CN116874544B - Compound Artemeriosides A-F, pharmaceutical composition thereof and preparation method thereof - Google Patents
Compound Artemeriosides A-F, pharmaceutical composition thereof and preparation method thereof Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 title claims description 62
- 201000007270 liver cancer Diseases 0.000 claims abstract description 25
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 25
- 239000003560 cancer drug Substances 0.000 claims abstract description 11
- 239000003937 drug carrier Substances 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 14
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002024 ethyl acetate extract Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000287 crude extract Substances 0.000 claims description 5
- 239000000499 gel Substances 0.000 claims description 5
- 230000001644 anti-hepatocarcinoma Effects 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims 2
- 238000010298 pulverizing process Methods 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 229930004725 sesquiterpene Natural products 0.000 abstract description 10
- 150000004354 sesquiterpene derivatives Chemical class 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 description 25
- 230000000694 effects Effects 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 235000001405 Artemisia annua Nutrition 0.000 description 12
- 240000000011 Artemisia annua Species 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000004566 IR spectroscopy Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 6
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 6
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 5
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 4
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229960004191 artemisinin Drugs 0.000 description 4
- 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 4
- 229930101531 artemisinin Natural products 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 238000011894 semi-preparative HPLC Methods 0.000 description 4
- 229960003787 sorafenib Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 201000004792 malaria Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012470 diluted sample Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 235000003826 Artemisia Nutrition 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229960000981 artemether Drugs 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- 235000009052 artemisia Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- -1 coumarin, flavonoids Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 238000002212 electronic circular dichroism spectrum Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Substances OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000000238 one-dimensional nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides Artemeriosides A ‒ F (1-6), a pharmaceutical composition thereof, a preparation method and application thereof, and belongs to the technical field of medicines. The 6 sesquiterpene 6' -O-crotonyl beta-glucopyranoside shown in the structural formula (I) has a sesquiterpene-flavonol hybrid, artemeriosides A ‒ F (1-6) has an inhibiting effect 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 6 sesquiterpenes 6' -O-crotonyl beta-glucopyranoside, artemeriosides A-F (1-6), a preparation method and application thereof, and application of a pharmaceutical composition taking the compounds 1-6 as active ingredients in preparing medicines for resisting liver cancer.
The background technology is as follows:
As a gift for humans in nature, medicinal plants play an important role in protecting our health and are generally considered safer and milder in treating various diseases. Artemisia is one of the largest genera of Compositae, distributed in North America, europe, and Asia in the North temperate region. Some of these have been widely used in the treatment of various diseases, including cancer, malaria, hepatitis, cancer, inflammation and infection, possibly due to their diverse chemical compositions and their important medicinal properties. Artemisia annua (ARTEMISIA ANNUA L.), also known as Artemisia annua, is a well-known traditional Chinese medicine, and can be used for treating malaria. Chemical studies have found that sesquiterpenes, diterpenes, phenylpropionic acid, coumarin, flavonoids, volatile oil and the like exist in artemisia annua. Among them, artemisinin having a hydrogen peroxide bridge is the most well known molecule and also its unique molecule. Artemisinin has strong antimalarial activity but its solubility in oil and water is poor, thus limiting its use. Thus, its two chemically synthesized derivatives, artemisinin and artemether, have been developed as clinical therapeutic drugs for malaria and cure millions of patients [10]. Thus, a nobel physiological or medical prize of 2015 was awarded to Tu Youyou professor to bring her and other chinese scientists into an influential research effort to develop artemisinin as a novel antimalarial drug. Recently, the Artemisia annua has liver cancer resisting activity, and the main active ingredient of the Artemisia annua is flavonoid. Continuing to study, we isolated 6 sesquiterpenes 6' -O-crotonyl beta-glucopyranoside, artemeriosides A-F (1-6) from Artemisia annua. No report exists in Artemeriosides A-F (1-6) in the prior art, no report exists in a pharmaceutical composition taking the same as an active ingredient, and no report exists in 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 preparation method, a pharmaceutical composition and application of Artemeriosides A-F (1-6) with medicinal value shown in a formula (I). The invention separates and identifies 6 sesquiterpene 6' -O-crotonyl beta-glucopyranoside from Artemisia annua, artemeriosides A-F (1-6). The compound has an inhibiting effect on human liver cancer cell strains HepG2, huh7 and SK-Hep-1, 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 6 sesquiterpene 6' -O-crotonyl beta-glucopyranoside, artemeriosides A-F (1-6), and the structure is shown as the following formula (I):
The invention further provides a method for preparing the compounds 1-6 shown in the formula I, which comprises the steps of crushing 48kg of dried aerial parts of artemisia annua, extracting twice with 3 times of 90% ethanol, mixing the extracting solutions, concentrating under reduced pressure to obtain crude extract, dispersing the crude extract in water, and extracting with ethyl acetate to obtain 3.1kg of ethyl acetate extract. Subsequently, the ethyl acetate extract fraction was subjected to silica gel column chromatography and eluted with a gradient of acetone-petroleum ether volume ratio of 10:90,20:80, 30:70 and ethyl acetate to give 4 fractions Frs.A-D. The fractions A and B were combined and then subjected to silica gel column chromatography, eluting with MeOH-CHCl 3 in a volume ratio of 1:99,2:98,5:95,10:90,20:80,40:60 and MeOH to give 5 fractions Frs.B-1-B-5. 51.6g Fr.B-2 were subjected to MCI GEL CHP P column chromatography eluting with 50:50, 70:30, 90:10 MeOH-H 2 O and MeOH to give four subfractions Frs.B-2a-B-2d.9.0g of Fr.B-2B was subjected to Rp-C 18 column chromatography eluting with a gradient of MeOH-H 2 O of 50:50, 60:40, 70:30 and 80:20 to give subfractions Frs.B-2B-1-B-2B-5.3g of Fr.B-2B-3 was subjected to silica gel column chromatography eluting with 2:98,5:95 and 10:90 MeOH-CHCl 3 as eluent to give 5 subfractions Frs.B-2B-3a-B-2B-3e.1g Fr.B-2b-3C was purified by Sephadex LH-20 column chromatography eluting with 50:50 MeOH-CHCl 3 followed by semi-preparative HPLC on an Agilent XDB-C 18 column with 65:35 methanol-water to give compounds 4 (14 mg) and 6 (38 mg). 560mg of Fr.B-2b-3d were chromatographed on a silica gel column, treated with 5:95 and 10:90 MeOH-CHCl 3, and purified by semi-preparative HPLC on an Agilent XDB-C 18 column with 40:60 acetonitrile-water to give compound 5 (402 mg). 170mg Fr.B-2b-3e was purified by semi-preparative high performance liquid HPLC on an Agilent XDB-C 18 column with 58:42 acetonitrile-water to give compounds 1 (20 mg), 2 (14 mg) and 3 (8 mg).
The invention provides application of compounds 1-6 shown in formula I in preparing anti-liver cancer drugs, and the application method is not particularly limited, and can be selected from methods well known in the art.
The invention also provides a pharmaceutical composition which comprises at least one of the compounds 1-6 shown in the formula (I) and a pharmaceutically acceptable carrier.
And also provides application of the pharmaceutical composition in preparing anti-liver cancer drugs. And simultaneously provides a preparation method of the pharmaceutical composition: the compounds 1-6 of the present invention are prepared by the above-described method of preparing compounds, and then a pharmaceutically acceptable carrier is added.
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 adjuvant. 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 preparing anti-liver cancer drugs, the application method is not particularly limited, and methods well known in the art can be selected.
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 present invention provides 6 new compounds, sesquiterpene 6' -O-crotonyl beta-glucopyranoside, artemeriosides 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, easy operation and suitability for industrial production.
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 inhibitory activity on three liver cancer cells HepG2, huh7 and SK-Hep-1. Wherein, at a concentration of 200.0. Mu.M, compounds 1 to 3 have an inhibitory effect on HepG2 cells with inhibition ratios of 77.0%, 88.0% and 52.0%, respectively; the compound 1 has a certain inhibition effect on Huh7 cells, and the inhibition rate is 56.8%; compounds 1 and 2 have inhibitory effects on SK-Hep-1 cells at inhibition rates of 86.8% and 83.9%, respectively. The results show that the compounds 1-6 separated from the artemisia annua can be used as medicaments 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;
FIG. 2 shows anti-liver cancer activity of the compounds 1-6 of the present invention on three liver cancer cells HepG2, huh7 and SK-Hep-1, with sorafenib as a positive control.
2. Results
The anti-hepatoma activity of compounds 1-6 against three hepatoma cells HepG2, huh7 and SK-Hep-1 was evaluated using the MTT method, with sorafenib as a positive control. The results are shown in figure 2 of the drawings,
The specific embodiment is as follows:
For a better understanding of the essence of the present invention, the following test examples and examples of the present invention will be used to further illustrate the preparation method, structural identification, pharmacological effects of the present invention Artemeriosides A-F (1-6), and the preparation method and pharmaceutical composition of the present invention, but the present invention is not limited to these test 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:
The preparation of sesquiterpene 6' -O-crotonyl beta-glucopyranoside, artemeriosides A-F (1-6) of the invention:
48kg of dried aerial parts of artemisia annua are crushed, extracted twice with 3 times of 90% ethanol, the obtained crude extract is dispersed in water after the decompression concentration of the combined extract, and 3.1kg of ethyl acetate extract is obtained by extraction with ethyl acetate. Subsequently, the ethyl acetate extract fraction was subjected to silica gel column chromatography and eluted with a gradient of acetone-petroleum ether volume ratio of 10:90,20:80, 30:70 and ethyl acetate to give 4 fractions Frs.A-D. The fractions A and B were combined and then subjected to silica gel column chromatography, eluting with MeOH-CHCl 3 in a volume ratio of 1:99,2:98,5:95,10:90,20:80,40:60 and MeOH to give 5 fractions Frs.B-1-B-5. 51.6g Fr.B-2 were subjected to MCI GEL CHP P column chromatography eluting with 50:50, 70:30, 90:10 MeOH-H 2 O and MeOH to give four subfractions Frs.B-2a-B-2d.9.0g of Fr.B-2B was subjected to Rp-C 18 column chromatography eluting with a gradient of MeOH-H 2 O of 50:50, 60:40, 70:30 and 80:20 to give subfractions Frs.B-2B-1-B-2B-5.3g of Fr.B-2B-3 was subjected to silica gel column chromatography eluting with 2:98,5:95 and 10:90 MeOH-CHCl 3 as eluent to give 5 subfractions Frs.B-2B-3a-B-2B-3e.1g Fr.B-2b-3C was purified by Sephadex LH-20 column chromatography eluting with 50:50 MeOH-CHCl 3 followed by semi-preparative HPLC on an Agilent XDB-C 18 column with 65:35 methanol-water to give compounds 4 (14 mg) and 6 (38 mg). 560mg of Fr.B-2b-3d were chromatographed on a silica gel column, treated with 5:95 and 10:90 MeOH-CHCl 3, and purified by semi-preparative HPLC on an Agilent XDB-C 18 column with 40:60 acetonitrile-water to give compound 5 (402 mg). 170mg Fr.B-2b-3e was purified by semi-preparative high performance liquid HPLC on an Agilent XDB-C 18 column with 58:42 acetonitrile-water to give compounds 1 (20 mg), 2 (14 mg) and 3 (8 mg).
Structural data for compounds 1-6:
The optical rotation was determined by Autopol VI polarimeter (Rudolph RESEARCH ANALYTICAL, hackettstown, USA); infrared spectroscopy (IR) was performed using KBr tabletting and was performed by a Bio-Rad FTS-135 infrared spectrometer (Hercules, california, USA); the UV spectrum was determined by UV-2401PC type UV spectrometer (Shimadzu, kyoto, japan); ECD spectra were measured by Applied Photophysics round dichro (Agilent, SANTA CLARA, united States); nuclear magnetic resonance spectroscopy (1D and 2D NMR) was performed using a AVANCE III-600 superconducting NMR (Bruker, bremerhaven, germany) with deuterated chloroform as solvent; high resolution mass spectrometry (hresis) was determined using a Shimadzu LCMS-IT-TOF mass spectrometer (Shimadzu, kyoto, japan); 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; sephadex LH-20 (Sephadex LH-20) is available from GE HEALTHCARE Bio-Sciences AB company; 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, the used chromatographic column model is Agilent-Eclipse XDB-C18 (5 μm, 9.4X1250 mm); chromatographic pure acetonitrile was purchased from merida; MCI GEL CHP20P (75-150 μm) was purchased from Mitsubishi Chemical Corporation (Tokyo, japan); the color reagent was a 10% H 2SO4 -EtOH solution.
Artemannuoid A(1)
The molecular formula: c 25H40O8
Molecular weight: 468
Traits: white powder;
HRESIMS m/z:469.2774[M+H]+(calcd.for C25H41O8,469.2796)；
IR(KBr)νmax:3429,1721,1634,1446,1381,1315,1293,1191,1076,1033cm–1；
ECD(c 0.25,MeOH)λmax(Δε):201(+1.37)nm；
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemannuoid B(2)
The molecular formula: c 25H40O8
Molecular weight: 468
Traits: white powder;
HRESIMS m/z:491.2605[M+Na]+(calcd.for C25H40O8Na,491.2615)；
IR(KBr)νmax:3429,1722,1634,1447,1380,1315,1188,1081,1049cm–1；
ECD(c 0.36,MeOH)λmax(Δε):206(-0.78),294(+0.30)nm；
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemannuoid C(3)
The molecular formula: c 25H40O8
Molecular weight: 468
Traits: white powder;
HRESIMS m/z:491.2606[M+Na]+(calcd.for C25H40O8Na,491.2615)；
IR(KBr)νmax:3428,1720,1631,1455,1384,1184,1080,1051cm–1；
ECD(c 0.36,MeOH)λmax(Δε):202(-0.18),244(+0.34)nm；
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemannuoid D(4)
The molecular formula: c 25H40O8
Molecular weight: 468
Traits: white powder;
HRESIMS m/z:491.2627[M+Na]+(calcd.for C25H40O8Na,491.2615)；
IR(KBr)νmax:3434,1719,1632,1448,1382,1191,1080,1032cm–1；
ECD(c 0.30,MeOH)λmax(Δε):210(-1.74),233(+0.42)nm；
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemannuoid E(5)
The molecular formula: c 25H40O8
Molecular weight: 468
Traits: white powder;
HRESIMS m/z:491.2621[M+Na]+(calcd.for C25H40O8Na,491.2615)；
IR(KBr)νmax:3429,1711,1630,1445,1384,1316,1190,1078,1030cm–1；
ECD(c 0.34,MeOH)λmax(Δε):211(+0.77),288(+1.13)nm；
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
Artemannuoid F(6)
The molecular formula: c 25H40O8
Molecular weight: 468
Traits: white powder;
HRESIMS m/z:491.2626[M+Na]+(calcd.for C25H40O8Na,491.2615)；
IR(KBr)νmax:3427,1709,1631,1446,1383,1190,1179,1080,1029cm–1；
ECD(c 0.40,MeOH)λmax(Δε):209(-0.25),233(+0.20),285(-2.18)nm；
1 H NMR and 13 C NMR (DEPT) data are shown in tables 1 and 2.
TABLE 1 13C NMR data(150MHz,δin ppm,CD3 OD) for compositions 1-6.
Example 2:
inhibitory 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 activity screening center, SK-Hep-1 and Huh7 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) The absorbance values were measured at 490nm wavelength using a microplate reader, the cell inhibition was calculated by the formula inhibition = (negative-experimental group)/(negative-blank group) ×100%, IC 50 was calculated by statistical software GRAPHPAD PRISM, and the experiment was repeated 3 times. FIG. 2 is a schematic view of Antihepatoma activity of compounds 1-6in HepG2,Huh7,and SK-Hep-1cells at 200.0and 100.0μM.Sorafenib was used as the positive control.Data were expressed as mean±SD(n＝3).
2. Results
The anti-hepatoma activity of compounds 1-6 against three hepatoma cells HepG2, huh7 and SK-Hep-1 was evaluated using the MTT method, with sorafenib as a positive control. As a result, as shown in FIG. 2, at a concentration of 200.0. Mu.M, compounds 1 to 3 had an inhibitory effect on HepG2 cells at inhibition rates of 77.0%, 88.0% and 52.0%, respectively, whereas compounds 4 to 6 had a weak inhibitory effect on HepG2 cells at inhibition rates of less than 25%. Compound 1 had a certain inhibitory effect on Huh7 cells, with an inhibition rate of 56.8% at a concentration of 200.0 μm, but other compounds had a weaker inhibitory effect on the cells, with an inhibition rate of less than 50%. Meanwhile, the compounds 1 and 2 have inhibition effects on SK-Hep-1 cells, the inhibition rates are 86.8% and 83.9% respectively, but the activity of the compound 3-6 is weaker, and the inhibition rate is lower than 50%. However, compounds 1-6 showed no significant inhibition of HepG2, huh7 and SK-Hep-1 cells when the concentration was reduced to 100.0 μm.
3. Conclusion(s)
The anti-liver cancer activity results of the compounds 1-6 on three liver cancer cells HepG2, huh7 and SK-Hep-1 show that when the concentration is 200.0 mu M, the compounds 1-3 have inhibition effects on the HepG2 cells, the inhibition rates are 77.0%, 88.0% and 52.0%, respectively, and the compounds 4-6 have weaker inhibition effects on the HepG2 cells, and the inhibition rate is lower than 25%. Compound 1 had a certain inhibitory effect on Huh7 cells, with an inhibition rate of 56.8% at a concentration of 200.0 μm, but other compounds had a weaker inhibitory effect on the cells, with an inhibition rate of less than 50%. Meanwhile, the compounds 1 and 2 have inhibition effects on SK-Hep-1 cells, the inhibition rates are 86.8% and 83.9% respectively, but the activity of the compound 3-6 is weaker, and the inhibition rate is lower than 50%. However, compounds 1-6 showed no significant inhibition of HepG2, huh7 and SK-Hep-1 cells when the concentration was reduced to 100.0 μm. The results show that the compounds 1-6 separated from the artemisia annua can be used as medicaments for treating liver cancer related diseases.
Formulation examples
In the following formulation examples, conventional reagents are selected and formulation preparation is performed according to the conventional methods, and this application example only embodies 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 with a small amount of DMSO, adding water for injection conventionally, fine filtering, filling 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 of the invention with a small amount of DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering with a sterile suction filter funnel, performing sterile fine filtration, sub-packaging in ampoule, freeze-drying at low temperature, and sealing in sterile manner to obtain the powder injection.
3. At least one of the compounds 1-6 is added with excipient according to the weight ratio of 9:1 to prepare powder.
4. At least one of the compounds 1-6 is added with excipient according to the weight ratio of 5:1, and the mixture is granulated and tabletted.
5. At least one of the compounds 1-6 is prepared into oral liquid according to the conventional oral liquid preparation method.
6. At least one of the compounds 1-6 is added with excipient according to the weight ratio of 5:1 to the excipient to prepare capsules.
7. At least one of the compounds 1-6 is added with excipient according to the weight ratio of 5:1 to be made into granule.
From the above examples, the present invention provides 6 novel sesquiterpene 6' -O-crotonyl beta-glucopyranoside (compounds 1-6), and preparation methods and applications thereof, pharmaceutical compositions and applications thereof. The 6 sesquiterpene 6' -O-crotonyl beta-glucopyranoside provided by the invention has different degrees of inhibition effects on liver cancer cells, can be combined with a pharmaceutically acceptable carrier 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 1-3 shown in the following structural formula,
2. A process for the preparation of compounds 1-3 of formula (I) according to claim 1, comprising the steps of:
Pulverizing dried aerial parts of herba Artemisiae Annuae, extracting with 3 times of 90% ethanol twice, mixing extractive solutions, concentrating under reduced pressure to obtain crude extract, dispersing in water, extracting with ethyl acetate to obtain ethyl acetate extract, subjecting the ethyl acetate extract to silica gel column chromatography, and gradient eluting with acetone-petroleum ether at volume ratio of 10:90,20:80, 30:70 and ethyl acetate to obtain 4 fractions Frs.A-D; combining the fractions A and B, and then subjecting the combined fractions A and B to silica gel column chromatography, wherein the fractions A and B are subjected to gradient elution by using MeOH-CHCl 3 in a volume ratio of 1:99,2:98,5:95,10:90,20:80,40:60 and MeOH to obtain 5 fractions Frs.B-1 to B-5; fr.B-2 was chromatographed over MCI GEL CHP P column, eluting with 50:50, 70:30, 90:10 MeOH-H 2 O and MeOH to give four subfractions Frs.B-2a through B-2d; subjecting Fr.B-2B to Rp-C 18 column chromatography, eluting with MeOH-H 2 O gradient of 50:50, 60:40, 70:30 and 80:20 to obtain subfractions Frs.B-2B-1 to B-2B-5; subjecting Fr.B-2B-3 to silica gel column chromatography, eluting with MeOH-CHCl 3 of 2:98,5:95 and 10:90 as eluent to obtain 5 subfractions Frs.B-2B-3a to B-2B-3e; fr.B-2b-3e was purified by semi-preparative high performance liquid HPLC on an Agilent XDB-C 18 column with 58:42 acetonitrile-water to give compounds 1, 2 and 3.
3. The use of the compounds 1-3 of the structural formula (I) as defined in claim 1 in the preparation of anti-hepatoma drugs.
4. A pharmaceutical composition comprising at least one of the compounds 1-3 of formula (I) 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. The method of preparing a pharmaceutical composition of claim 4: the preparation method is characterized by comprising the following steps:
Pulverizing dried aerial parts of herba Artemisiae Annuae, extracting with 3 times of 90% ethanol twice, mixing extractive solutions, concentrating under reduced pressure to obtain crude extract, dispersing in water, extracting with ethyl acetate to obtain ethyl acetate extract, subjecting the ethyl acetate extract to silica gel column chromatography, and gradient eluting with acetone-petroleum ether at volume ratio of 10:90,20:80, 30:70 and ethyl acetate to obtain 4 fractions Frs.A-D; combining the fractions A and B, and then subjecting the combined fractions A and B to silica gel column chromatography, wherein the fractions A and B are subjected to gradient elution by using MeOH-CHCl 3 in a volume ratio of 1:99,2:98,5:95,10:90,20:80,40:60 and MeOH to obtain 5 fractions Frs.B-1 to B-5; fr.B-2 was chromatographed over MCI GEL CHP P column, eluting with 50:50, 70:30, 90:10 MeOH-H 2 O and MeOH to give four subfractions Frs.B-2a through B-2d; subjecting Fr.B-2B to Rp-C 18 column chromatography, eluting with MeOH-H 2 O gradient of 50:50, 60:40, 70:30 and 80:20 to obtain subfractions Frs.B-2B-1 to B-2B-5; subjecting Fr.B-2B-3 to silica gel column chromatography, eluting with MeOH-CHCl 3 of 2:98,5:95 and 10:90 as eluent to obtain 5 subfractions Frs.B-2B-3a to B-2B-3e; fr.B-2b-3e was purified by semi-preparative high performance liquid HPLC on an Agilent XDB-C 18 column with 58:42 acetonitrile-water to give compounds 1, 2 and 3; and then taking one or any combination of the compounds 1-3, and adding a pharmaceutically acceptable carrier.
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