CN107746421A - Compound DICTYOPTERISINF and its application in antineoplastic is prepared - Google Patents
Compound DICTYOPTERISINF and its application in antineoplastic is prepared Download PDFInfo
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- CN107746421A CN107746421A CN201710940978.XA CN201710940978A CN107746421A CN 107746421 A CN107746421 A CN 107746421A CN 201710940978 A CN201710940978 A CN 201710940978A CN 107746421 A CN107746421 A CN 107746421A
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- wing algae
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- antineoplastic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Abstract
The present invention relates to pharmaceutical technology field, it is related to and new natural drug isolated, that there is antitumor action is extracted from the wavy wing algae Dictyopteris undulata Holmes of China, the medicine is steroid compound wing algae element F (dictyopterisin F).Anti tumor activity in vitro experiment shows that the compound is to human acute myeloid leukaemia (HL 60) and the IC of human lung carcinoma cell (A 549)50Value is respectively 2.45 and 2.85 μM, therefore available for antineoplastic is prepared, antineoplastic pharmaceutical compositions can be made with other drugs, the formulations such as injection, tablet, pill, capsule, solution, suspending agent and emulsion can be made with pharmacy acceptable auxiliary material；Its method of administration can be by oral administration, vein, muscle or percutaneous drug delivery.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to from the wavy wing algae Dictyopteris undulata of China
New natural drug isolated, that there is antitumor action is extracted in Holmes, the medicine is new steroid compound wing
Algae element F (dictyopterisin F).
Background technology
With the development of the society, the operating pressure thereby resulted in continues to increase and global environment constantly deteriorates, it is pernicious swollen
For the incidence of disease of knurl in ascendant trend year by year, malignant tumour turns into endangers one of major disease of human health.According to world health
(WHO) newest announcement as shown by data is organized, the whole world there are 8,800,000 people to die from cancer every year, accounts for global annual total toll nearly six
/ mono-.There are ten thousand new cancer cases more than 1400 every year, it is contemplated that will be added to more than 2,100 ten thousand to this numeral of the year two thousand thirty, cancer will
Surmount the number one killer that angiocardiopathy turns into the mankind.Find and the antineoplastic of exploitation high-efficiency low-toxicity has turned into world's medicine
One of most great research topic in boundary.
Marine organisms are based on its special ecological environment, so as to have novel structure, notable biological activity day as discovery
The important source of right lead compound.Record according to Marilet databases, sent out from miscellaneous marine organisms at present
Show more than 22000 and planted new marine natural products, wherein the ocean medicine with notable special physiological activity and potential applicability in clinical practice
Thing lead compound just has hundreds of.China possesses extremely abundant living marine resources, wherein identified biological species are just
Planted up to more than 20,000, this provides abundant material base for China ocean innovation drug research.Therefore, provided from China marine organisms
Original new drug lead compound is found in source has huge potentiality.
Wing Trentepohlia (Dicyopteris) marine alga is entoilage algae section (Dictyotaceae) sea-plant (Phaeophyta, entoilage
Cutleriales), the whole world there are about more than 35 and plant, and wherein China marine site is identified 5 kinds, be distributed in from intertidal zone to the sea as deep as hundreds of meters
Bottom, and from the Tropical Ocean Area of sweltering heat to the two poles of the earth sea area of cold.In past more than 60 years, domestic and international researcher is
The chemical composition and its bioactivity research of system have been carried out to more than 20 kind wing Trentepohlia marine algas, be therefrom found that sequiterpene,
Sequiterpene, sequiterpene phenols, C drop11Carbohydrate, C11The change of seven kinds of structure types such as sulfur-containing compound, steroidal and aliphatic acid
Compound.Wherein sequiterpene is the most important chemical composition of category marine alga.Modern pharmacology activity research shows, in wing Trentepohlia marine alga
It was found that part of compounds also have various biology such as anti-inflammatory, antibacterial, food refusal, desinsection, neurotrosis protection and cell toxicant living
Property.
Wavy wing algae Dictyopteris undulata Holmes are wing Trentepohlia marine alga, are distributed mainly on the Liao Dynasty of China
Rather, Fujian, Taiwan and Coast of Guangdong Province, it is less to its chemical composition and pharmacological research report.We endeavour always in recent years
In finding bioactive substance from China marine organisms, wing algae element F (dictyopterisin F) is from wavy wing algae
In a kind of isolated stigmastane type steroid compound.Wing algae element F is noval chemical compound, and its antitumor activity has no report.
The content of the invention
The invention provides one kind, extraction is isolated from China's wavy wing algae (D.undulata), it is anti-swollen to have
New steroid compound --- the wing algae element F (dictyopterisin F) of knurl effect.Show through pharmacological testing research, the change
Compound shows that obvious cell toxicant is lived to human acute myeloid leukaemia (HL-60) and human lung carcinoma cell (A-549)
Property, its IC50Value is respectively 2.45 and 2.85 μM.
An object of the present invention is to provide new steroid compound wing algae element F.
The second object of the present invention is to provide the preparation method of the wing algae element F.
The third object of the present invention is to provide the purposes of the wing algae element F.Specifically, the wing algae element F can use
In preparing antineoplastic, antineoplastic pharmaceutical compositions can be made with other drugs, can be made with pharmacy acceptable auxiliary material
The formulations such as injection, tablet, pill, capsule, solution, suspending agent and emulsion；Its method of administration can be by oral administration, vein, flesh
Meat or percutaneous drug delivery.
According to first purpose of the present invention, the present invention is found that wing algae element F from wavy wing algae first, its chemistry
Structure is as follows：
According to second object of the present invention, the present invention provides the preparation method of the wing algae element F, and it is from wavy net
It is isolated in wing algae, comprise the following steps that：
1) extract medicinal extract is prepared
By the wavy wing algae (D.undulata) of freezing with ethanol routinely seepage pressure effects, extract solution is obtained, by extract solution
Be concentrated under reduced pressure recovery ethanol, obtains coarse extract；
2) isolate and purify
(1) above-mentioned coarse extract is dispersed in water into suspension, suspension extracted with ether, gained extract is concentrated to give
To extracted by ether medicinal extract；
(2) ether medicinal extract is subjected to silica gel column chromatography, successively with petroleum ether/acetone and dichloro methanol/methanol elution gradient,
Similar fraction is merged according to TLC colour developings and obtains 12 components (A-L)；Wherein component G is petroleum ether/acetone volume ratio 8:2 elutions
Part is through Sephadex LH-20 gel filtration chromatographies, with methylene chloride/methanol volume ratio 1:1 elution；Developed the color according to TLC and merge phase
4 components (G1-G4), component G2 (i.e. methylene chloride/methanol volume ratios 1 are obtained like fraction:1 elution volume is that 75~90mL is washed
De- part) again through silica gel column chromatography, with petroleum ether/acetone volume ratio 8:2 elutions, most afterwards through semi-preparative HPLC, with methanol/water
85:15 volume ratios elute, and obtain the compounds of this invention wing algae element F.
In above-mentioned preparation method, in extract medicinal extract step is prepared, the ethanol used that extracts is 95% ethanol.
In above-mentioned preparation method, in separating step, the concentration of petroleum ether/acetone gradient elution is followed successively by volume ratio
100:0、90:10、80:20、70:30、50:50 and 40:60.The concentration of dichloro methanol/methanol elution gradient is followed successively by volume ratio
70:30、60:40 and 50:50.
In above-mentioned preparation method, in separating step, the filler of the chromatographic column of the semi-preparative HPLC is RP-18.
According to third object of the present invention, can be used for preparing antineoplastic the invention provides the wing algae element F,
Antineoplastic pharmaceutical compositions can be made with other drugs.
In order to reach application purpose, injection, tablet, pill, capsule, solution, suspending agent and emulsion etc. can be made
Form.Its method of administration can be by oral administration, vein, muscle or percutaneous drug delivery.
Embodiment
Signified wing algae element F chemical structural formula (being of Arabic numerals in structural formula in examples below
Learn the mark of carbon atom in structure)：
Embodiment 1：The preparation of the wing algae element F
1. prepare wavy wing algae extract medicinal extract
(1) extract solution is prepared
Chinese wavy wing algae (D.undulata) (it is coastal the to pick up from Zhanjiang) 1.8kg (weight in wet base) of freezing is used respectively
The ethanol percolations of 5L 95% extract three times, each diacolation 2 days, merge extract solution；
(2) extract medicinal extract is prepared
Said extracted liquid is concentrated under reduced pressure in temperature≤45 DEG C recovery ethanol, obtains coarse extract 174.5g；
2. isolate and purify
1) above-mentioned coarse extract is scattered in 2L water into suspension, suspension extracted four times with ether (1.5L), gained
Extract is concentrated under reduced pressure to give extracted by ether medicinal extract (54.3g)；
2) ether medicinal extract is subjected to silica gel column chromatography, successively with petroleum ether/acetone and dichloro methanol/methanol elution gradient；
The concentration of petroleum ether/acetone gradient elution is followed successively by volume ratio 100:0、90:10、80:20、70:30、50:50 and 40:60, two
The concentration of chloromethane alcohol/methanol elution gradient is followed successively by volume ratio 70:30、60:40 and 50:50.Similar stream is merged according to TLC colour developings
Part obtains 12 components (A-L)；
3) component G is petroleum ether/acetone volume ratio 8:2 elution fractions are through Sephadex LH-20 gel filtration chromatographies【Chromatography
Post specification：3.1 (diameter) × 120 (length) cm；Sephadex LH-20 gel dry weights：150 g】, with methylene chloride/methanol body
Product ratio 1:1 elution, similar fraction is merged according to TLC colour developings and obtains 4 components (G1-G4)；
4) component G2, i.e. methylene chloride/methanol volume ratio 1:1 elution volume is 75~90mL elution fractions, then through silica gel
Column chromatography, with petroleum ether/acetone volume ratio 8:2 elutions, most afterwards through semi-preparative HPLC (filler of chromatographic column is RP-18), with
Methanol/water volume ratio 85:15 elutions, flow velocity 3.5mL/min, retention time 28.2min, obtain the compounds of this invention wing
Algae element F, is identified as noval chemical compound.
3. Structural Identification
Routinely through the various modern spectral technique such as NMR, HRESIMS, UV and IR, it is determined that compound wing algae element F's
Chemical constitution, its physicochemical property are as follows：
White powder, molecular formula C29H46O3；
Specific rotatory power
Ultraviolet spectra UV (MeOH) λmax(logε):236(3.58)nm；
Infrared spectrum IR (KBr) νmax:3428,1665,1548,1490,1327,1217,1032cm–1；
High resolution mass spectrum HR-ESI-MS m/z 465.3347 [M+Na]+(calcd for C29H46O3Na,
465.3345)；
Proton nmr spectra1H NMR (600MHz) and carbon-13 nmr spectra13C NMR (150MHz) data are shown in Table 1.
Wing algae element F described in table 11H and13C NMR(ppm in CDCl3)
Embodiment 2：The anti tumor activity in vitro experiment of the wing algae element F
Cell line：Human acute myeloid leukaemia (HL-60) and human lung carcinoma cell (A-549).
Test method：Using fragrant red bright B methods (SRB) measure inhibitory rate of cell growth.Specially take the logarithm the HL- in growth period
60 and A-549 cell lines, matched somebody with somebody with the DMEM/F12 culture mediums of sodium benzylpenicillin containing 50U/mL, 50 μ g/mL streptomysins and 10%FCS
3.0 × 105/mL cell suspension is made, is inoculated into 96 orifice plates, per the μ L of hole 100.It is incubated overnight in 37 DEG C of cell culture incubators
The μ L of testing sample solution 100 of the various concentrations of the DMEM/F12 of serum-free containing antibiotic culture mediums dilution are added afterwards, continue to cultivate
After 30 minutes, cell is moved into the incubator of 5%CO2/95% air and is incubated 48 hours.Each hole inoculating cell of 96 orifice plates is added
100 μ L 20%TCA solution, 1 hour is fixed at 4 DEG C, removes supernatant, and cell is washed 4 times, adds 100 μ L 0.4% after drying
SRB, dye 12 minutes at room temperature, 1% acetic acid washs 4 times, and it is molten to add 200 μ L Tris solution (10Nm, PH 7.4) after drying
Solution, makes the SRB whole dissolutions in cell, shake well determines administration using ELIASA after 5 minutes under wavelength 490nm at room temperature
Hole and blank well OD values.Inhibitory rate of cell growth=(1- medications group mean OD value/control group hole OD values) × 100%
The judge and explanation of result of the test：Drug concentration IC during cell half growth inhibition50Carried out according to dose-effect data
Conversion.In triplicate, absorption value difference is less than 5%, IC for each experiment50Difference is less than 30%.With IC50≤ 20 μ g/ml are to have
Criterion is accurate.
Result of the test：As a result as shown in table 2, the compounds of this invention wing algae element F is to human acute myeloid leukaemia
(HL-60) and human lung carcinoma cell (A-549) shows obvious cytotoxic activity, its IC50Value is respectively 2.45 and 2.85 μM.
Conclusion (of pressure testing)：Pass through molecular biology test, it can be seen that compound wing algae element F is to people's acute morning white blood of young grain
Sick cell (HL-60) and human lung carcinoma cell (A-549) show obvious cytotoxic activity.Therefore, wing algae element F of the invention
Available for antineoplastic is prepared, antineoplastic pharmaceutical compositions can be made with other drugs.
The wing algae element F of table 2 cytotoxicity test result (IC50Value, μM)
* positive control drug.
Claims (5)
- A kind of 1. steroid compound wing algae element F with antitumor action, it is characterised in that：With following chemical constitution：
- 2. wing algae element F according to claim 1, it is characterised in that：Described compound is from entoilage algae section brown alga ripple Isolated in shape wing algae, wavy wing algae scientific name is Dictyopteris undulata Holmes.
- A kind of 3. antineoplastic pharmaceutical compositions, it is characterised in that：Containing the wing algae element F described in claim 1.
- 4. wing algae element F according to claim 1, it is characterised in that：It is antitumor preparing as the active component of medicine Application in medicine.
- 5. wing algae element F according to claim 4, it is characterised in that：The formulation of the antineoplastic is injection, piece Agent, pill, capsule, solution, suspending agent or emulsion.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722096A (en) * | 2017-10-11 | 2018-02-23 | 南昌大学 | A kind of steroid natural drug with antitumor action and its production and use |
| CN107805269A (en) * | 2017-10-11 | 2018-03-16 | 南昌大学 | DICTYOPTERISINF and its prepare application in diabetes or obesity drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722096A (en) * | 2017-10-11 | 2018-02-23 | 南昌大学 | A kind of steroid natural drug with antitumor action and its production and use |
| CN107805269A (en) * | 2017-10-11 | 2018-03-16 | 南昌大学 | DICTYOPTERISINF and its prepare application in diabetes or obesity drug |
-
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- 2017-10-11 CN CN201710940978.XA patent/CN107746421B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722096A (en) * | 2017-10-11 | 2018-02-23 | 南昌大学 | A kind of steroid natural drug with antitumor action and its production and use |
| CN107805269A (en) * | 2017-10-11 | 2018-03-16 | 南昌大学 | DICTYOPTERISINF and its prepare application in diabetes or obesity drug |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722096A (en) * | 2017-10-11 | 2018-02-23 | 南昌大学 | A kind of steroid natural drug with antitumor action and its production and use |
| CN107805269A (en) * | 2017-10-11 | 2018-03-16 | 南昌大学 | DICTYOPTERISINF and its prepare application in diabetes or obesity drug |
| CN107722096B (en) * | 2017-10-11 | 2020-04-03 | 南昌大学 | Natural steroid medicine with anti-tumor effect and its prepn and use |
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