps lactone E (5)
The molecular formula: c 32H40O8
Molecular weight: 552.27
Traits: white amorphous powder
Optical rotation: HRESIMS (-) m/z experimental 597.2491[ M+HCOO ] –, calculated 597.2494[ M+HCOO ] –.IRνmax:3468,1754,1631,1458,1380,1254,1216,1053cm-1.
ECD (methanol) lambda max (. DELTA.. Epsilon.) 195 (+10.80), 252 (-0.91), 297 (+0.25), 301 (+0.21) nm.
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemisia princeps lactone F (6)
The molecular formula: c 32H40O8
Molecular weight: 552.27
Traits: white amorphous powder
Optical rotation: HRESIMS (-) m/z Experimental values 597.2708[ M+HCOO ] –, calculated 597.2705[ M+HCOO ] –.IR(KBr)νmax:3435,1763,1631,1456,1378,1243,1177,1088cm-1.
ECD (methanol) lambda max (Deltaε) 195 (+10.46), 208 (-8.88), 233 (+0.60), 256 (-0.45) nm.
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
TABLE 1 1 H NMR data for Compounds 1-6 (600 MHz, CDCl 3, δin ppm, J in Hz)
”ol”is used to indicate overlapped signals,for which the coupling constants could not be read.
TABLE 2 13 C NMR data for Compounds 1-6 (150 MHz, CDCl 3, δin ppm, J in Hz)
Example 2:
cytotoxic activity of Compounds 1-6 against three liver cancer cell lines.
1. Materials and methods
1.1 Materials
HepG2 cell lines were given by the Kunming plant institute of China academy of sciences active screening center, and Huh7 and SK-Hep-1 cell lines were purchased from Shanghai Ji Ning Biotechnology Co., ltd; medium (Dulbecco's Modified Eagle Medium, DMEM) was purchased from Thermo FISHER SCIENTIFIC (Suzhou, china); serum (fetal bovine serum, FBS) was purchased from Life Technologies (NY, USA); RPMI-1640 is purchased from ThermoFisher Biochemical Products (Beijing, china).
1.2 Instruments
Flex Station 3 bench-top multifunctional microplate reader (Bio-RAD 680, USA); analytical balances (AG 135, metler Toledo, china); incubator (DHP-9082, shanghai).
1.3 Experimental procedure
1) Taking liver cancer cells growing in log phase, discarding old culture medium, washing twice with PBS, discarding PBS;
2) Digesting the cells with 0.25% trypsin, and rapidly absorbing trypsin when the outline of the cells is deepened and the rounding trend is observed under a microscope;
3) Stopping digestion and resuspending cells with DMEM complete medium containing 10% FBS, taking 10 μl of cell suspension, counting with a cell counter, adjusting cell concentration to 1×10 4/mL with medium, inoculating onto 96-well plates, adding 100 μl of cell suspension per well, incubating in an incubator at 37 ℃ with 5% CO 2 for 24h, and allowing cells to adhere;
4) Sucking the culture medium, adding diluted samples into the plate, adding 100 mu L of the diluted samples into each hole, setting 3 compound holes for each concentration, and continuously incubating in an incubator for 48 hours;
5) Sucking out the culture medium, adding the prepared MTT solution (1 mg/mL), adding 100 mu L of the solution into each hole, and incubating in an incubator for 4 hours;
6) Sucking MTT solution, adding DMSO, adding 100 μl per well, and incubating in incubator for 10min;
7) Absorbance values were measured at 490nm wavelength using a microplate reader by the formula: inhibition ratio = (negative-experimental group)/(negative-blank group) ×100% the cell inhibition ratio was calculated, IC 50 was calculated with statistical software GRAPHPAD PRISM, and the experiment was repeated 3 times.
2. Results
The cytotoxic activity of the compounds 1-6 on three liver cancer cells (HepG 2, huh7 and SK-Hep-1) is shown in Table 3, and the compound 1 has stronger cytotoxic activity on the HepG2 cells, and the IC 50 value is 9.9 mu M, which is better than that of the positive medicine sorafenib; compounds 2 and 3 showed a certain cytotoxic activity with IC 50 values of 26.4 and 24.9. Mu.M, respectively.
For Huh7 cells, the compound 1 has stronger cytotoxic activity, and the IC 50 value is 9.2 mu M, which is better than that of a positive medicine sorafenib; compounds 3 and 5 also have a cytotoxic activity with IC 50 values of 20.1 and 24.6. Mu.M, respectively.
For SK-Hep-1 cells, the compound 1 has stronger cytotoxic activity, and the IC 50 values of the compound are respectively 5.0 mu M, which is superior to the positive medicine sorafenib; compounds 2-4 also have a cytotoxic activity with IC 50 values of 18.8,19.7 and 28.1. Mu.M, respectively. Interestingly, compound 1 had strong cytotoxic activity against all three liver cancer cells, with IC 50 values of 9.9,9.2 and 5.0 μm, respectively.
TABLE 3 results of cytotoxic Activity of Compounds 1-6 against three liver cancer cells
a The numerical value is expressed as IC 50 + -SD
3. Conclusion(s)
Experimental results show that the cytotoxic activity of the compounds 1-6 on three liver cancer cells (HepG 2, SK-HEP-1 and Huh 7) is shown in table 3, and the compound 1 has stronger cytotoxic activity on the HepG2 cells, and the IC 50 value is 9.9 mu M, which is better than that of the positive medicine sorafenib; compounds 2 and 3 showed a certain cytotoxic activity with IC 50 values of 26.4 and 24.9. Mu.M, respectively. For Huh7 cells, the compound 1 has stronger cytotoxic activity, and the IC 50 value is 9.2 mu M, which is better than that of a positive medicine sorafenib; compounds 3 and 5 also have a cytotoxic activity with IC 50 values of 20.1 and 24.6. Mu.M, respectively. For SK-Hep-1 cells, the compound 1 has stronger cytotoxic activity, and the IC 50 values of the compound are respectively 5.0 mu M, which is superior to the positive medicine sorafenib; compounds 2-4 also have a cytotoxic activity with IC 50 values of 18.8,19.7 and 28.1. Mu.M, respectively. Interestingly, compound 1 had strong cytotoxic activity against all three liver cancer cells, with IC 50 values of 9.9,9.2 and 5.0 μm, respectively. The results show that the compounds 1-6 separated from the artemisia kui can be used as medicaments for treating liver cancer related diseases. Formulation examples 1-7:
In the following formulation examples, conventional reagents are selected and formulation preparation is performed according to the conventional methods, and the present examples only embody that at least one of the compounds 1 to 6 of the present invention can be prepared into different formulations, and specific reagents and operations are not particularly limited:
1. dissolving at least one of the compounds 1-6 prepared in the embodiment 1 with DMSO, adding water for injection according to a conventional method, finely filtering, encapsulating and sterilizing to prepare injection, wherein the concentration of the injection is 0.5-5 mg/mL.
2. Dissolving at least one of the compounds 1-6 prepared in example 1 with DMSO, dissolving in sterile injectable water, stirring to dissolve, filtering with sterile suction filter funnel, sterile fine filtering, packaging in ampoule, freeze-drying at low temperature, and sealing under sterile condition to obtain powder for injection.
3. At least one of the compounds 1 to 6 prepared in example 1 is added with excipient according to the mass ratio of the excipient to the excipient of 9:1 to prepare powder.
4. At least one of the compounds 1-6 prepared in example 1 is added with excipient according to the mass ratio of 5:1, and the mixture is granulated and tableted.
5. At least one of the compounds 1-6 prepared in the embodiment 1 is prepared into oral liquid according to a conventional oral liquid preparation method.
6. At least one of the compounds 1-6 prepared in example 1 is added with excipient according to the mass ratio of 5:1, and made into capsule.
7. At least one of the compounds 1-6 prepared in example 1 is added with excipient according to the mass ratio of 5:1 to prepare granules.
From the above examples, the present invention provides a compound of artemisia kui, its preparation method and application, pharmaceutical composition and its application. The kui haoenolide provided by the invention mainly comprises 6 compounds with novel structures, and the compounds have different degrees of cytotoxic activity on liver cancer cells, can be combined with a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition, and can be used for preparing anti-liver cancer drugs.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (6)
1. Compounds 1 to 6 shown in the following structural formula, namely compounds artesenolide A to F,
2. A process for the preparation of compounds 1-6 of formula (la) according to claim 1, characterized in that it comprises the steps of: pulverizing the dried aerial parts of the artemisia kui, carrying out cold leaching extraction twice by using 90% ethanol with the amount of 10 times, combining ethanol extract, concentrating under reduced pressure until no ethanol smell exists, obtaining ethanol extract, dispersing the extract in water, extracting for 3 times by using ethyl acetate, obtaining an ethyl acetate extraction part, carrying out silica gel column chromatography on the ethyl acetate extraction part, and carrying out gradient elution by using acetone-petroleum ether 10:90,20:80,30:70,40:60, v/v and acetone to obtain 5 fractions Fr.1-Fr.5; fr.2 is subjected to medium pressure MCI CHP 20P column chromatography, and is subjected to gradient elution by water-methanol 50:50,30:70,10:90 and 0:100 to obtain 4 components Fr.2-1-Fr.2-4; subjecting Fr.2-3 to silica gel column chromatography, and subjecting ethyl acetate-petroleum ether, 20:80,30:70,40:60,100:0, v/v to obtain 4 components Fr.2-3-1-Fr.2-3-4; fr.2-3-3 is subjected to medium pressure RP-C18 column chromatography, and water-methanol 40:60,20:80 and 0:100 are used for gradient elution to obtain 3 components Fr.2-3-3-1-Fr.2-3-3-3; fr.2-3-3-1 is subjected to Sephadex LH-20 gel column chromatography, methanol-chloroform 50:50 is subjected to preparative HPLC, and water-acetonitrile 47:53 is purified to obtain compounds 2 and 3; fr.3 is subjected to medium pressure MCI CHP 20P column chromatography, and is subjected to gradient elution by water-methanol 50:50,30:70,10:90 and 0:100 to obtain 4 components Fr.3-1-Fr.3-4; subjecting Fr.3-2 to medium pressure RP-C18 column chromatography, and gradient eluting with water-methanol 50:50,40:60,30:70 to obtain 3 components Fr.3-2-1-Fr.3-2-3; subjecting Fr.3-2-2 to medium pressure RP-C18 column chromatography, and gradient eluting with water-acetonitrile 70:30,65:35,60:40,55:45,50:50 to obtain 5 components Fr.3-2-2-1-Fr.3-2-2-5; fr.3-2-2-2 was purified by preparative HPLC, water-acetonitrile 60:40 to give 5 subfractions Fr.3-2-2-2a-3-2-2-2e; fr.3-2-2-2b was purified by semi-preparative HPLC, water-methanol 42:58 to give compound 1; fr.3-2-2-2c was purified by semi-preparative HPLC, water-acetonitrile 62:38 to give compound 4; fr.3-2-2-2d was purified by semi-preparative HPLC, water-acetonitrile 62:38 to give 4 subfractions Fr.3-2-2-2d-1-Fr.3-2-2-2d-4; fr.3-2-2-2d-4 was purified by semi-preparative HPLC, water-acetonitrile 58:42 to give compounds 5 and 6.
3. The use of compounds 1-6 according to claim 1 for the preparation of an anti-hepatoma medicament.
4. A pharmaceutical composition comprising at least one of compounds 1-6 according to claim 1 and a pharmaceutically acceptable carrier.
5. The use of the pharmaceutical composition of claim 4 in the preparation of an anti-liver cancer drug.
6. A process for the preparation of a pharmaceutical composition according to claim 4, comprising the steps of: pulverizing the dried aerial parts of the artemisia kui, carrying out cold leaching extraction twice by using 90% ethanol with the amount of 10 times, combining ethanol extract, concentrating under reduced pressure until no ethanol smell exists, obtaining ethanol extract, dispersing the extract in water, extracting for 3 times by using ethyl acetate, obtaining an ethyl acetate extraction part, carrying out silica gel column chromatography on the ethyl acetate extraction part, and carrying out gradient elution by using acetone-petroleum ether 10:90,20:80,30:70,40:60, v/v and acetone to obtain 5 fractions Fr.1-Fr.5; fr.2 is subjected to medium pressure MCI CHP 20P column chromatography, and is subjected to gradient elution by water-methanol 50:50,30:70,10:90 and 0:100 to obtain 4 components Fr.2-1-Fr.2-4; subjecting Fr.2-3 to silica gel column chromatography, and subjecting ethyl acetate-petroleum ether, 20:80,30:70,40:60,100:0, v/v to obtain 4 components Fr.2-3-1-Fr.2-3-4; fr.2-3-3 is subjected to medium pressure RP-C18 column chromatography, and water-methanol 40:60,20:80 and 0:100 are used for gradient elution to obtain 3 components Fr.2-3-3-1-Fr.2-3-3-3; fr.2-3-3-1 is subjected to Sephadex LH-20 gel column chromatography, methanol-chloroform 50:50 is subjected to preparative HPLC, and water-acetonitrile 47:53 is purified to obtain compounds 2 and 3; fr.3 is subjected to medium pressure MCI CHP 20P column chromatography, and is subjected to gradient elution by water-methanol 50:50,30:70,10:90 and 0:100 to obtain 4 components Fr.3-1-Fr.3-4; subjecting Fr.3-2 to medium pressure RP-C18 column chromatography, and gradient eluting with water-methanol 50:50,40:60,30:70 to obtain 3 components Fr.3-2-1-Fr.3-2-3; subjecting Fr.3-2-2 to medium pressure RP-C18 column chromatography, and gradient eluting with water-acetonitrile 70:30,65:35,60:40,55:45,50:50 to obtain 5 components Fr.3-2-2-1-Fr.3-2-2-5; fr.3-2-2-2 was purified by preparative HPLC, water-acetonitrile 60:40 to give 5 subfractions Fr.3-2-2-2a-3-2-2-2e; fr.3-2-2-2b was purified by semi-preparative HPLC, water-methanol 42:58 to give compound 1; fr.3-2-2-2c was purified by semi-preparative HPLC, water-acetonitrile 62:38 to give compound 4; fr.3-2-2-2d was purified by semi-preparative HPLC, water-acetonitrile 62:38 to give 4 subfractions Fr.3-2-2-2d-1-Fr.3-2-2-2d-4; fr.3-2-2-2d-4 was purified by semi-preparative HPLC, water-acetonitrile 58:42 to give compounds 5 and 6; at least one of the above compounds 1-6 is taken and added with a pharmaceutically acceptable carrier.
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| CN112225746A (en) * | 2020-11-15 | 2021-01-15 | 中国科学院昆明植物研究所 | Artemisia sphaerocephala lactone A-R and pharmaceutical composition and application thereof |
| CN114524825A (en) * | 2022-03-04 | 2022-05-24 | 中国科学院昆明植物研究所 | Artemisia sphaerocephala lactone A-T, pharmaceutical composition thereof, and preparation method and application thereof |
| CN115010720A (en) * | 2022-06-02 | 2022-09-06 | 中国科学院昆明植物研究所 | Sesquiterpene dimer in Zhongdianai, pharmaceutical composition thereof, and preparation method and application thereof |
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| CN114524825A (en) * | 2022-03-04 | 2022-05-24 | 中国科学院昆明植物研究所 | Artemisia sphaerocephala lactone A-T, pharmaceutical composition thereof, and preparation method and application thereof |
| CN115010720A (en) * | 2022-06-02 | 2022-09-06 | 中国科学院昆明植物研究所 | Sesquiterpene dimer in Zhongdianai, pharmaceutical composition thereof, and preparation method and application thereof |
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