CN107011170A - Fucoxanthine derivative and its preparation method and application - Google Patents
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Abstract
The present invention relates to five kinds of fucoxanthine derivatives, the preparation method of the derivative is, using fucoxanthine as raw material, fucoxanthine derivative crude extract to be obtained by concentrating after adding reducing agent reaction；By fucoxanthine derivative crude extract by silica gel column chromatography initial gross separation, it is divided into different component, then isolated and purified by half preparation/preparative high performance liquid chromatography.Fucoxanthine derivative prepared by the present invention has the effect of stronger suppression tumor cell proliferation, with good potential applicability in clinical practice.
Description
Technical field
The present invention relates to compound and preparation method thereof, and in particular to a kind of fucoxanthine derivative and preparation method thereof and
Using, more particularly to fucoxanthine derivative prepare treating cancer medicine in apply.
Background technology
Fucoxanthine (fucoxanthin) is also known as brown alga flavine, be from edible brown alga, such as undaria pinnitafida (Alariaceae,
Undaria pinnatifida), the natural carotenoids extracted in sea-tangle (Laminaria japonica Aresch)
Element, there is 5, the 6- epoxy unsaturation allene bond that a chemical property is active at the two ends of its rigid alltrans long-chain respectively
Structure, thus again different from other carotenoid molecules, with very strong bioactivity.Its various biological is active in recent years
It is proved, among some potential activity are also actively being sought by scientists, oneself turns into the research of current marine drug at present
One of with the main attack focus of exploitation.
Chinese medicine or natural drug show diversity and complexity in type of compounds, structure, are one and naturally occur
" combinatorial chemistry sample library ", it has also become in new drug development find lead compound important sources.China possess it is abundant in
Herbal medicine resource, therefrom extracts isolated lead compound, and structural modification, enhancing pharmacological activity, reduction poison are carried out to it
Side effect, improves pharmacokinetic property, is the effective way for realizing the modernization of Chinese medicine and innovation new drug.
At present, the report both at home and abroad on fucoxanthine derivative is less.Fucoxanthol is the fucoxanthine being currently known
One of derivative, is the metabolite that it sloughs an acetyl group, and its structure is similar with the structure of fucoxanthine, with very strong
Bioactivity.Recent study shows, can be translated into fucoxanthine derivative after Mouse oral fucoxanthine and obtain profit
With.Hayato Maeda etc. are studied it has also been found that fucoxanthine metabolite fucoxanthine derivative in 3T3-L1 cell lines can be with
By reducing PPAR γ (Peroxisome Proliferator-activated Receptors) so as to reach that suppression 3T3-L1 preadipocytes are tied to fat
The purpose of fat cell line differentiation, so as to reach the effect of fat-reducing.At present both at home and abroad there is not yet fucoxanthine series derivates batch
Measure the report of preparation research, it is impossible to high-valued development and application are carried out to fucoxanthine series derivates product, therefore, it is necessary to send out
A kind of preparation method of bright high-purity fucoxanthine series derivates, the bioactivity of the serial fucoxanthine derivative of research, to be
The development and application of row derivative functional product provide important foundation.
The content of the invention
It is an object of the invention to provide a series of fucoxanthine derivatives and its preparation method and application, by semi-synthetic
Five kinds of fucoxanthine derivatives are prepared for, and illustrate its bioactivity, it was demonstrated that it has significant suppression activity of tumor cells,
Prepare and had broad application prospects in treating cancer medicine.
Specifically, one aspect of the present invention is related to fucoxanthine derivative or its salt, it is characterised in that structure such as following formula
(I) shown in-formula (V)：
The salt of heretofore described derivative includes but is not limited to, inorganic acid salt, inorganic acid be, for example, hydrochloric acid, sulfuric acid,
Phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid, or organic acid salt, organic acid be, for example, acetic acid, propionic acid, butyric acid,
Tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, glactaric acid, gluconic acid, benzoic acid, butanedioic acid,
Oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzene sulfonic acid, salicylic acid, p-aminobenzene sulfonic acid, asparatate, glutamic acid, according to ground
Acid, stearic acid, palmitic acid, oleic acid, laurate, pantothenic acid, tannic acid, ascorbic acid and valeric acid.
Second aspect of the present invention is to provide a kind of pharmaceutical composition, wherein including above-mentioned fucoxanthine derivative or its salt
As active component, and pharmaceutic adjuvant can be used as.
It is described can be as pharmaceutic adjuvant the conventional diluent of pharmaceutical field, excipient, filler, adhesive, wetting agent,
Disintegrant, sorbefacient, surfactant, absorption carrier, lubricant etc..
Preferably, formulation is injection, capsule, tablet, powder, oral liquid.
Third aspect present invention is related to described fucoxanthine derivative or its salt in the medicine for preparing treating cancer
Using.
Wherein described cancer includes but is not limited to malignant mela noma, cancer of pancreas, anaplastic thyroid carcinoma, metastatic bone
Malignant tumour, leukaemia, lymph cancer, osteoma, chondrosarcoma, prostate cancer, cancer of the esophagus, stomach cancer, liver cancer, gallbladder cancer, the carcinoma of the rectum,
Colorectal cancer, colon cancer, lung cancer, nasopharyngeal carcinoma, nervous system cancer, breast cancer, oophoroma, cervical carcinoma, uterine cancer.
Fourth aspect present invention is the preparation method for providing the fucoxanthine derivative, comprises the following steps：
1), using fucoxanthine or the extract containing fucoxanthine is raw material；
2), raw material is dissolved with solvent, fucoxanthine derivative must be contained by adding certain proportion reducing agent reduction reaction
Reaction solution；
3), reaction solution is concentrated to dryness, initial gross separation is carried out using silica gel column chromatography, obtains deriving containing different fucoxanthines
The component of thing；
4), each several part separating liquid is concentrated to dryness, flowing phased soln is added, using half preparation/preparative liquid chromatography point
Obtain preparing liquid phase refined solution from purifying；
5) by each several part preparation liquid phase refined solution concentrate respectively, after concentrate is dried, obtain fucoxanthine derivative
Thing each component, carries out structure elucidation, determines that compound is respectively:Shown in formula (I), formula (II), formula (III), formula (IV), formula (V).
Preferably, step 2) described in solvent be organic solvent, preferably methanol, ethanol, tetrahydrofuran.
Preferably, step 2) described in raw material and reducing agent weight ratio be 50：1 to 1：1.It may be selected from 50:Isosorbide-5-Nitrae 0:1,
30:1,20:1,10:1,5:1,1:1.
Preferably, reducing agent is sodium borohydride, lithium aluminium hydride reduction, stannous chloride, oxalic acid, potassium borohydride, ferrous sulfate, sulfurous
One or several kinds of combinations of sour sodium etc.；Wherein most preferably lithium aluminium hydride reduction.
Preferably, step 2) described in reaction temperature be 20-50 DEG C, may be selected from 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45
℃、50℃；Reaction time is 0.5-48h, may be selected from 0.5h, 1h, 2h, 4h, 8h, 10h, 12h, 16h, 20h, 24h, 48h.
Preferably, step 3) described in silica gel column chromatography carry out initial gross separation, purification on normal-phase silica gel may be selected and anti-in silicagel column
Phase silica gel.
Preferably, step 3) described in use normal-phase silica gel column chromatography when, the optional petroleum ether-ethyl acetate of eluant, eluent or
Petroleum ether-acetone is eluant, eluent, and ratio is 20：1-1：1, during using reversed-phase silica gel column chromatography column chromatography, the optional methanol of eluant, eluent-
Water or alcohol-water, ratio are 7：3 to 10：0.
Preferably, step 4) described in mobile phase for methanol-water, acetonitrile-water, three kinds of system solvents of alcohol-water and
The solvent that three kinds of system solvents are mixed with arbitrary proportion.
Preferably, the preparation method of described fucoxanthine derivative, step 4) be, by step 3) obtain fucoxanthine
Derivative series derivates component flowing phased soln, is transferred in half preparation/preparative high performance liquid chromatography sample injection bottle, starts half
Preparation/preparative high performance liquid chromatography is isolated and purified, and detects that signal triggers fraction collector and received automatically by on-line ultraviolet
Collect fucoxanthine derivative refined solution.
Preferably, step 4) half preparation/preparative high performance liquid chromatography use half prepare/prepares column packing for C8
Post or C18 posts.
Preferably, step 4) half preparation/preparative high performance liquid chromatography use half prepare/prepares a diameter of of post
10-50mm。
Preferably, step 4) described in the sample size that uses of half preparation/preparative high performance liquid chromatography for 100 μ L/ times-
20mL/ times.
Preferably, step 4) described in the flow rate of mobile phase that uses of half preparation/preparative high performance liquid chromatography for 5-
200mL/min, preferably 5,6,10,20,28,50,80,100,120,150,180,200mL/min.
Preferably, step 4) described in the detector that uses of half preparation/preparative high performance liquid chromatography for UV-detector
Or PDAD, Detection wavelength is 400-500nm, preferably 450nm.
Preferably, step 5) in serial fucoxanthine derivative refined solution be concentrated under reduced pressure after, take concentrate to carry out
Freeze-drying, obtains five kinds of high-purity fucoxanthine derivatives, respectively formula (I), formula (II), formula (III), formula (IV), formula (V).
Brief description of the drawings
Fig. 1 represents fucoxanthine derivative mixture chromatogram
Fig. 2 represents the liquid chromatogram of the collection of illustrative plates of expression (I) compound, wherein Fig. 2-1 expressions (I) compound, figure
The hydrogen spectrogram of 2-2 expressions (I) compound, the carbon spectrogram of Fig. 2-3 expressions (I) compound；
The liquid chromatogram of the collection of illustrative plates of Fig. 3 expressions (II) compound, wherein Fig. 3-1 expressions (II) compound, Fig. 3-2
The hydrogen spectrogram of expression (II) compound, the carbon spectrogram of Fig. 3-3 expressions (II) compound；
The liquid chromatogram of the collection of illustrative plates of Fig. 4 expressions (III) compound, wherein Fig. 4-1 expressions (III) compound, Fig. 4-2
The hydrogen spectrogram of expression (III) compound, the carbon spectrogram of Fig. 4-3 expressions (III) compound；
The liquid chromatogram of the collection of illustrative plates of Fig. 5 expressions (IV) compound, wherein Fig. 5-1 expressions (IV) compound, Fig. 5-2
The hydrogen spectrogram of expression (IV) compound, the carbon spectrogram of Fig. 5-3 expressions (IV) compound；
The liquid chromatogram of the collection of illustrative plates of Fig. 6 expressions (V) compound, wherein Fig. 6-1 expressions (V) compound, Fig. 6-2
The hydrogen spectrogram of expression (V) compound, the carbon spectrogram of Fig. 6-3 expressions (V) compound；
Embodiment
Embodiment 1
1) preparation of fucoxanthine derivative mixture：Fucoxanthine (purity is 99%) 500mg is taken, methanol 200mL is used
Dissolving, adds lithium aluminium hydride reduction 100mg, and in being reacted at 37 DEG C after 10h, liquid chromatographic detection has multiple fucoxanthine derivative chromatograms
Peak, is concentrated into and closely does, standby；
2) fucoxanthine derivative mixture initial gross separation：Fucoxanthine derivative concentrate is taken, using silica gel column chromatography
Separation, eluant, eluent is petroleum ether-ethyl acetate (20：1-2:1), obtain fucoxanthine derivative silica gel column chromatography isolate 1-A,
1-B, 1-C, 1-D, 1-E, 1-F, are concentrated respectively, standby；
3) it is prepared by fucoxanthine derivative (I) separation：
A) configuration of raw material：1-A fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Semipreparative high performance liquid chromatography；
C) chromatographic condition：Half prepares chromatographic column for C8 posts (250mm × 10mm), and flow phase system is 85%
Methanol aqueous solution, flow rate of mobile phase is 3mL/min, and Detection wavelength is 450nm；
D) sampling volume：100μL；
Fucoxanthine derivative preparation solution 80mL is obtained by running semipreparative high performance liquid chromatography, is depressurized at 30 DEG C
Concentration, concentrate is freeze-dried, fucoxanthine derivative 23mg is produced, and determines that the compound is formula through Structural Identification
(Ⅰ)。
4) it is prepared by fucoxanthine derivative (II) separation：
A) configuration of raw material：1-B fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Semipreparative high performance liquid chromatography；
C) chromatographic condition：Half prepares chromatographic column for C8 posts (250mm × 10mm), and flow phase system is 85%
Methanol aqueous solution, flow rate of mobile phase is 3mL/min, and Detection wavelength is 450nm；
D) sampling volume：100μL；
Fucoxanthine derivative preparation solution 60mL is obtained by running semipreparative high performance liquid chromatography, is depressurized at 30 DEG C
Concentration, concentrate is freeze-dried, fucoxanthine derivative 18mg is produced, and determines that the compound is formula through Structural Identification
(Ⅱ)。
5) it is prepared by fucoxanthine derivative (III) separation：
A) configuration of raw material：1-C fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Semipreparative high performance liquid chromatography；
C) chromatographic condition：Half prepares chromatographic column for C8 posts (250mm × 10mm), and flow phase system is that 85% methanol is water-soluble
Liquid, flow rate of mobile phase is 3mL/min, and Detection wavelength is 450nm；
D) sampling volume：100μL；
Fucoxanthine derivative preparation solution 80mL is obtained by running semipreparative high performance liquid chromatography, is depressurized at 30 DEG C
Concentration, concentrate is freeze-dried, fucoxanthine derivative 23mg is produced, and determines that the compound is formula through Structural Identification
(Ⅲ)。
6) prepared by fucoxanthine derivative (IV), (V) separation：
A) configuration of raw material：1-B fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Semipreparative high performance liquid chromatography；
C) chromatographic condition：Half prepares chromatographic column for C8 posts (250mm × 10mm), and flow phase system is that 90% methanol is water-soluble
Liquid, flow rate of mobile phase is 3mL/min, and Detection wavelength is 450nm；
D) sampling volume：100μL；
By running semipreparative high performance liquid chromatography, fucoxanthine derivative (IV), (V) preparation solution are obtained respectively,
It is concentrated under reduced pressure at 30 DEG C, concentrate is freeze-dried, fucoxanthine derivative (IV), (V) 25mg, 29mg is produced respectively,
Determine that the compound is formula (IV), (V) through Structural Identification.
Embodiment 2
1) preparation of fucoxanthine derivative mixture：Fucoxanthine (purity is 90%) 1000mg is taken, methanol 500mL is used
Dissolving, adds lithium aluminium hydride reduction 150mg, and in being reacted at 37 DEG C after 10h, liquid chromatographic detection has multiple fucoxanthine derivative chromatograms
Peak, is concentrated into and closely does, standby；
2) fucoxanthine derivative mixture initial gross separation：Fucoxanthine derivative concentrate is taken, using reverse phase silica gel post
Chromatographic isolation, eluant, eluent is 60%, 70%, 80%, 90,100% methanol aqueous solution, and gradient elution is collected into and obtains rock algae Huang
Matter derivative reversed phase column chromatography isolate 2-A, 2-B, 2-C, 2-D, 2-E, are concentrated respectively, standby；
3) prepared by fucoxanthine derivative (I), (II) (IV) separation：
A) configuration of raw material：2-C fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Preparative high performance liquid chromatography；
C) chromatographic condition：Half prepares chromatographic column for C18 posts (250mm × 20mm), and flow phase system is that 80% methanol is water-soluble
Liquid, flow rate of mobile phase is 10mL/min, and Detection wavelength is 450nm；
D) sampling volume：500μL；
It is respectively by running preparative high performance liquid chromatography acquisition fucoxanthine derivative (I), (II) (IV) preparation solution
210mL, 250mL, 170mL, are concentrated under reduced pressure at 30 DEG C, concentrate are freeze-dried, and fucoxanthine derivative is obtained respectively
23mg, 17mg, 38mg, determine that structural formula of compound is respectively through Structural Identification：(Ⅰ)、(Ⅱ)(Ⅳ).
4) it is prepared by fucoxanthine derivative (V) separation：
A) configuration of raw material：2-D fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Semipreparative high performance liquid chromatography；
C) chromatographic condition：Preparation chromatographic column is C18 posts (250mm × 20mm), and flow phase system is 85% methanol aqueous solution,
Flow rate of mobile phase is 10mL/min, and Detection wavelength is 450nm；
D) sampling volume：500μL；
Fucoxanthine derivative preparation solution 300mL is obtained by running semipreparative high performance liquid chromatography, is subtracted at 30 DEG C
Pressure concentration, concentrate is freeze-dried, fucoxanthine derivative 78mg is produced, and determines that the compound is formula through Structural Identification
(Ⅴ)。
5) it is prepared by fucoxanthine derivative (III) separation：
A) configuration of raw material：2-E fucoxanthine derivative crude products are configured to 5mg/mL solution；
B) instrument：Preparative high performance liquid chromatography；
C) chromatographic condition：Preparation chromatographic column is C18 posts (250mm × 20mm), and flow phase system is 90% methanol aqueous solution,
Flow rate of mobile phase is 10mL/min, and Detection wavelength is 450nm；
D) sampling volume：500μL；
Fucoxanthine derivative preparation solution 330mL is obtained by running semipreparative high performance liquid chromatography, is subtracted at 30 DEG C
Pressure concentration, concentrate is freeze-dried, fucoxanthine derivative 33mg is produced, and determines that the compound is formula through Structural Identification
(Ⅲ)。
The fucoxanthine derivative Anti-tumor angiogenesis of embodiment 3 is screened
1) five kinds of fucoxanthine derivatives, 5 concentration gradients are prepared
Five kinds of fucoxanthine derivative powders will be added respectively DMSO to be made into 20mg/mL as mother liquor, dispense -20 DEG C of guarantors
Deposit.Mother liquor is diluted to 20 μ g/mL with 1640 culture mediums, and gradient dilution is 10 μ g/mL, 5 μ g/mL, 2.5 μ g/mL, 1.25 μ
g/mL。
2) cell culture cultivates H460, A549, MCF-7 cell respectively according to corresponding cell culture processes；
3) bed board takes H460, A549, MCF-7 cell in logarithmic phase normally cultivated, and uses 0.25%Typsin+
0.02%EDTA digests, 1500rpm centrifugation 5min, is counted under tally, spreads 96 orifice plates, 5 × 10 are added per hole3Individual cell, puts
Enter and 24h is stood in incubator.It is separately added into the fucoxanthine derivative solution of various concentrations.
4) CCK8 is detected after cell viability various concentrations fucoxanthol solution effects different time points, siphons away culture medium, often
Hole adds the 1640 detection μ L of liquid 100 containing 10 μ L CCK8, sets blank control wells, and 37 DEG C of lucifuges are reacted to be read at 2h, 450nm
Each hole OD values.
IC50 value of the fucoxanthine derivative of table 1 to H460, A549, MCF-7
Claims (10)
1. fucoxanthine derivative or its salt, it is characterised in that shown in structure such as following formula (I)-formula (V)：
2. a kind of pharmaceutical composition, it is characterised in that be used as work comprising the fucoxanthine derivative or its salt described in claim 1
Property composition, and pharmaceutically acceptable auxiliaries.
3. pharmaceutical composition as claimed in claim 2, formulation is injection, capsule, tablet, powder, oral liquid.
4. the application of fucoxanthine derivative as claimed in claim 1 or its salt in the medicine for preparing treating cancer.
5. application as claimed in claim 4, wherein described cancer includes malignant mela noma Ps, cancer of pancreas, thyroid gland not
Break up cancer, metastatic bone malignant tumour, leukaemia, lymph cancer, osteoma, chondrosarcoma, prostate cancer, cancer of the esophagus, stomach cancer, liver
Cancer, gallbladder cancer, the carcinoma of the rectum, colorectal cancer, colon cancer, lung cancer, nasopharyngeal carcinoma, nervous system cancer, breast cancer, oophoroma, cervical carcinoma, son
Palace cancer.
6. the preparation method of the fucoxanthine derivative described in claim 1, it is characterised in that comprise the following steps：
1), using fucoxanthine or the extract containing fucoxanthine is raw material；
2), raw material is dissolved with solvent, certain proportion reducing agent reduction reaction is added and obtains the reaction containing fucoxanthine derivative
Liquid；
3), reaction solution is concentrated to dryness, initial gross separation is carried out using silica gel column chromatography, obtained containing different fucoxanthine derivatives
Component；
4), each several part separating liquid is concentrated to dryness, flowing phased soln is added, it is pure using half preparation/preparative liquid chromatography separation
Change obtains preparing liquid phase refined solution；
5) by each several part preparation liquid phase refined solution concentrate respectively, after concentrate is dried, obtain fucoxanthine derivative each
Component, carries out structure elucidation, determines that compound is respectively:Shown in formula (I), formula (II), formula (III), formula (IV), formula (V).
7. the preparation method of fucoxanthine derivative as claimed in claim 6, it is characterised in that step 2) described in solvent
For organic solvent, preferably methanol, ethanol, tetrahydrofuran.
8. the preparation method of fucoxanthine derivative as claimed in claim 6, it is characterised in that step 2) described in raw material with
The weight ratio of reducing agent is 50：1 to 1：1.
9. the preparation method of fucoxanthine derivative as claimed in claim 6, it is characterised in that step 2) described in reduction
Agent is a kind of or several of sodium borohydride, lithium aluminium hydride reduction, stannous chloride, oxalic acid, potassium borohydride, ferrous sulfate, sodium sulfite etc.
Plant combination.
10. the preparation method of fucoxanthine derivative as claimed in claim 6, it is characterised in that step 2) described in reaction
Temperature is 20-50 DEG C, and the reaction time is 0.5-48h.
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| CN109876079A (en) * | 2019-04-24 | 2019-06-14 | 上海市皮肤病医院 | The application of Haizao Yuhu Tang and its active constituent fucoxanthine in the drug of preparation treatment liver cancer |
| CN110092766A (en) * | 2019-04-18 | 2019-08-06 | 自然资源部第三海洋研究所 | Fucoxanthine derivative with anti-inflammatory effect and preparation method thereof |
| CN112804996A (en) * | 2019-03-05 | 2021-05-14 | 加特治疗有限公司 | Use of carotenoids in the treatment of age-related disorders |
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| K.BERNARD 等: "Absolute configuration of fucoxanthin", 《TETRAHEDRON LETTERS》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112804996A (en) * | 2019-03-05 | 2021-05-14 | 加特治疗有限公司 | Use of carotenoids in the treatment of age-related disorders |
| CN110092766A (en) * | 2019-04-18 | 2019-08-06 | 自然资源部第三海洋研究所 | Fucoxanthine derivative with anti-inflammatory effect and preparation method thereof |
| CN109876079A (en) * | 2019-04-24 | 2019-06-14 | 上海市皮肤病医院 | The application of Haizao Yuhu Tang and its active constituent fucoxanthine in the drug of preparation treatment liver cancer |
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