CN108440458A - A kind of new tetrahydrofuran derivatives class compound and its preparation method and application - Google Patents
A kind of new tetrahydrofuran derivatives class compound and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to natural medicine fields, the preparation method and its application in antitumor drug, the compound trigonohowine for being related to a kind of tetrahydrofuran derivatives class compound with novel chemical constitution from long sequence Trigonostemon chinensis show through a variety of external activity evaluation results：The compound has significant antitumor activity and the inhibitory activity with the comparable protein tyrosine kinase of positive control drug, the antitumor drug using protein tyrosine kinase as target can be developed further into, it can be applied in antitumor drug, separation purifying technique is simple, reaction condition is mild, has realistic meaning.
Description
Technical field
The invention belongs to natural medicine fields, and in particular to a kind of to have novel chemical constitution from long sequence Trigonostemon chinensis
Tetrahydrofuran derivatives class compound preparation method and its application in antitumor drug.
Background technology
Malignant tumour is a kind of frequently-occurring disease, and the death rate is high, is just seriously threatening the life and health of the mankind at present, and just by
Gradually more than angiocardiopathy as the number one killer of threat human life and health.With the rapid development of life science, dislike
Property elaboration of tumour mechanism constantly be elucidated with and antitumor action target spot constantly be found, targeted inhibition tumor signal transduction
As one of the important directions of new type antineoplastic medicine exploitation.
Molecular targeted antitumor drug can be directed to the specific target point selectivity in growth of tumour cell and breeding
Ground killing tumor cell brings revolutionary progress without damaging normal structure to therapeutic field of tumor.With conventional cell poison
Drug is different, this kind of drug do not express mainly for normal cell or seldom express and in growth of tumour cell and breeding
Existing certain specific moleculars or target spot, therefore tumour cell can be specifically acted on without damaging normal tissue and thin
Born of the same parents.The appearance of molecular targeted antitumor drug brings hope to good, the small anti-cancer agent of toxic side effect the development of selectivity.
The small molecule anti-tumor drugs targeting clinically used at present is mainly tyrosine kinase inhibitor class antineoplastic
Object, including single target spot tyrosine kinase inhibitor and multiple receptor tyrosine kinases inhibitor.Tyrosine kinase passes through a complexity
Intracellular network path control cell Proliferation, existence, Apoptosis, angiogenesis, invasion and transfer, tumor tissues initially may be used
There can be reaction to single target spot tyrosine kinase inhibitor, but antagonistic ability can be obtained by number of mechanisms, there are these for tumour
Escape mechanism is the basis of multiple target point treatment necessity.Clinical practice again shows that single target spot tyrosine kinase inhibitor class is anti-
Tumour medicine, as Tarceva and Gefitinib are also easy to produce resistance in use although selectivity is strong, toxic side effect is small
Pharmacological property can not thoroughly kill tumour cell, and drug combination can bring serious adverse reaction, and it is special to influence respective pharmacokinetics
Property.For single target drug and a variety of single target drug drug combinations, multiple target point drug has more superiority.It is more
Target drug can effectively avoid generate drug between interaction, reduce adverse reaction, therapeutic effect more comprehensively the advantages that.Greatly
Multiple receptor tyrosine kinases inhibitor series antineoplastic medicament is measured, because its curative effect is high, the clinical characters of small toxicity, has been increasingly becoming certain
The fiest-tire medication of a little oncotherapies, such as Imatinib and Sutent.Therefore, the discovery of multiple receptor tyrosine kinases inhibitor
It is the research hotspot direction of current targeting anti-tumor medicine.
Euphorbiaceae Trigonostemon (Trigonostemon) the plant whole world is distributed in the torrid zone and Asia in Asia there are about 50 kinds
Torrid areas, China have 10 kinds, originate in the southern provinces and regions [Chinese Academy of Sciences Chinese Plants will editorial member such as Hainan, Yunnan and Guangxi
It can the Beijing Chinese Plants will the 44th (2) volume Science Press:1996,pp162-169.].Trigonostemon is because rich in antitumor
Active constituent, anti-inflammatory active ingredient, Antibacterial Constituents and HIV-resistant activity ingredient and the extensive pass by domestic and foreign scholars
Note, separation identifies compound a large amount of and with significant bioactivity from the category various plants so far, such as raw
The multiple types compounds such as alkaloids class, Diterpenes and phenanthrene derivatives class [Jayasuriya H, Zink DL, Singh SB,
Borris RP,Nanakorn W,Beck HT,Balick MJ,Goetz MA,Slayton L,Gregory L,Zakson-
Aiken M.Structure and stereochemistry of rediocide A,a highly modified
daphnane from Trigonostemon reidioides exhibiting potent insecticidal
activity.J.Am.Chem.Soc.2000,122:4998-4999.；Tan CJ,Di YT,Wang YH,Zhang Y,Si
YK,Zhang Q,Gao S,Hu XJ,Fang X,Li SF,Hao XJ.Three new indole alkaloids from
Trigonostemon lii.Org.Lett.2010,12:2370-2373.；Dong SH,Liu HB,Xu CH,Ding J,Yue
JM.Constituents of Trigonostemon heterophyllus.J.Nat.Prod.2011,74:2576-2581.；
Dong SH,Zhang CR,Xu CH,Ding J,Yue JM.Daphnane-type diterpenoids from
Trigonostemon howii.J.Nat.Prod.2011,74:1255-1261.；Tang GH,He HP,Gu YC,Di YT,
Wang YH,Li SF,Li SL,Zhang Y,Hao XJ.3,4-seco-Diterpenoids from Trigonostemon
flavidus.Tetrahedron 2012,68:9679-9684.；Tang GH,Zhang Y,Gu YC,Li SF,Di YT,
Wang YH,Yang CX,Zuo GY,Li SL,He HP,Hao XJ.Trigoflavidols A–C,degraded
diterpenoids with antimicrobial activity,from Trigonostemon
flavidus.J.Nat.Prod.2012,75:996-1000.；Tang GH,Zhang Y,Yuan CM,Li Y,Gu YC,Di
YT,Wang YH,Zuo GY,Li SF,Li SL,He HP,Hao XJ.Trigohowilols A–G,degraded
diterpenoids from the stems of Trigonostemon howii.J.Nat.Prod.2012,75:1962-
1966.；Kaemchantuek P,Chokchaisiri R,Prabpai S,Kongsaeree P,Chunglok W,Utaipan
T,Chamulitrate W,Suksamrarn A.Terpenoids with potent antimycobacterial
activity against Mycobacterium tuberculosis from Trigonostemon reidioides
roots.Tetrahedron 2017,73:1594-1601.]。
Long sequence Trigonostemon chinensis (T.howii) is Euphorbiaceae Trigonostemon plant, is Hainan Native Plants.There is customs director so far
Chemical research report is more rare in sequence Trigonostemon chinensis, and novel Diterpenes chemical composition of series structure is found that in previous studies
[Dong SH,Zhang CR,Xu CH,Ding J,Yue JM.Daphnane-type diterpenoids from
Trigonostemon howii.J.Nat.Prod.2011,74:1255-1261.；Tang GH,Zhang Y,Yuan CM,Li
Yan,Gu,YC,Di YT,Wang YH,Zuo GY,Li SF,Li SL,He HP,Hao XJ,Trigohowilols A-G,
degraded diterpenoids from the stems of Trigonostemon howii.J.Nat.Prod.2012,
75:1962-1966.；Bourjot M,Delang L,Nguyen VH,Neyts J,Gueritte F,Leyssen P,
Litaudon M.Prostratin and 12-O-tetradecanoylphorbol 13-acetate are potent and
selective inhibitors of chikungunya virus replication.J.Nat.Prod.2012,75,
2183-2187.；Ma J,Yang XY,Wang PX,Dong BJ,Su GC,Tuerhong M,Jin DQ,Xu J,Lee D,
Ohizumi Y,Lin JP,Guo YQ.Phytochemicals with NO inhibitory effects and
interactions with iNOS protein from Trigonostemon howii.Bioorg.Chem.2017,75:
71-77.]。
Invention content
The object of the present invention is to provide a kind of from long sequence Trigonostemon chinensis branches and leaves isolated has novel chemical constitution
Tetrahydrofuran derivatives class compound trigonohowine, the compound have significant antitumor activity and and positive control
The inhibitory activity of the comparable protein tyrosine kinase of medicine can be developed further into using protein tyrosine kinase as the anti-swollen of target
Tumor medicine.
To achieve the goals above, the technical scheme is that：A kind of tetrahydrofuran derivatives class compound, chemical name
For trigonohowine, chemical constitution is as follows：
It is a further object of the present invention to provide one kind isolating and purifying compound trigonohowine from long sequence Trigonostemon chinensis branches and leaves
Preparation method, its step are as follows：
A. three times by long sequence Trigonostemon chinensis branches and leaves methanol or the extraction of 90% ethanol solution, filtering is collected filtrate, then is depressurized dense
Contracting drying obtains alcohol extracting thing；
B. add water that suspension is made alcohol extracting thing, extracted successively with petroleum ether and ethyl acetate, ethyl acetate extraction
It takes liquid through being concentrated under reduced pressure, obtains ethyl acetate extraction medicinal extract；
C. ethyl acetate extraction medicinal extract is subjected to column chromatography separating purification, obtains monomeric compound trigonohowine.
Further, the step C includes：1. ethyl acetate extraction medicinal extract silica gel column chromatography is drawn section, body is pressed respectively
Product ratio 95:5,90:10,80:20,50:50 carry out chloroform-acetone gradient elution, and collected volume ratio is 90:10 chloroform-acetone
Eluate；2. taking chloroform-acetone (volume ratio 90:10) eluate removes pigment through MCI resin column chromatographies, is 70 with volume ratio:
30,80:20,90:10 methanol-water gradient elution, collected volume ratio are 80:20 methanol-water eluate；3. taking methanol-water
(volume ratio 80:20) eluate carries out reversed-phase silica gel column chromatography, is 70 with volume ratio:30,75:25,90:10 methanol-water ladder
Degree elution, collected volume ratio are 75:25 methanol-water eluate concentration；4. taking methanol-water (volume ratio 75:25) eluate is used
Preparative high performance liquid chromatography detaches, and mobile phase is acetonitrile-water, volume ratio 60:30, obtain monomeric compound
trigonohowine。
It is still another object of the present invention to provide tetrahydrofuran derivatives class compound trigonohowine to prepare anti-swell
Application in tumor medicine is provided in particular in tetrahydrofuran derivatives class compound trigonohowine and is preparing with albumen junket ammonia
Acid kinase is the application in terms of the anti-tumor drugs targeting of target.
Further, the tumor cell line includes HL-60 (people's promyelocytic leukemia cell), (human lung cancer is thin by A549
Born of the same parents), SMMC-7721 (human liver cancer cell), 5 kinds of tumours such as MCF-7 (human breast cancer cell) and SW480 (human colon cancer cell) it is thin
Born of the same parents' strain.
The present invention is extracted from ethyl acetate for the first time by carrying out system research to the chemical composition in long sequence Trigonostemon chinensis branches and leaves
Separation identifies the novel tetrahydrofuran derivatives class compound trigonohowine of a chemical constitution in position.A variety of bodies
Outer Activity evaluation shows：The compound have significant antitumor activity and with the comparable protein-tyrosine of positive control drug
The inhibitory activity of kinases can be developed further into the antitumor drug using protein tyrosine kinase as target.
Specific implementation mode
With reference to embodiment, the embodiment of the present invention is furthur described in detail.Following embodiment is used for
Illustrate the present invention, but is not limited to the scope of the present invention.In the following examples, the experimental methods for specific conditions are not specified, usually
According to conventional laboratory conditions.
Embodiment one：The preparation method (one) of compound trigonohowine
The dried powder (19.2kg, Hainan) of long sequence Trigonostemon chinensis branches and leaves is extracted three times, every time with 90% ethanol solution cold soaking
Extraction one week, filtering collect filtrate, ethanol extract 2018.3g are concentrated under reduced pressure to obtain；Add water that suspension is made the alcohol extracting thing
Liquid uses petroleum ether and ethyl acetate to extract successively, and acetic acid ethyl acetate extract obtains acetic acid ethyl ester extract through being concentrated under reduced pressure
309.1g；Acetic acid ethyl ester extract 308.0g is subjected to column chromatography separating purification：Ethyl acetate is extracted into medicinal extract silica gel column layer
Analysis segmentation, chloroform-acetone gradient elution (95:5,90:10,80:20,50:50) chloroform-acetone (volume ratio 90, is collected:10) it washes
De- object, takes chloroform-acetone (volume ratio 90:10) eluate MCI resins column chromatography removes pigment, with methanol-water gradient elution (body
Product ratio 70:30,80:20,90:10) methanol-water (volume ratio 80, is collected:20) eluate takes methanol-water (volume ratio 80:20)
Eluate carries out reversed-phase silica gel column chromatography, with methanol-water gradient elution (volume ratio 70:30,75:25,90:10) methanol-, is collected
Water (volume ratio 75:25) eluate concentrates, and takes methanol-water (volume ratio 75:25) eluate preparative high performance liquid chromatography point
From mobile phase is acetonitrile-water (volume ratio 60:40) pure compound trigonohowine (35.8mg) is obtained.
Structural identification：Pass through the various moderns wave such as optical rotational activity spectrum, ultraviolet spectra, infrared spectrum, nuclear magnetic resoance spectrum and mass spectrum
The integration analysis of spectral technology, it is determined that the chemical constitution of compound trigonohowine.
Trigonohowine, colorless oil；(c 0.11,CH3OH)；IR(KBr)vmax 3448,
1758,1719,1609,1463,1378,1122,1078,1031,978 and 716cm–1；UV(CH3OH)λmax(logε)230
(2.78)nm；1H NMR(400MHz,CDCl3) and13C NMR(100MHz,CDCl3) data are as shown in table 1；ESIMS m/z 425
[M+H]+；HRESIMS m/z 425.2899(M+H；calcd for C24H41O6,425.2898)。
1 compound trigonohowine's of table1H and 13C NMR datas
aMeasured at 400MHz.
bMeasured at 100MHz.
Embodiment two：The preparation method (two) of compound trigonohowine
The dried powder (9.8kg, Hainan) of long sequence Trigonostemon chinensis branches and leaves is extracted three times with methanol cold soaking, five days every time, filtering,
Filtrate is collected, ethanol extract (1018.2g) is concentrated under reduced pressure to obtain.Suspension is made in methanolic extract plus water, uses oil successively
Ether and ethyl acetate extraction, acetic acid ethyl acetate extract are concentrated under reduced pressure, and obtain acetic acid ethyl ester extract 158.8g；Ethyl acetate is extracted
Object 158.0g carries out column chromatography separating purification：Ethyl acetate extract medicinal extract is segmented with silica gel column chromatography, chloroform-acetone gradient is washed
De- (95:5,90:10,80:20,50:50) chloroform-acetone (volume ratio 90, is collected:10) eluate takes chloroform-acetone (volume
Than 90:10) eluate MCI resins column chromatography removes pigment, with methanol-water gradient elution (volume ratio 70:30,80:20,90:
10) methanol-water (volume ratio 80, is collected:20) eluate takes methanol-water (volume ratio 80:20) eluate carries out reverse phase silica gel column
Chromatography, with methanol-water gradient elution (volume ratio 70:30,75:25,90:10) methanol-water (volume ratio 75, is collected:25) it elutes
Object concentrates, and takes methanol-water (volume ratio 75:25) eluate is detached with preparative high performance liquid chromatography, and mobile phase is acetonitrile-water
(volume ratio 60:40) monomeric compound II (19.8mg) is obtained.
The structural identification of compound II：Colorless oil；HR-ESIMS shows [M+H] of compound II+For m/
z425.2897；The total TLC of compound trigonohowine that compound II is obtained with preparation method in embodiment one are opened up at three kinds
[petroleum ether-acetone (7 is opened under system:3), petroleum ether-ethyl acetate (5:And chloroform-acetone (8 5):2)] it is uniform spot,
Illustrate that the compound and compound trigonohowine are same compound.
Embodiment three：The antitumor activity of compound trigonohowine
1, experimental method：Five kinds of kinds of tumor cell line HL-60s, A549, SMMC-7721, MCF-7 and SW480 are distinguished
With the RPMI-1640 culture mediums containing 10% calf serum, in 37 DEG C, 5%CO2It is cultivated in incubator.Cell is carried out using mtt assay
Proliferation Ability is tested, and primary operational is：The tumor cell line of logarithmic growth phase, with 0.25% trypsin digestion, 10%
The RPMI-1640 culture solutions of newborn calf serum are modulated into 5 × 104The cell suspension of a/mL is inoculated in 96 orifice plates, per hole
It is inoculated with 180 μ L.At 37 DEG C, 5%CO28-10h is cultivated under the conditions of saturated humidity, waits for that its is adherent, what each hole addition was prepared with PBS
Sample liquid so that sample final concentration is respectively 0.1,1 and 10 μ g/mL.Each parallel 3 hole of concentration is continued after cultivating 44h, per hole
50 μ L MTT (1mg/mL are added-1, PBS prepares), at 37 DEG C, 5%CO2Under the conditions of continue incubate 4h, suction abandon culture supernatant in hole
150 μ L DMSO are added per hole for liquid, and 15min is shaken up on microoscillator and is selected on enzyme-linked immunosorbent assay instrument after crystallization dissolving
570nm is selected, the light absorption value in each hole is measured, while blank group (celliferous culture solution is only added) and control group are set (with culture
Liquid alternative medicine), calculate cell proliferation inhibition rate.Inhibiting rate (%)=(3 hole OD values average value of 1- experimental groups/3 hole OD of control group
It is worth average value) × 100%.Make ordinate with inhibiting rate, make regression curve, calculates sample IC50Value.It is counted using SPSS13.0
Software package carries out data processing and statistical analysis.
2, antitumor activity experimental result (being shown in Table 2)
The compound trigonohowine obtained by embodiment one is to selected tumor cell line HL-60, A549, SMMC-
7721, the proliferation inhibition activity of the equal showed differents of MCF-7 and SW480.
The antitumor activity evaluation result of 2 compound trigonohowine of table
Example IV：The inhibition protein tyrosine kinase activity of compound trigonohowine
The extraction of PTKs in rat cerebral tissue：Rat brain is taken out, meninx is rejected, weighs, the cooled homogenate of 4 times of amounts is added
Liquid.Glass homogenizer high-speed homogenization, centrifugation is used to collect supernatant, then centrifuge 10min in ice bath.Supernatant is collected, in supernatant
Containing endochylema type tyrosine kinase, and precipitates and can be used as receptor type tyrosine kinase use.A small amount of supernatant is left and taken for extracting
The assay of protein in object, remaining packing, is placed in -70 DEG C and saves backup.
ELISA Plate is coated with：Substrate dilution is added in 96 hole elisa Plates (per 125 μ L of hole), 37 DEG C of overnight incubations.It removes
Excess substrate liquid in plate is added phosphate buffer (PBS-Tween 20) and washs, in 37 DEG C of dry 2h.4 DEG C save backup.
Ptk inhibitor screens：First sample is added in ELISA Plate, 37 DEG C of incubations, addition kinase buffer liquid is diluted
ATP, 37 DEG C of incubations remove the reaction solution in plate, washing；Antibody complex, 37 DEG C of incubations are added；Remove plate moderate resistance bluk recombination
Tetramethyl benzidine (TMB) developing solution is added in object, washing, and room temperature is protected from light, and terminate liquid is added, and is measured at 450nm wavelength
Absorbance (A) value.Positive control drug is Imatinib.The inhibiting rate of compound trigonohowine according to the following formula：Suppression
Rate %=(A processedNormally-ASample)/(ANormally-ABlank) * 100%
The result shows that compound trigonohowine has significant inhibiting effect (inhibiting rate to protein tyrosine kinase
77.28%), inhibitory activity and the inhibitory activity of positive control drug Imatinib are suitable (inhibiting rate 71.56%).
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, several improvements and modifications can also be made, these improvements and modifications
Also it should be regarded as protection scope of the present invention.
Claims (6)
1. a kind of tetrahydrofuran derivatives class compound, the entitled trigonohowine of chemistry, chemical constitution are as follows：
2. the preparation method of tetrahydrofuran derivatives class compound trigonohowine as described in claim 1, feature exist
In its step are as follows：
A. three times by long sequence Trigonostemon chinensis branches and leaves methanol or the extraction of 90% ethanol solution, filtering is collected filtrate, then is concentrated under reduced pressure dry
It is dry, obtain alcohol extracting thing；
B. add water that suspension is made alcohol extracting thing, extracted successively with petroleum ether and ethyl acetate, acetic acid ethyl acetate extract
Through being concentrated under reduced pressure, ethyl acetate extraction medicinal extract is obtained；
C. ethyl acetate extraction medicinal extract is subjected to column chromatography separating purification, obtains monomeric compound trigonohowine.
3. the preparation method of tetrahydrofuran derivatives class compound trigonohowine as claimed in claim 2, feature exist
In：The step C includes：1. ethyl acetate extraction medicinal extract silica gel column chromatography is drawn into section, respectively by volume 95:5,90:10,
80:20,50:50 carry out chloroform-acetone gradient elution, and collected volume ratio is 90:10 chloroform-acetone eluate；2. taking chloroform-
Acetone eluate removes pigment through MCI resin column chromatographies, is 70 with volume ratio:30,80:20,90:10 methanol-water gradient is washed
De-, collected volume ratio is 80:20 methanol-water eluate；3. methanol-water eluate is taken to carry out reversed-phase silica gel column chromatography, body is used
Product is than being 70:30,75:25,90:10 methanol-water gradient elution, collected volume ratio are 75:25 methanol-water eluate is dense
Contracting；4. methanol-water eluate is taken to be detached with preparative high performance liquid chromatography, mobile phase is acetonitrile-water, volume ratio 60:30, it obtains
To monomeric compound trigonohowine.
4. tetrahydrofuran derivatives class compound trigonohowine described in claim 1 is in the preparation of antitumor drugs
Using.
5. tetrahydrofuran derivatives class compound trigonohowine as claimed in claim 4 is being prepared with protein-tyrosine
Kinases is the application in terms of the anti-tumor drugs targeting of target.
6. application as described in claim 4 or 5, it is characterised in that：The tumor cell line includes HL-60 (people's original myelocytes
Leukaemia cell), A549 (human lung carcinoma cell), SMMC-7721 (human liver cancer cell), MCF-7 (human breast cancer cell) and SW480
5 kinds of tumor cell lines such as (human colon cancer cell).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347492A (en) * | 2008-09-02 | 2009-01-21 | 韩长日 | Use of Trigonostemon xyphophylloides extract in preparing anti-AIDS medicament |
| CN102724990A (en) * | 2009-07-29 | 2012-10-10 | 印第安纳大学研究及科技有限公司 | Extracts of medicinal plant and uses thereof |
| KR20160147540A (en) * | 2015-06-15 | 2016-12-23 | 대한민국(환경부 국립생물자원관장) | Composition for Anti-inflammation Using an Extract of Trigonostemon reidioides |
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2018
- 2018-04-10 CN CN201810317894.5A patent/CN108440458B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347492A (en) * | 2008-09-02 | 2009-01-21 | 韩长日 | Use of Trigonostemon xyphophylloides extract in preparing anti-AIDS medicament |
| CN102724990A (en) * | 2009-07-29 | 2012-10-10 | 印第安纳大学研究及科技有限公司 | Extracts of medicinal plant and uses thereof |
| KR20160147540A (en) * | 2015-06-15 | 2016-12-23 | 대한민국(환경부 국립생물자원관장) | Composition for Anti-inflammation Using an Extract of Trigonostemon reidioides |
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