CN106518873B - Matrine and Oxymatrine alkali derivant and the preparation method and application thereof - Google Patents

Matrine and Oxymatrine alkali derivant and the preparation method and application thereof Download PDF

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CN106518873B
CN106518873B CN201610946260.7A CN201610946260A CN106518873B CN 106518873 B CN106518873 B CN 106518873B CN 201610946260 A CN201610946260 A CN 201610946260A CN 106518873 B CN106518873 B CN 106518873B
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formula
matrine
oxymatrine
preparation
alkali derivant
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CN106518873A (en
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顾湘
章爱玲
倪美鑫
冒小平
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Nantong Tumor Hospital
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Nantong Tumor Hospital
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system

Abstract

The invention discloses a kind of matrines and Oxymatrine alkali derivant and the preparation method and application thereof.Matrine and Oxymatrine alkali derivant provided by the present invention, structural formula are formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and formula Ⅹ.The present invention utilizes microbiological transformation technology, structural modification has successfully been carried out to matrine and oxymatrine, obtain various new compound, it is confirmed by extracorporeal anti-tumor test cell line, these compounds have preferable anti-tumor activity, it can be used as the active constituent of anti-tumor drug, tool has been widely used.

Description

Matrine and Oxymatrine alkali derivant and the preparation method and application thereof
Technical field
The present invention relates to biomedicine fields, and in particular to matrine and Oxymatrine alkali derivant and preparation method thereof with And the medical usage of the derivative.
Background technique
Malignant tumour is to endanger one of principal disease of human health, and research and development anti-tumor drug is always medicine neck The important research content in domain.Natural products is always the source that the mankind find effective active composition, during new drug development, one There is aspect the natural products of excellent activity can be used directly to clinic；On the other hand, with active skull cap components for guideization Close object, found by the methods of organic synthesis, structure of modification and develop new high-efficiency low-toxicity drug, be proved it is most capable it One of the approach of effective developing new drug.
Matrine and oxymatrine are the effective component of leguminous plant kuh-seng.Traditional medicine thinks that kuh-seng has heat-clearing dry Wet, desinsection, diuresis effect, modern pharmacological research thinks that the effective component of kuh-seng has antitumor, anti-arrhythmia, disease-resistant The effect of poison, increasing leucocyte.Recent domestic is active to the research of matrine and oxymatrine, and it is various to explore its Pharmacological activity and clinical function especially cause extensive concern in anti-tumor aspect.
The essence of microorganism conversion is the catalysis reaction by the enzyme effect generated in microorganism system metabolic process.Organism Enzyme in system can be catalyzed a variety of biochemical reactions, and Catalysis Rate, beyond the imagination, catalysis reaction can not only carry out in vivo, more can Promote native compound and a variety of conversion reactions of artificial-synthetic compound in vitro.
Summary of the invention
The object of the present invention is to provide a series of matrines and Oxymatrine alkali derivant and preparation method thereof.
Specific technical solution of the present invention is as follows：
A kind of matrine derivative replaced with 13 hydroxyls：13- ammothamnine has structure shown in formula I：
One kind having 13, the matrine derivative that 14 hydroxyls replace：13,14- dihydroxyl matrines have II knot of formula Structure：
A kind of matrine derivative replaced with 12 hydroxyls：12- ammothamnine has III structure of formula：
A kind of matrine derivative replaced with 13 carbonyls：13- carbonyl matrine has IV structure of formula：
A kind of matrine derivative replaced with 12 carbonyls：12- carbonyl matrine has V structure of formula：
A kind of Oxymatrine alkali derivant replaced with 13 hydroxyls：13- hydroxyl oxymatrine has VI knot of formula Structure：
One kind having 13, the Oxymatrine alkali derivant that 14 hydroxyls replace：13,14- dihydroxy oxymatrines, tool There is VII structure of formula：
A kind of Oxymatrine alkali derivant replaced with 12 hydroxyls：12- hydroxyl oxymatrine has VIII knot of formula Structure：
A kind of Oxymatrine alkali derivant replaced with 13 carbonyls：13- Carbonyl group oxidation matrine has Ⅸ knot of formula Structure：
A kind of Oxymatrine alkali derivant replaced with 12 carbonyls：12- Carbonyl group oxidation matrine has Ⅹ knot of formula Structure：
The present invention also provides the preparation methods of above-mentioned matrine and Oxymatrine alkali derivant, include the following steps：1) Fermented and cultured microorganism, matrine is added into culture medium or oxymatrine then carries out conversion culture, after removing mycelium Fermentation liquid is obtained, the microorganism is Cunninghamella sp (Cunninghamella), and Mucor (Mucor), total mould (Syncephalastrum) or head mold (Rhizopus) belong to bacterial strain；2) by the fermentation liquid after extracting, it is evaporated extract liquor, Obtain conversion product residue；3) the conversion product residue is collected with gel column purification and is merged component；4) by the component reverse phase High-efficient liquid phase chromatogram purification, preferably preparation condition are partly to prepare to use chromatographic column Kromasil 100-5-NH2,5 μm, 10.0 × 250mm (Sweden), methanol-water (80:20, V/V), flow velocity 3.0mL/min, Detection wavelength 220nm obtain structural formula be formula I, The compound of formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and formula Ⅹ.
Wherein, microorganism is preferably that Cunninghamella sp (Cunninghamella) belongs to bacterial strain, the small gram of Mildy Way of more preferable short thorn It is mould.The concentration of matrine and oxymatrine is 2-2000 μ g/mL in culture medium in above method step 1).
Extractant is conventional type organic solvent, preferably methylene chloride in above method step 2).
It is a further object of the present invention to provide ginseng triol derivates formula I of the present invention, formula II, formula III, formulas IV, formula V, formula VI, the purposes of the compound of formula VII, formula VIII, formula Ⅸ and formula Ⅹ.
The present invention experiments prove that, matrine of the invention and Oxymatrine alkali derivant have good antitumor work Property, it can be used as the active constituent of anti-tumor drug.
It is formula I, formula II, formula III, formula IV, formula V, formula that the active constituent of these anti-tumor drugs, which can be selected from structural formula, VI, one or more of formula VII, formula VIII, formula Ⅸ and compound of formula Ⅹ.
Can also be added in the drug using above compound as active constituent, when needs it is one or more pharmaceutically Acceptable carrier.The carrier includes the diluent of pharmaceutical field routine, excipient, filler, adhesive, wetting agent, collapses Agent, sorbefacient, surfactant, absorption carrier, lubricant etc. are solved, it can be according to the conventional method system of pharmaceutical field It is standby.
The present invention utilizes microbiological transformation technology, has successfully carried out structural modification to matrine and oxymatrine, has obtained A new class of matrine and Oxymatrine alkali derivant were obtained, was confirmed by extracorporeal anti-tumor test cell line, these compounds tool There is preferable anti-tumor activity, can be used as the active constituent of anti-tumor drug, tool has been widely used.
Detailed description of the invention
Fig. 1 is the HPLC liquid chromatogram of matrine derivative of the present invention.
Fig. 2 is the HPLC liquid chromatogram of Oxymatrine alkali derivant of the present invention.
Specific embodiment
Embodiment 1, the change that structural formula is formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and formula Ⅹ Close the preparation of object
The present invention through everfermentation, is mentioned using microbial conversion process respectively using matrine and oxymatrine as raw material It takes, separate, preparing the compounds of this invention.Microorganism with conversion capability includes：Cunninghamella sp (Cunninghamella), Mucor (Mucor), micro- life that mould (Syncephalastrum) or head mold (Rhizopus) belong to altogether Object；Wherein conversion capability it is stronger be Cunninghamella sp (Cunninghamella) belong to bacterial strain.These bacterial strains can be purchased from Microbiological Culture Collection Administrative Center of the Chinese Academy of Sciences (CGMCC) or the industrial microorganism preservation management of Chinese food fermentation research institute Center (CICC) is saved in being set in 4 DEG C of refrigerators in solid slope culture medium.Fungi culture medium selects potato culture, bacterium Culture medium selects LB culture medium.
The preparation (PDA culture medium) of potato culture：200g peeled potatoes are taken, are thinly sliced, are put into suitable quantity of water, 80 DEG C of heat preservation 1h after boiling.Filtrate is taken after being filtered with double gauze, and 20g glucose is added, stirring is completely dissolved glucose, with Water is settled to 1000mL.It prepares solid slope culture medium and 3% agar is added in liquid medium again.
By taking cunninghamella blakesleana Cunninghamella blaksleana AS 3.970 as an example, preparation structure formula is formula I, the process of the compound of formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and formula Ⅹ is as follows：
1) it ferments, convert and extracts
Cunninghamella blakesleana Cunninghamella blaksleana AS 3.970 is accessed into 2 250mL triangular flasks In (100mL potato culture is housed), as seed liquor.At 160rpm on shaking table, 26 DEG C after shaken cultivation 1 day, to bacterium Silk growth is in animated period, and the seed liquor of 1mL is drawn with Sterile pipette, is added to 20 1000mL shaking flasks (equipped with 400mL horse Bell potato culture medium) in.After shaken cultivation 1 day, respectively using matrine or oxymatrine as reaction substrate, add into each shaking flask Enter 20mg matrine or oxymatrine (0.2mL, 100mg/mL ethanol solution), shares 500mg matrine or 500mg oxygen Change matrine.Continue conversion 7 days under the same terms, by filtering fermentation liquor, filters out mycelium, the isometric methylene chloride of filtrate Extraction 3 times, extract liquor is concentrated to dryness, and respectively obtains conversion product residue about 1.6g.
2) gel column purification
Gained matrine or oxymatrine conversion product residue are dissolved in a small amount of methanol respectively, added to equipped with 100g LH-20 The chromatography capital of gel, is eluted with methanol, collects elution fraction, TLC analysis method (silica gel g thin-layer plate, dichloromethane is respectively adopted Alkane-methanol (10:1) it is unfolded, Wagner's reagent develops the color by spraying) obtained similar elution fraction is merged.
3) high-efficient liquid phase chromatogram purification
Merge component to be purified with reversed-phase high performance liquid chromatography.Preparation condition is half preparation chromatographic column Kromasil 100- 5-NH2,5 μm, 10.0 × 250mm (Sweden), methanol-water (80:20, V/V), flow velocity 3.0mL/min, Detection wavelength 220nm. Obtaining structural formula is formula I, formula II, formula III, V 5 formula IV, formula matrine converted products, and chromatogram is as shown in Figure 1, and formula VI, Ⅹ 5 formula VII, formula VIII, formula Ⅸ and formula oxymatrine converted products, chromatogram are as shown in Figure 2.
Chemical compounds I, 13- ammothamnine, white amorphous powder：HR-ESI-MS(m/z)265.1924[M+H]+ (calculated for C15H25N2O2,[M+H]+,265.1916).Its13C-NMR data are as shown in table 1.
Compound ii, 13,14- dihydroxyl matrines, white amorphous powder：HR-ESI-MS(m/z)281.1817[M+ Na]+(calculated for C15H25N2O3,[M+Na]+,281.1865).Its13C-NMR data are as shown in table 1.
Compound III, 12- ammothamnine, white amorphous powder：HR-ESI-MS(m/z)265.1926[M+Na]+ (calculated for C15H25N2O2,[M+Na]+,265.1916).Its13C-NMR data are as shown in table 1.
Compounds Ⅳ, 13- carbonyl matrine, white amorphous powder：HR-ESI-MS(m/z)263.1767[M+Na]+ (calculated for C15H23N2O2,[M+Na]+,263.1759).Its13C-NMR data are as shown in table 1.
Compound V, 12- carbonyl matrine, white amorphous powder：HR-ESI-MS(m/z)263.1765[M+Na]+ (calculated for C15H23N2O2,[M+Na]+,263.1759).Its13C-NMR data are as shown in table 1.
Compound VI, 13- hydroxyl oxymatrine, white amorphous powder：HR-ESI-MS(m/z)281.1869[M+ Na]+(calculated for C15H25N2O3,[M+Na]+,281.1865).Its13C-NMR data are as shown in table 1.
Compound VII, 13,14- dihydroxy oxymatrine, white amorphous powder：HR-ESI-MS(m/z)297.1818 [M+Na]+(calculated for C15H25N2O4,[M+Na]+,297.1814).Its13C-NMR data are as shown in table 1.
Compound VIII, 12- hydroxyl oxymatrine, white amorphous powder：HR-ESI-MS(m/z)281.1817[M+ Na]+(calculated for C15H25N2O3,[M+Na]+,281.1865).Its13C-NMR data are as shown in table 1.
Compound Ⅸ, 13- Carbonyl group oxidation matrine, white amorphous powder：HR-ESI-MS(m/z)279.1714[M+ Na]+(calculated for C15H23N2O3,[M+Na]+,279.1709).Its13C-NMR data are as shown in table 1.
Compound Ⅹ, 12- Carbonyl group oxidation matrine, white amorphous powder：HR-ESI-MS(m/z)279.1713[M+ Na]+(calculated for C15H23N2O3,[M+Na]+,279.1709).Its13C-NMR data are as shown in table 1.
The carbon modal data of 1. formula I of table, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and formula Ⅹ (CDCl3)
Position Formula I Formula II Formula III Formula IV Formula V Formula VI Formula VII Formula VIII Formula Ⅸ Formula Ⅹ
2 57.6 57.5 57.5 57.5 57.5 68.2 68.2 68.1 68.3 68.3
3 21.3 21.3 21.3 21.3 21.3 17.1 17.2 17.1 17.2 17.2
4 27.1 27.1 27.1 27.1 27.0 26.1 26.1 27.0 26.0 26.0
5 35.4 35.3 35.3 35.3 35.2 34.5 34.5 34.6 34.6 24.5
6 63.8 63.8 63.9 63.8 63.8 66.7 66.7 66.7 66.7 66.7
7 42.4 42.4 42.2 42.2 42.4 42.4 42.4 42.4 42.0 42.3
8 26.2 26.2 26.3 26.2 26.2 24.4 24.4 24.4 24.4 24.3
9 20.7 20.7 20.6 20.7 20.7 17.1 17.2 17.2 17.1 17.2
10 57.3 57.4 57.4 57.4 57.4 69.3 69.3 69.3 69.2 69.3
11 52.7 52.1 65.2 52.3 65.2 52.7 52.1 65.2 52.3 65.2
12 42.1 41.5 75.2 41.6 211.4 42.1 41.6 75.2 41.6 211.6
13 67.3 69.1 34.2 210.2 34.2 67.3 69.1 34.2 210.2 34.2
14 47.0 71.5 31.5 45.3 31.6 46.9 71.5 31.5 45.3 31.6
15 169.8 170.2 169.5 169.3 168.9 169.8 170.2 169.3 169.3 168.9
17 43.4 43.4 43.2 43.3 43.3 43.4 43.4 43.3 43.3 43.3
The above result shows that gained compound structure is correct.
2 structure of the invention formula of embodiment is formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and formula Ⅹ antitumor activity of compound.
1) experimental material
Instrument and reagent：CO2Incubator (Jouan IGO150)；Microplate reader (Bio-TEK ELx800)；Fluorescence is inverted aobvious Micro mirror (Olympus IX51)；MTT cell Proliferation and citotoxicity detection kit (green skies biotechnology research institute), RPM 1640 culture medium of I (Gibcol BRL), Rnase A, fetal calf serum, dimethyl sulfoxide (DMSO), trypsase (upper marine growth Engineering Co., Ltd).
Tumor cell line is used in test：Hela cell (human cervical carcinoma cell), K562 cell (human leukemia cell), K562/ ADR cell (human leukemia mdr cell), SH-SY5Y cell (human neuroblastoma cells), (human prostata cancer is thin by Du-145 Born of the same parents), HePG2 cell (human liver cancer cell), MCF-7 cell (human breast cancer cell), be purchased from Chinese Academy of Medical Sciences's tumor research Institute.
Test sample：The chemical compounds I-Ⅹ obtained synthesized by embodiment 1, purity is 90% or more；Meanwhile it choosing cis-platinum and being Positive control medicine, each compound dilute after being dissolved with DMSO.
2) experimental method
Each test-compound is measured to the half inhibiting rate IC of tumor cell line using mtt assay50Value：Logarithmic growth phase Tumour cell is 5 × 10 with the RPM I 1640 culture medium adjustment cell concentration containing 10% calf serum5/ mL is inoculated in 96 holes Every 100 μ L cell suspension of hole is added in culture plate, drug-treated group and cell controls group, and every group sets 3 multiple holes, and blank control group is only The full culture medium of RPM I 1640, every 100 μ L of hole, if 3 multiple holes is added.96 well culture plates are placed in 37 DEG C, 5%CO2Incubator After culture for 24 hours, the given the test agent of various concentration is added, makes final concentration of 0..1-100 μM, continues to cultivate 72h.By mtt assay in enzyme Mark instrument, measure absorbance (A) value of 570nm, calculate inhibiting rate [inhibiting rate=(1- experimental group A value/control group A value) × 100%].Experiment is repeated 3 times.Make regression equation using 11.5 software of SPSS, calculates each given the test agent and tumour cell is acted on Half-inhibitory concentration (the IC of 72h50)。
3) experimental result
According to mtt assay test result, the IC of I-Ⅹ pair of above-mentioned cell of the compounds of this invention is calculated50Value, as a result such as 2 institute of table Show.
2. test sample in vitro cytotoxic effect the selection result of table
The result shows that the compound of the present invention I-Ⅹ has good anti-tumor activity, anti-tumor drug can be used as Active constituent.

Claims (2)

1. with following structural matrine and Oxymatrine alkali derivant and its pharmaceutically can at salt preparation method,
Include the following steps：
1) matrine or oxymatrine are added into culture medium for fermented and cultured microorganism, then carry out conversion culture, remove bacterium Fermentation liquid is obtained after filament, the microorganism is the bacterial strain of Cunninghammella；
2) fermentation liquid that step 1) obtains is extracted, obtains conversion crude extract；
3) the conversion crude extract for obtaining step 2) passes through gel column chromatography, collects and merges component；
4) elution fraction that step 3) obtains is further purified with high performance liquid chromatography, obtaining structural formula is formula I, formula II, formula III, the compound of formula IV, formula V, formula VI, formula VII, formula VIII, formula Ⅸ and Formula X.
2. preparation method as described in claim 1, it is characterised in that the microorganism is cunninghamella blakesleana Cunninghamella blaksleana AS 3.970。
CN201610946260.7A 2016-11-02 2016-11-02 Matrine and Oxymatrine alkali derivant and the preparation method and application thereof Active CN106518873B (en)

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