CN110818613B - Carbazole compound, preparation method thereof and application thereof in anti-HIV (human immunodeficiency virus) medicines - Google Patents
Carbazole compound, preparation method thereof and application thereof in anti-HIV (human immunodeficiency virus) medicines Download PDFInfo
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- CN110818613B CN110818613B CN201910975721.7A CN201910975721A CN110818613B CN 110818613 B CN110818613 B CN 110818613B CN 201910975721 A CN201910975721 A CN 201910975721A CN 110818613 B CN110818613 B CN 110818613B
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- petroleum ether
- ethyl acetate
- carbazole compound
- extract
- dichloromethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Abstract
The invention discloses a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, belonging to the technical field of drugs. The carbazole compound has the chemical structural formula
Named as carbazole compound Clauolenzoles A. The carbazole compound Clauolenzoles A has the inhibition activity on HIV (human immunodeficiency Virus), EC (infectious bronchitis Virus) 50 The value was 2.4. Mu.g/mL; the carbazole compound Clauolenzoles A and a medicinal carrier and/or an excipient can be prepared into an anti-HIV medicinal composition, and the anti-HIV medicinal composition is in the dosage form of injection, tablets, pills, capsules, solution, suspending agent or emulsion.
Description
Technical Field
The invention relates to a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, belonging to the technical field of drugs.
Background
Current aids treatment regimens rely on a series of drugs, known as combined antiretroviral therapy (cART), which can improve the quality of life of HIV positive patients (Trends in pharmaceutical Sciences 2011,32 (12), 715.); another is the development of molecules capable of interacting with multiple targets simultaneously (Drug discov. Today,2004,9, 641.; med. Chem.,2014, 22, 4658.); however, due to increasing drug resistance and side effects of current drugs, new molecules of anti-HIV drugs are constantly being discovered (clin trials,2005,6,5.; BMB rep.2015,48, 121.); therefore, the search and development of highly effective and low-toxic anti-HIV drugs have become one of the most important research subjects in the world medical field.
Disclosure of Invention
Aiming at the problem of toxic and side effects of anti-HIV drugs in the prior art, provides a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, wherein the carbazole compound Clauolenzoles A is prepared fromThe extract of Clausena anisum-olens Merr has HIV inhibiting activity and EC 50 The value is 2.4 mu g/mL, and can be used for preparing anti-HIV pharmaceutical compositions.
A carbazole compound with the following chemical structural formula
An anti-HIV pharmaceutical composition comprises a medicinal carrier and/or an excipient, and the carbazole compound Clauolenzoles A.
The anti-HIV pharmaceutical composition is in the dosage form of injection, tablet, pill, capsule, solution, suspension or emulsion.
The extraction method of the carbazole compound comprises the following specific steps:
(1) Percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;
(2) Suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;
(3) Performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed liquor system and a dichloromethane/methanol mixed liquor system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H;
(4) Subjecting the fraction B of step (3) to gel column chromatography, eluting with dichloromethane, and combining similar fractions according to thin layer chromatography to obtain 6 fractions (a, B, c, d, e and f);
(5) And (4) performing silica gel column chromatography on the component c, and eluting and purifying by adopting a dichloromethane/methanol mixed solution to obtain the carbazole compound Clauolenzoles A.
Further, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution in the step (3) is, in order, 8, 2, 1, 5,4 and 0, and the component B is the elution part of the volume ratio of petroleum ether to ethyl acetate of 2.
Further, the step (3) gradient elution is carried out by sequentially using dichloromethane/methanol mixed solution at a volume ratio of dichloromethane to methanol of 8.
Further, the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution in the step (5) is 50.
Further, the mass percentage content of the carbazole compound Clauolenzoles A in the clausena lansium extract is 0.05%;
the pharmaceutically acceptable carrier and/or excipient is non-toxic to both humans and animals and is inert;
the medicinal carrier is one or more of solid diluent, semisolid diluent, liquid diluent, filler and pharmaceutical product adjuvant;
the pharmaceutical composition is administered in the form of an amount administered per unit body weight;
the medicine can be administered by injection (intravenous injection, intramuscular injection), oral administration or skin administration.
The invention has the beneficial effects that:
(1) The carbazole compound Clauolenzoles A has the inhibitory activity on HIV, EC 50 The value was 2.4. Mu.g/mL; the carbazole compound Clauolenzoles A and a medicinal carrier and/or an excipient can be prepared into an anti-HIV medicinal composition;
(2) The carbazole compound Clauolenzoles A is derived from edible natural plant components, and the anti-HIV medicinal composition prepared from the carbazole compound Clauolenzoles A is non-toxic or low-toxic.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but the scope of the present invention is not limited to the description.
Example 1: the extraction method of the carbazole compound comprises the following specific steps:
(1) Percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;
(2) Suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;
(3) Performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed liquor system and a dichloromethane/methanol mixed liquor system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H; wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution is 8; the component B is an elution part of petroleum ether and ethyl acetate in a volume ratio of 2;
(4) Subjecting the component B in the step (3) to Sephadex LH-20 gel column chromatography, eluting with dichloromethane, and checking and combining similar fractions according to thin-layer chromatography to obtain 6 components, namely a, B, c, d, e and f; wherein the diameter of the gel column is 3cm, the length is 160cm, and the dry weight of Sephadex LH-20 gel is 150g;
(5) Performing silica gel column chromatography on the component c in the step (4), and eluting and purifying by adopting a dichloromethane/methanol mixed solution to obtain a carbazole compound Clauolenzoles A, wherein the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution is 50;
the carbazole compound of the embodiment has the following chemical structural formula
preparation of carbazole-based Compound of the present example 1 H-NMR data (600 MHz) (. Delta.in ppm, J in Hz) and 13 c NMR data (. Delta.in ppm, J in Hz) are shown in Table 1,
TABLE 1 preparation of carbazole-based compounds 1 H-NMR data and 13 c NMR data
The carbazole compound Clauolenzoles A is a white solid, and the molecular formula is C 15 H 13 NO 2 High resolution mass spectrum HRESIMS262.0839[ M + Na ]] + (calcd.262.0838)。
Example 2: in vitro anti-HIV activity assay of the carbazole compound Clauolenzoles a of example 1;
anti-HIV-1 activity of carbazole compound Clauolenzoles A, MT4 cells (1 x 10) in 96-well plate 5 cells/mL) at 50TCID in the presence of various concentrations of each test compound 50 The dose per well was infected with HIV-1NL4-3 Nonoluc-sec; on day 3 post-infection, supernatants were collected and assayed for luciferase activity using the Nano-Glo luciferase assay System (Promega); antiviral efficacy is defined as the concentration of compound that reduces luciferase activity by 50% (EC) 50 )；
The test result of the inhibitory activity is as follows: EC (EC) 50 The (. Mu.g/mL) values were: 2.4 +/-0.53, CC 50 The (. Mu.g/mL) values were: 17 plus or minus 2.5;
through molecular biology tests, it can be seen that the carbazole compound Clauolenzoles A shows anti-HIV activity and can act with HIV, so that the carbazole compound Clauolenzoles A can be used for preparing anti-HIV medicines and can be prepared into anti-HIV medicinal compositions with other medicines;
taking carbazole compound Clauolenzoles A as a raw material, and adding a medicinal carrier and/or an excipient to obtain a pharmaceutical composition containing the carbazole compound Clauolenzoles A;
the carbazole compound Clauolenzoles A is derived from edible natural plant components, and the anti-HIV pharmaceutical composition prepared from the carbazole compound Clauolenzoles A is non-toxic or low-toxic;
the pharmaceutically acceptable carrier and/or excipient is non-toxic to both humans and animals and is inert;
the medicinal carrier is one or more of solid diluent, semisolid diluent, liquid diluent, filler and pharmaceutical product adjuvant;
the pharmaceutical composition is administered in the form of a unit weight dose;
the medicine can be administered by injection (intravenous injection, intramuscular injection), oral administration or skin administration.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (1)
1. The extraction method of the carbazole compound is characterized in that the carbazole compound
Has the following chemical structural formula
the extraction method comprises the following specific steps:
(1) Percolating with ethanol to extract cortex PhellodendriClausena anisum-olensMerr. Dry powder to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;
(2) Suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction water phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction water phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;
(3) Performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed liquor system and a dichloromethane/methanol mixed liquor system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H; wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution is 8, 2, 5,6 and 0 in sequence, and the component B is an elution part of the volume ratio of petroleum ether to ethyl acetate 2; the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution for gradient elution is 8, 7, 6, 4, 1 and 0;
(4) Subjecting the fraction B of step (3) to gel column chromatography, eluting with dichloromethane, and combining similar fractions according to thin layer chromatography to obtain 6 fractions (a, B, c, d, e and f);
(5) And (5) performing silica gel column chromatography on the component c in the step (4), and eluting and purifying by adopting a dichloromethane/methanol mixed solution to obtain a carbazole compound Clauolenzoles A, wherein the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution is 50.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988356A (en) * | 2013-01-08 | 2013-03-27 | 中国科学院昆明植物研究所 | Medicine composition with carbazole alkaloid in clausena plants as antineoplastic activity ingredient and preparation method and application thereof |
| CN103012417A (en) * | 2013-01-08 | 2013-04-03 | 中国科学院昆明植物研究所 | Carbazole alkaloids in clausena plants, medicine composition with carbazole alkaloids as anti-tumor active component, and preparation method and application of carbazole alkaloids |
| CN104387400A (en) * | 2014-12-06 | 2015-03-04 | 西宁意格知识产权咨询服务有限公司 | Novel carbazole alkaloid in clausena and preparation method and application of carbazole alkaloid |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988356A (en) * | 2013-01-08 | 2013-03-27 | 中国科学院昆明植物研究所 | Medicine composition with carbazole alkaloid in clausena plants as antineoplastic activity ingredient and preparation method and application thereof |
| CN103012417A (en) * | 2013-01-08 | 2013-04-03 | 中国科学院昆明植物研究所 | Carbazole alkaloids in clausena plants, medicine composition with carbazole alkaloids as anti-tumor active component, and preparation method and application of carbazole alkaloids |
| CN104387400A (en) * | 2014-12-06 | 2015-03-04 | 西宁意格知识产权咨询服务有限公司 | Novel carbazole alkaloid in clausena and preparation method and application of carbazole alkaloid |
Non-Patent Citations (2)
| Title |
|---|
| Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening Against the Flap Site of HIV Protease;Nanjie Deng等;《J. Phys. Chem》;20140905;表1 * |
| Small Molecule Regulation of Protein Conformation by Binding in the Flap of HIV Protease;Theresa Tiefenbrunn等;《ACS Chem. Biol》;20130329;增补数据 * |
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