CN114075213A - Cephalotaxus fortunei alkali N-oxide derivative and preparation method and application thereof - Google Patents
Cephalotaxus fortunei alkali N-oxide derivative and preparation method and application thereof Download PDFInfo
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- CN114075213A CN114075213A CN202010794022.5A CN202010794022A CN114075213A CN 114075213 A CN114075213 A CN 114075213A CN 202010794022 A CN202010794022 A CN 202010794022A CN 114075213 A CN114075213 A CN 114075213A
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- cephalotaxus
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- 150000001204 N-oxides Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003513 alkali Substances 0.000 title abstract description 11
- 241000931913 Cephalotaxus fortunei Species 0.000 title description 10
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229930013930 alkaloid Natural products 0.000 claims abstract description 12
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 11
- 201000000050 myeloid neoplasm Diseases 0.000 claims abstract description 11
- 150000003797 alkaloid derivatives Chemical class 0.000 claims abstract description 10
- HAVJATCHLFRDHY-UHFFFAOYSA-N Harringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HAVJATCHLFRDHY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 9
- 201000005202 lung cancer Diseases 0.000 claims abstract description 9
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 9
- 208000032839 leukemia Diseases 0.000 claims abstract description 8
- -1 harringtonine N-oxide Chemical class 0.000 claims abstract description 7
- 241000488899 Cephalotaxus Species 0.000 claims description 15
- 241001330438 Cephalotaxus oliveri Species 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000011894 semi-preparative HPLC Methods 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 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 claims description 5
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- YMNCVRSYJBNGLD-KURKYZTESA-N cephalotaxine Chemical compound C([C@@]12C=C([C@H]([C@H]2C2=C3)O)OC)CCN1CCC2=CC1=C3OCO1 YMNCVRSYJBNGLD-KURKYZTESA-N 0.000 abstract description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
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- 229940041181 antineoplastic drug Drugs 0.000 description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- HAVJATCHLFRDHY-JZTSUELASA-N harringtonine Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@](O)(CCC(C)(C)O)CC(=O)OC)[C@@H]4C2=CC2=C1OCO2 HAVJATCHLFRDHY-JZTSUELASA-N 0.000 description 4
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 4
- 235000015110 jellies Nutrition 0.000 description 4
- 239000008274 jelly Substances 0.000 description 4
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- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 125000000815 N-oxide group Chemical group 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 3
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- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
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- UFJORDZSBNSRQT-UHFFFAOYSA-N 3-(4-oxo-2-phenylchromen-3-yl)-2-phenylchromen-4-one Chemical compound O1C2=CC=CC=C2C(=O)C(C=2C(C3=CC=CC=C3OC=2C=2C=CC=CC=2)=O)=C1C1=CC=CC=C1 UFJORDZSBNSRQT-UHFFFAOYSA-N 0.000 description 1
- 201000002045 Ancylostomiasis Diseases 0.000 description 1
- 208000033211 Ankylostomiasis Diseases 0.000 description 1
- 241000489438 Cinchona pubescens Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- 125000001271 cephalosporin group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a harringtonine N-oxide derivative, a preparation method thereof and application thereof in preparing an anti-tumor medicine. The cephalotaxine alkali component (cephalotaxines A-D) in the form of N-oxide is separated from branches and leaves of cephalotaxine plant cephalotaxines in cephalotaxaceae, and in-vitro activity tests prove that the alkaloid component (cephalotaxines A-D) has obvious inhibition activity on the proliferation of cell strains such as human non-small cell lung cancer (A549), human large cell lung cancer (NCI-H460), human promyelocytic acute leukemia (HL60), human plasma cell leukemia (NCI-H929), human myeloma MI (RPMI-8226) and the like, and therefore can be used for preparing medicaments for treating tumor diseases such as lung cancer, leukemia, myeloma and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a cephalotaxus fortunei alkali N-oxide derivative in cephalotaxus oliveri, a preparation method thereof and application thereof in preparing antitumor drugs, in particular to application in preparing drugs for treating tumor diseases such as lung cancer, leukemia or myeloma.
Background
It is known that malignant tumors are seriously threatening the health and life of human beings, and have become one of the leading causes of death worldwide. The current situation of malignant tumor in China is particularly severe, and the malignant tumor is in an increasing trend in recent years. According to the latest data published by the national cancer center, the number of new cases of cancer in China is about 380.4 ten thousands, wherein the incidence and the mortality of lung cancer are in the top (Siegel et al, CACACANCER J Clin 2017,67, 7-30). The existing treatment scheme aiming at malignant tumor diseases still mainly adopts chemotherapy and radiotherapy, and medical practice shows that the treatment measures have large side effects, high recurrence rate, easy generation of drug resistance and unsatisfactory clinical treatment effect. Therefore, the research and development of the anti-tumor drugs with high efficiency and low toxicity is a major subject which actively attacks the medical community and urgently hopes to make a breakthrough. The traditional Chinese medicine is more and more paid attention by medical workers due to the unique medicine property theory and the exact clinical curative effect. Meanwhile, natural products derived from traditional Chinese medicines often have the characteristics of structural complexity and diversity, and are important sources for developing innovative medicines. Therefore, the development of new antitumor drugs from the active ingredients of traditional Chinese medicines has a wide prospect (Newman and Cragg, Jnat Prod 2020,83, 770-.
Cephalotaxus oliveri (Cephalotaxus oliveri Mast.) is a rare or endangered plant of Cephalotaxus genus of Cephalotaxaceae family (Cephalotaxaceae), grows sporadically in primary and secondary evergreen broad-leaved forests with elevation of 300 + 1800 m, and is distributed in Sichuan, Yu, Yue, Gui, Hunan, Huo, Qian, Dian and other provinces of China. The natural quantity of cephalotaxus oliveri is reduced sharply due to the low level of genetic diversity, the limited self-proliferation capacity, the combination of artificial cutting and ecological environment destruction, etc., and the cephalotaxus oliveri is classified as a gradually-critical species by Chinese Plant Red bark Book and is classified as a national secondary protective Plant in 1999 (Fu et al, Chinese Plant Red Data Book: Rare and Endangered Plants, Science Press: Beijing,1992, pp 26). Cephalotaxus genus was once belonging to the taxaceae family, but later on, based on its special characteristics of plant morphology, tissue anatomy, geographical distribution, etc., in particular the uniqueness of its phytochemical composition, the genus was subsequently promoted to an independent family (cephalotaxaceae, cephalotaxus genus 1 genus only) (Aldelkafi et al, Nat Prod Rep 2012,29, 845-. The seed of the cephalotaxus has the functions of removing food retention, moistening lung, expelling parasites and the like, and has the efficacy of treating ascariasis, ancylostomiasis, dyspepsia and other diseases in the traditional application of China. Meanwhile, researches show that the cephalotaxus plants are rich in alkaloid and biflavone components, wherein alkaloids are main active components of the cephalotaxus plants. Alkaloid components were first isolated from Cephalotaxus fortunei and Cephalotaxus japonica plants in the early 60 s 20 th century (Paudler et al, J Org Chem 1963,28, 2194-. Since the unique five-membered fused ring structure and the obvious pharmacological activity of the cephalotaxines attract the attention of researchers in various countries in the world, the research results are endless and deep. A cooperative group of cephalotaxus researches is established in China in the early 70 th 20 th century, resources general investigation and chemical composition research are carried out on cephalotaxus plants distributed in China, and harringtonine and homoharringtonine are developed into anticancer drugs at first, and the cephalotaxus plants are listed as 36 common anticancer drugs in the world and are clinically used for treating Chronic Myelogenous Leukemia (CML) and acute non-lymphocytic leukemia (ANLL) (Mei et al, nese Herb Med 2006, 452-one 458). The FDA in the united states approved homoharringtonine (HHT, synribo) for the treatment of Chronic Myeloid Leukemia (CML) in month 10 2012, for adult patients with chronic or accelerated phase CML who are resistant and/or tolerant to two or more Tyrosine Kinase Inhibitors (TKIs) (Kantarjian et al, Lymph myo Leuk 2013,13, 530-533).
However, the research on the chemical components of the unique plant cephalotaxus oliveri in China is only rarely reported at present. Based on the current state of the prior art, the inventor of the application aims to search a novel antitumor drug lead compound and further explore and expand the clinical application range (not limited to leukemia) of harringtonine components, and researches novel alkaloid components with N-oxide functional groups in cephalotaxus oliveri and antitumor activity of the alkaloid components.
Disclosure of Invention
The invention aims to provide a cephalotaxus fortunei alkali N-oxide derivative in cephalotaxus oliveri, a preparation method thereof and application thereof in preparing anti-tumor medicaments, in particular application in preparing medicaments for treating tumor diseases such as lung cancer, leukemia, myeloma and the like.
The invention extracts and separates the cephalotaxus oliveri alkali N-oxide derivatives from the unique rare or endangered medicinal plant cephalotaxus oliveri in China, and in vitro anti-tumor activity tests show that the alkaloid components have obvious cytotoxic activity on various tested human tumor cell strains and can be used for preparing anti-tumor medicaments or lead compounds of the medicaments.
The cephalotaxine N-oxide derivative (cephalotaxine ester A-D,1-4) is mainly structurally characterized in that a nitrogen atom in a cephalotaxine mother nucleus forms an N-oxide form (nitrogen oxide, N → O), and has the following structural formula, and cephalotaxines A-D are natural cephalotaxine ester-type N-oxide derivatives which are reported for the first time.
The cephalotaxus base N-oxide derivative provided by the invention has any one of the following structural formulas (cephaloverinesA-D, (1) - (4):
the preparation method of the cephalotaxus fortunei alkali N-oxide derivative provided by the invention comprises the following specific steps:
pulverizing branch and leaf of Cephalotaxus oliveri, extracting with 95% ethanol at room temperature, concentrating the extractive solution under reduced pressure, suspending in appropriate amount of 3% tartaric acid water solution, extracting with equal volume of ethyl acetate for 3-5 times, dissolving the extracted tartaric acid in waterLiquid passing through Na2CO3Adjusting pH to 10, and extracting with chloroform to obtain chloroform extract (total alkaloid fraction); the chloroform extract is separated by MCI resin, polyamide resin, Sephadex LH-20 gel column chromatography and reversed phase semi-preparative HPLC chromatography to prepare the compound cephaloverines A-D.
The invention provides an application of cephalotaxus fortunei alkali N-oxide derivatives in preparing medicaments for treating tumor diseases.
In the present invention, the tumor disease is any one of lung cancer, leukemia and myeloma.
In the invention, the cephalotaxus fortunei alkali N-oxide derivative is used for preparing a medicament for treating tumor diseases independently or jointly.
In the invention, the cephalotaxus fortunei alkali N-oxide derivative is combined with a pharmaceutically acceptable carrier or excipient to prepare an oral or non-oral dosage form.
The compound can be obtained by separating and purifying branches and leaves of cephalotaxus oliveri; can also be obtained by chemical synthesis methods well known to those skilled in the art.
The cephalotaxoids N-oxide derivatives (cephalosporines A-D) obtained by the invention are subjected to in vitro anti-cytotoxic activity test, and the results show that the compounds have obvious inhibition activity on the proliferation of various tested human tumor cell strains (human non-small cell lung cancer A549, human large cell lung cancer NCI-H460, human promyelocytic acute leukemia HL60, human plasma cell leukemia NCI-H929 and human myeloma cells RPMI-8226), so that the compounds can be used for preparing anti-tumor medicaments, in particular for preparing medicaments for treating tumor diseases such as lung cancer, leukemia and myeloma or used as lead compounds of the medicaments.
The invention has the beneficial effects that:
the target compound (cephaloverinesA-D,1-4) is a natural cephalotaxine ester type component with an N-oxide form for the first time, has a novel chemical structure, and has no literature report so far; and cephaloverinesA-D is an N-oxide derivative with significant anti-tumor activity, which is reported for the first time in Cephalotaxus alkaloids (Cephalotaxus alkaloids). In addition, the present inventors evaluated the antitumor activity of harringtonine-based fractions on human plasma cell leukemia (NCI-H929) cell lines for the first time. The compounds (cephalovertines A-D) show obvious cytotoxic activity to 5 tested human tumor cells, and have considerable application prospect in the treatment of increasingly severe tumor diseases (such as lung cancer).
Detailed Description
The invention is further illustrated below with reference to examples, which are in no way limiting. Any variations that may be made in the practice of the invention by those skilled in the art in light of the teachings herein will fall within the scope of the appended claims.
In the following examples, the specific rotation test was carried out by JASCO P-1020 polarimeter; the ultraviolet and infrared spectrum data are respectively obtained by a Shimadzu UV-2550 ultraviolet spectrometer and a Nicolet AVATAR 360 type infrared spectrometer; NMR was measured using Bruker Avance model II 400 and model 600 nuclear magnetic instruments; MS was measured by an Agilent 1100Series LC/MSD G1946D model, HR-MS was measured by an AB Sciex TripleTOF 5600 model; sephadex LH-20 Gel is produced by GE Healthcare Bio-Sciences, Switzerland, MCI Gel CHP 20P (75-150 μm) is produced by Mitsubishi, Japan, and polyamide resin (30-60 mesh) is produced by TMC, Tanzhou; semi-preparative HPLC was Waters e2695 equipped with 2998PDA and 2424 evaporative light scattering double detectors and SunAire ODS (5 μm, 250X 10mm) semi-preparative columns; all reagents are produced by Shanghai national drug group chemical reagent limited.
Example 1: preparation of natural harringtonine N-oxide derivatives (cephaloverines A-D,1-4)
Dried branches and leaves (9.0kg) of cephalotaxus oliveri are fully crushed and then extracted for 4 times by 95 percent ethanol at room temperature, and the extracting solutions are combined and concentrated under reduced pressure to obtain 700g of total extract. Dispersing the total extract with 3% tartaric acid water solution, extracting with ethyl acetate (4 times), collecting the ethyl acetate layer as non-alkaloid part, and collecting the remaining water layer with Na2CO3Adjusting pH to 10, extracting with chloroform, and concentrating to obtain chloroform layer (14.0 g). Firstly, MCI column chromatography (MeOH-H) is adopted2O,1:1-1:0, v/v) pairsThe total alkaloid fraction is roughly divided into 6 fractions (Fr.A-Fr.F). Fr.A (800mg) was subjected to crude separation by polyamide column chromatography with MeOH-H2Gradient elution of O system (1:2-1:0, v/v) gives subfractions A1-A3. Compound 3(4.0mg, t)R22.0min) and 4(3.1mg, t)R14.6min) from fr.a3 by semi-preparative HPLC [ MeOH-H)2O (containing 0.05% Et)2NH,v/v)11:89,v/v；flow rate,3.0mL/min]And (4) preparing. Fr.B (600mg) was roughly fractionated with Sephadex LH-20(MeOH) to give Fr.B 1-B3. Compound 1(6.5mg, t)R13.9min) from fr.b3 via semi-preparative HPLC [ MeOH-H)2O (containing 0.05% Et)2NH,v/v)40:60,v/v；flow rate,3.0mL/min]Purifying to obtain the product. Crude fractionation of Fr.D (1.0g) on Sephadex LH-20(MeOH) column gave four subfractions D1-D4, and subsequent purification of Fr.D2 by semi-preparative HPLC gave Compound 2(9.4mg, tR＝14.7min；MeOH/H2O-48/52, v/v) cepaloverinesa-D (1-4) isolated as new compounds with the following spectral and physicochemical data:
cephaloverine A (1) is colorless jelly; [ alpha ] to]D 20–57(c 0.10,MeOH)；UV(MeOH)λmax(logε)291(3.47)nm；IR(film)νmax:3386,2970,2921,2853,1747,1656,1591,1500and 1488cm-1；1H NMR(400MHz,CDCl3):δ6.67(1H,s,H-17),6.47(1H,s,H-14),5.99(1H,d,J＝9.6Hz,H-3),5.92(1H,d,J＝1.2Hz,H-18),5.86(1H,d,J＝1.2Hz,H-18),5.13(1H,s,H-1),3.87(1H,d,J＝9.6Hz,H-4),3.80(3H,s,OMe-19),3.78(1H,m,H-8b),3.75(1H,m,H-10a),3.73(1H,m,H-10b),3.60(3H,s,OMe-5'),3.58(1H,m,H-8a),3.44(1H,ddd,J＝14.0,13.5,6.0Hz,H-11b),2.69(1H,m,H-6a),2.54(1H,ddd,J＝14.0,6.0,2.0Hz,H-11a),2.29(1H,d,J＝16.5Hz,H-3'),1.97(1H,m,H-6b),1.97(1H,m,H-7a),1.93(1H,m,H-7b),1.81(1H,d,J＝16.5Hz,H-3'),1.57(2H,m,H2-1"),1.53(1H,dt,J＝4.6,13.5Hz,H-2"),1.25(1H,m,H-2"),1.16(3H,s,OMe-5"),1.14(3H,s,OMe-4")；13C NMR(100MHz,CDCl3):δ173.7(C-1'),170.7(C-4'),162.5(C-2),146.4(C-16),146.2(C-15),130.6(C-12),128.4(C-13),111.8(C-14),109.6(C-17),101.2(C-18),99.5(C-1),86.3(C-5),74.9(C-2'),72.9(C-3),70.1(C-3"),69.3(C-8),62.2(C-10),58.6(C-19),52.3(C-4),51.9(C-5'),42.8(C-3'),39.2(C-6),36.8(C-2"),33.3(C-1"),29.9(C-5"),29.0(C-4"),28.4(C-11),18.2(C-7)；ESIMS m/z 548[M+H]+；HRESIMS m/z 548.2486[M+H]+(calcd for C28H38NO11,548.2490)；
Cephaloverine B (2) colorless jelly; [ alpha ] to]D 20–77(c 0.10,MeOH)；UV(MeOH)λmax(logε)292(3.55)nm；IR(film)νmax:3385,2967,2920,2850,1747,1650,1589,1500and 1489cm-1；1H NMR(400MHz,CDCl3):δ6.61(1H,s,H-17),6.60(1H,s,H-14),5.94(1H,br s,H-18),5.93(1H,br s,H-18),5.88(1H,d,J＝8.5Hz,H-3),5.40(1H,s,H-1),4.04(1H,ddd,J＝13.0,11.6,6.0Hz,H-10a),3.82(3H,s,OMe-19),3.73(1H,m,H-10b),3.70(1H,d,J＝8.5Hz,H-4),3.58(1H,m,H-11b),3.53(3H,s,OMe-5'),3.50(1H,m,H-8b),3.07(1H,dd,J＝16.0,8.6Hz,H-8a),2.94(1H,ddd,J＝14.5,10.3,7.0Hz,H-6a),2.83(1H,ddd,J＝15.0,8.5,6.0Hz,H-11a),2.45(1H,d,J＝16.2Hz,H-3'),2.28(1H,d,J＝16.2Hz,H-3'),1.87(1H,ddd,J＝14.5,9.3,3.2Hz,H-6b),2.27(1H,m,H-7a),1.72(1H,m,H-7b),1.68(2H,m,H2-1"),1.51(1H,dt,J＝5.1,13.0Hz,H-2"),1.22(1H,m,H-2"),1.17(3H,s,OMe-5"),1.13(3H,s,OMe-4")；13C NMR(100MHz,CDCl3):δ173.9(C-1'),170.3(C-4'),161.1(C-2),148.2(C-16),146.9(C-15),130.4(C-12),125.4(C-13),112.3(C-14),109.6(C-17),101.6(C-18),101.8(C-1),90.3(C-5),75.0(C-2'),75.8(C-3),69.6(C-3"),65.7(C-8),61.6(C-10),58.0(C-19),56.2(C-4),51.7(C-5'),43.4(C-3'),38.1(C-6),36.7(C-2"),33.5(C-1"),30.2(C-5"),28.8(C-4"),30.4(C-11),19.7(C-7)；ESIMS m/z 548[M+H]+,1095[2M+H]+；HRESIMS m/z 548.2486[M+H]+(calcd for C28H38NO11,548.2490)；
Cephaloverine C (3) colorless jelly; [ alpha ] to]D 20–68(c 0.10,MeOH)；UV(MeOH)λmax(logε)291(3.50)nm；IR(film)νmax:3384,2970,2922,2850,1753,1649,1594and 1488cm-1；1H NMR(400MHz,DMSO-d6):δ6.74(1H,s,H-17),6.51(1H,s,H-14),5.90(1H,br s,H-18),5.82(1H,br s,H-18),5.78(1H,d,J＝9.6Hz,H-3),5.31(1H,s,H-1),4.03(1H,d,J＝9.6Hz,H-4),3.79(1H,m,H-8b),3.76(1H,m,H-8a),3.70(1H,m,H-10a),3.67(3H,s,OMe-19),3.66(1H,m,H-10b),3.31(1H,m,H-11b),2.56(1H,dd,J＝14.0,6.5Hz,H-11a),2.45(1H,m,H-6a),1.98(1H,m,H-6b),1.91(1H,m,H-7a),1.74(1H,d,J＝16.2Hz,H-3'),1.72(1H,m,H-7b),1.45(1H,d,J＝16.2Hz,H-3'),1.35(1H,m,H-1"),1.34(1H,m,H-2"),1.30(1H,m,H-1"),1.08(1H,m,H-2"),0.99(3H,s,OMe-5"),0.95(3H,s,OMe-4")；13C NMR(100MHz,DMSO-d6):δ172.8(C-1'),170.9(C-4'),162.0(C-2),145.5(C-16),145.3(C-15),130.6(C-12),128.6(C-13),111.3(C-14),109.1(C-17),100.5(C-18),99.4(C-1),86.5(C-5),74.4(C-2'),71.6(C-3),68.3(C-3"),67.5(C-8),60.7(C-10),57.8(C-19),50.7(C-4),43.0(C-3'),38.0(C-6),36.7(C-2"),33.5(C-1"),29.9(C-5"),28.5(C-4"),27.2(C-11),17.3(C-7)；ESIMS m/z 534[M+H]+；HRESIMS m/z534.2329[M+H]+(calcdfor C27H36NO10,534.2334)；
Cephaloverine D (4) colorless jelly; [ alpha ] to]D 20–45(c 0.10,MeOH)；UV(MeOH)λmax(logε)291(3.48)nm；IR(film)νmax:3386,2970,2924,2853,1731,1649,1500and 1488cm-1；1H NMR(600MHz,DMSO-d6):δ6.74(1H,s,H-17),6.57(1H,s,H-14),5.89(1H,br s,H-18),5.84(1H,d,J＝9.6Hz,H-3),5.80(1H,br s,H-18),5.34(1H,s,H-1),4.10(1H,d,J＝9.6Hz,H-4),3.95(1H,m,H-8b),3.89(1H,m,H-8a),3.84(1H,m,H-10a),3.80(1H,m,H-10b),3.70(3H,s,OMe-19),3.38(1H,m,H-11b),2.85(1H,s,H-3'),2.62(1H,dd,J＝14.0,6.5Hz,H-11a),2.51(1H,m,H-6a),2.07(1H,m,H-6b),2.04(1H,m,H-7a),2.01(1H,m,H-7b),1.45(1H,ddd,J＝12.4,12.0,6.0Hz,H-1"),1.33(1H,m,H-1"),1.32(1H,m,H-2"),1.11(1H,m,H-2"),1.01(3H,s,OMe-5"),0.97(3H,s,OMe-4")；13C NMR(150MHz,DMSO-d6):δ173.3(C-4'),171.9(C-1'),162.6(C-2),145.7(C-16),145.4(C-15),130.4(C-12),128.1(C-13),111.6(C-14),109.4(C-17),100.5(C-18),98.9(C-1),87.2(C-5),79.2(C-2'),73.6(C-3'),71.7(C-3),68.4(C-3"),67.6(C-8),60.6(C-10),57.9(C-19),50.6(C-4),37.7(C-6),36.7(C-2"),29.2(C-1"),29.8(C-5"),28.7(C-4"),27.2(C-11),17.4(C-7)；ESIMS m/z 550[M+H]+；HRESIMS m/z 550.2253[M+H]+(calcd for C27H36NO11,550.2283)。
Example 2: determination of inhibition of cephalotaxus fortunei alkali N-oxide derivatives on tumor cell proliferation
Experimental materials and methods: human non-small cell lung carcinoma A549, human large cell lung carcinoma NCI-H460, human promyelocytic acute leukemia HL60, human plasma cell leukemia NCI-H929 and human myeloma cell RPMI-8226 were purchased from ATCC. All cells were cultured in RPMI-1640 medium (Thermo Fisher Scientific) containing 10% Fetal Bovine Serum (FBS), 100units/mL penicillin and 100units/mL streptomycin (Invitrogen). All cells were stored at 37 ℃ in 5% CO2Culturing under the condition. Cell viability was tested using the standard MTT method: after the cells were cultured in 96-well plates at a final density of 5000cells/well for 12 hours, predetermined concentration gradients (10) were applied-2-102mu.M) and in order to eliminate the influence of phototoxic action, the whole operation process should avoid strong light and culture in a dark incubator. Harringtonine was a positive control. After 48 hours, the cells were washed with fresh medium (FBS-free), then MTT solution (5mg/mL) was added and incubation continued for 4 hours, after discarding the suspension 100. mu.L of DMSO (Sigma-Aldrich) was added, and the absorbance at 570nm, IC, was measured for each well using a microplate reader (FLX 800, Bio-TEK instruments, INC. USA)50Values were obtained by calculating the log concentration of viability ratio of cells in the curve by the sigmaplot10.0 software, and the test results are shown in table 1.
TABLE 1 cytotoxic Activity of CephaloverinesA-D (1-4)
a IC50 value of each tested compound was defined as the concentration that caused 50％inhibition of cell growth.The results are averages of six independentexperiments.bPositive control.。
The result of the anti-tumor activity test shows that the compound cephaloverinesA-D (1-4) is applied to 5 tested human tumor cells (human)The growth of non-small cell lung cancer A549, human large cell lung cancer NCI-H460, human promyelocytic acute leukemia HL60, human plasma cell leukemia NCI-H929 and human myeloma cell RPMI-8226) has obvious inhibition activity (Table 1), IC50The main range of the value is 0.45-9.34 mu M, which indicates that the compound can be used for preparing medicines for treating tumor diseases such as lung cancer, leukemia or myeloma, and the like, or lead compounds of the medicines.
Claims (6)
1. The cephalotaxus base N-oxide derivative is characterized in that the structural formula of the cephalotaxus base N-oxide derivative is any one of the following structural formulas (cephaloverines A-D, (1) - (4):
2. a method for preparing the harringtonine N-oxide derivative according to claim 1, which comprises the following steps:
pulverizing branch and leaf of Cephalotaxus oliveri, extracting with 95% ethanol at room temperature, concentrating the extractive solution under reduced pressure, suspending in appropriate amount of 3% tartaric acid aqueous solution, extracting with equal volume of ethyl acetate for 3-5 times, and subjecting the extracted tartaric acid aqueous solution to Na extraction2CO3Adjusting pH to 10, and extracting with chloroform to obtain chloroform extract (total alkaloid fraction); the chloroform extract is separated by MCI resin, polyamide resin, Sephadex LH-20 gel column chromatography and reversed phase semi-preparative HPLC chromatography to prepare the compound cephaloverines A-D.
3. Use of the harringtonine N-oxide derivative of claim 1 in the preparation of medicaments for treating tumor diseases.
4. Use according to claim 3, wherein the neoplastic disease is any one of lung cancer, leukemia or myeloma.
5. The use according to claim 3, characterized in that said cephalotaxoid N-oxide derivatives are used alone or in combination for the preparation of a medicament for the treatment of neoplastic diseases.
6. The use as claimed in claim 3, wherein the harringtonine N-oxide derivative is combined with a pharmaceutically acceptable carrier or excipient to make an oral or non-oral dosage form.
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| CN102675327A (en) * | 2012-03-01 | 2012-09-19 | 南开大学 | Harringtonine alkaloid and preparation method and application thereof |
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| CN1463975A (en) * | 2002-06-28 | 2003-12-31 | 中国医学科学院药物研究所 | Novel harringtonlne derivative, method for making same and its pharmaceutical composition and use thereof |
| CN102675327A (en) * | 2012-03-01 | 2012-09-19 | 南开大学 | Harringtonine alkaloid and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
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| ICHIRO TAKANO: ""Modification of the Skeleton of Homoharringtonine through Unusual Rearrangements"", 《J. ORG. CHEM》, pages 8251 - 8254 * |
| YI-REN HE: ""Alkaloids from Cephalotaxus lanceolata and Their Cytotoxicities"", 《CHEMISTRY & BIODIVERSITY》, vol. 10, pages 584 - 585 * |
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