CN103709227B - Double bond substitution triptolide derivatives and its preparation method and application - Google Patents
Double bond substitution triptolide derivatives and its preparation method and application Download PDFInfo
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- CN103709227B CN103709227B CN201210380144.5A CN201210380144A CN103709227B CN 103709227 B CN103709227 B CN 103709227B CN 201210380144 A CN201210380144 A CN 201210380144A CN 103709227 B CN103709227 B CN 103709227B
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- triptolide
- cancer
- double bond
- methylene
- preparation
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- 238000006467 substitution reaction Methods 0.000 title claims description 7
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- RXHIKAIVEMAPRU-JRIGQVHBSA-N sequiterpene Natural products C1=C(C)[C@@H](OC(C)=O)[C@H](O)[C@@]2(O)[C@H](C)CC[C@@H](C(C)=C)[C@H]21 RXHIKAIVEMAPRU-JRIGQVHBSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of formula（Ⅰ）Shown double bond replaces triptolide derivatives or its pharmaceutically acceptable salt or hydrate or their optical isomer, wherein R1=OH, R2=H, or R1=H, R2=OH.The invention also discloses its preparation method and the application in the medicine for treating cancer and with cancer-related diseases is prepared.
Description
Technical field
The present invention relates to the structure of modification and activity research of biological active constituents from natural medicines, and in particular to double bond replaces thunder godvine
The research of lactone derivatives and preparation method and treatment hyperplastic tumours disease.
Background technology
Thunder godvine, popular name gelsemium elegan is Celastraceae (Celastraceae) Thunder God Calamus bejuco, is China's tool
Some resources are than a kind of more rich plant.Thunder God Calamus (Tripterygium) plant has four kinds, i.e. thunder godvine
(Tripterygium wilfordii Hook f.), tripterygium hypoglaucum hutcs (Tripterygium hypoglaucum
Levl.Hutch), Tripterygium regeli (black climing) (Tripterygium regelii Sprague et Takeda) and Cangshan thunder
Public rattan (Tripterygium forretii Dicls), is distributed in China.Thunder godvine record earliest in《Legendary god of farming's book on Chinese herbal medicine
Through》, its main chemical compositions has diterpene, triterpene, sequiterpene, alkaloid etc., so far the isolating from tripterygium plant
Nearly 200 kinds of compound.The research that recent two decades come shows that it has antitumor, anti-inflammatory, immunosupress, antifertility, antibacterial etc. various
Activity.
Among the people for treating tumour history for many years, wherein one of active component is Triptolide to thunder godvine plant
Alcohol.Triptolide also once enters clinical test in addition to having obtained extensive antitumor action and having studied, white for treating
Blood disease, but the larger toxic and side effect of triptolide, excessively narrow treatment window, limit it and are applied in clinic.With
It is confined in the introduction of water soluble group mostly toward the structure of modification to triptolide, essence is had no in agent structure and is changed
It is dynamic.After this kind of prodrug enters in vivo, drug effect is played in vivo by being still transformed into triptolide after hydrolysis or metabolism
Effect, this just determines that they can not possibly fundamentally improve the toxic and side effect of triptolide.Simultaneously in thunder godvine
Ester alcohol C14Found when-position is transformed, the group configuration of the position is very notable for the influence of compound activity, optical siomerism
The problem of body increased very big difficulty to synthesis and mask work.
The research focused on to triptolide structure-activity relationship of the invention, has been carried out different from existing to its structure
The transformation and modification of technology, obtain the triptolide derivatives of a collection of new structure, so as to complete the present invention.
The content of the invention
One of technical problems to be solved by the invention be for the problems of existing triptolide
Triptolide C5- position or C15- position introduces hydroxyl, C14- position introduces exocyclic double bond, forms a collection of double bond substitution Triptolide
Derivative.
The two of the technical problems to be solved by the invention are to provide one kind with 14- double bond Triptolides as basic structure
Hydroxyl replace triptolide derivatives preparation method.
The three of the technical problems to be solved by the invention are by the hydroxyl with 14- double bond Triptolides as basic structure
Base replaces the pharmacological toxicology experimental study of triptolide derivatives, finds it for tumor disease, especially reproductive system
Tumour has good therapeutic action, with efficient, low toxicity, with conventional cell poison spy of the antineoplastic without cross-resistance
Point, with the DEVELOPMENT PROSPECT for being used to treat the proliferative diseases such as tumour well.
The double bond substitution triptolide derivatives that the present invention is provided are formula（Ⅰ）Shown compound or its can pharmaceutically connect
The salt or hydrate or their optical isomer received：
Wherein, R1=OH, R2=H, or R1=H, R2=OH。
In a preferred embodiment of the invention, formula（Ⅰ）Middle R1=OH, R2=H, i.e., following structural formula（Ⅰa）Shownization
Compound：
In a preferred embodiment of the invention, formula（Ⅰ）Middle R1=H, R2=OH, i.e., following structural formula（Ⅰb）Shownization
Compound：
Preparation method of the invention is as follows：
1st, structural formula（Ⅰa）The preparation method of shown compound, comprises the steps of：
Step 1：With triptonide（1）It is starting material, in non-protonic solvent, is entered using iodomethane grignard reagent
C14 carbonyl for attacking triptonide is obtained（14S）- 14 Beta-methyl Epitriptolides（2）；
Step 2：（14S）- 14 Beta-methyl Epitriptolides（2）It is dehydrated with TFAA in non-protonic solvent
Obtain C14 exocyclic double bond product 14- dehydroxylation -14- methylene triptolide（3）；
Step 3：14- dehydroxylation -14- methylene triptolides（3）In the potato culture medium containing Neurospora crassa
Middle culture prepares 14- dehydroxylation -14- methylene -5- hydroxy triptolides（Ⅰa）
2nd, structural formula（Ⅰb）The preparation method of shown compound, comprises the steps of：
Step 1：14- dehydroxylation -14- methylene triptolides（3）It is micro- using rats'liver in phosphate buffer solution
Mitochondrial protein is incubated and prepares 14- dehydroxylation -14- methylene -15- hydroxy triptolides（Ⅰb）
Fluorine of the invention substitution triptolide derivatives prepare for treating cancer and with cancer-related diseases
Application in medicine.
The cancer is kidney, breast cancer, lung cancer, malignant mela noma, colon cancer, prostate cancer or oophoroma.
Term used has following meaning in this specification：
" pharmaceutically acceptable salt " can specifically be enumerated and propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, Malaysia
The acidic amino acid such as the organic acids such as acid, lactic acid, malic acid, tartaric acid, citric acid and aspartic acid, glutamic acid formed ester after again with
The salt that inorganic base is formed, such as sodium, potassium, calcium, aluminium salt and ammonium salt, or the salt formed with organic base, such as methylamine salt, ethylamine salt, ethanol
Amine salt etc., or with the basic amino acid such as lysine, arginine, ornithine formed the hydrochloric acid after ester, hydrobromic acid, hydrofluoric acid, sulfuric acid,
The salt of the inorganic acids such as nitric acid, phosphoric acid, or the salt with the organic acid such as formic acid, acetic acid, picric acid, methanesulfonic acid, ethyl sulfonic acid.
The implication of " hydrate " includes monohydrate, dihydrate, trihydrate.
The implication of " optical isomer " includes enantiomter, diastereoisomer, the mixture of optical isomer and pure
Optical isomer.
Double bond substitution triptolide derivatives of the invention, its pharmaceutically acceptable salt or optical isomer can be made into
0.001-99.9% containing active component（Weight）And the various preparations of appropriate pharmaceutically acceptable carrier, as suited for it is oral,
The dosage form that injection or intestinal canal administration are used.
Can be according to the age of subject（Monthly age or week old）, general health, disease severity and the course of disease, administration
Approach, human body apply the pharmaceutical preparation of the compounds of this invention containing therapeutically effective amount to sensitiveness of medicine etc. to subject.
Brief description of the drawings
Fig. 1 is the 14- dehydroxylation -14- methylene -5- hydroxy triptolides of the preparation of the embodiment of the present invention 1 to external
Cultivate the amount-effect curve schematic diagram of HOC's SK-OV-3 Carbazole alkaloids.
Fig. 2 is the 14- dehydroxylation -14- methylene -15- hydroxy triptolides of the preparation of the embodiment of the present invention 2 to external
Cultivate the amount-effect curve schematic diagram of HOC's SK-OV-3 Carbazole alkaloids.
Specific embodiment
The present invention is further elaborated with reference to example, but these embodiments are definitely not to any limit of the invention
System, the scope of the present invention is determined by claim.
First, embodiment is prepared
Embodiment 1
Structural formula（Ⅰa）The preparation of 14- dehydroxylation -14- methylene -5- hydroxy triptolides
Step 1
The preparation of the Beta-methyl Epitriptolide of structural formula (2) (14S) -14
10mL absolute ethers are added under argon gas protection contains magnesium chips（264mg, 11mmol）Reaction bulb in, will be dissolved in
The MeI of 5mL absolute ethers（1.42g, 10mmol）It is added drop-wise in above-mentioned reaction system through constant pressure funnel.Finish the dark gray
Reaction system is stirred at room temperature half an hour.The freshly prepared MeMgI grignard reagents solution of 1.37mL is taken, is added dropwise over having dissolved
In the triptonide 1 of 8mL dry tetrahydrofurans（90mg, 0.25mmmol）In.Stop reaction after reacting 2 hours at room temperature,
Reaction system is quenched with saturated ammonium chloride solution, and ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is done
It is dry, the crude by column chromatography purifying after concentration（Ethyl acetate：Petroleum ether=1：5）Obtain the Beta-methyl of white solid (14S) -14
Epitriptolide 2（70mg, yield 73%）.MS(ESI):m/z375[M+1]+。1H NMR(CDCl3,300MHz):δ4.66
(s,2H),3.75(d,1H,J=3.2Hz),3.74(d,1H,J=3.2Hz),2.75-2.63(m,1H),2.47(sept,1H,J=
6.9Hz),2.34-2.22(m,1H),2.21-2.03(m,2H),1.85(t,1H,J=14.1Hz),1.58-1.48(m,4H),
1.24-1.10(m,1H),1.03(s,3H),0.94(d,3H,J=6.9Hz),0.79(d,3H,J=6.9Hz)。
Step 2
The preparation of structural formula (3) 14- dehydroxylation -14- methylene triptolides
By MsCl（0.18mL, 2.2mmol）, dry TEA（2.17mL, 15.6mmol）With dry pyridine（2.4mL,
29.6mmol）In sequentially adding the dry DCM solution of 7mL.At room temperature, by (14S) -14 Beta-methyl Epitriptolide 2
（130mg, 0.35mmol）It is dissolved in the dry DCM of 5mL, adds in above-mentioned reaction system, is dripped to reaction system under stirring
Plus trifluoro-acetic anhydride（0.24mL, 1.7mmol）, add water terminating reaction after reaction 2h at room temperature.Removal of solvent under reduced pressure, residue is used
Ethyl acetate is extracted, organic layer water, saturated common salt water washing, anhydrous sodium sulfate drying.Crude by column chromatography after concentration
Purifying（Ethyl acetate：Petroleum ether=1：5）Obtain white solid 14- dehydroxylation -14- methylene triptolide 3（102mg,
Yield 82%）.MS(ESI):m/z355[M+1]+。1H NMR(CDCl3,300MHz):δ5.53(s,1H),5.39(s,1H),
4.83-4.80(m,2H),3.97(d,1H,J=3.0Hz),3.64(d,1H,J=3.0Hz),3.54-3.52(m,1H),3.07-
3.05(m,1H),2.87-2.83(m,1H),2.53-2.42(m,1H),2.29-2.14(m,2H),1.99-1.89(m,1H),
1.53-1.46(m,1H),1.42-1.33(m,1H),1.09(s,3H),0.97(d,3H,J=6.9Hz),0.87(d,3H,J=
6.9Hz)。
Step 3
The preparation of structural formula (I a) 14- dehydroxylation -14- methylene -5- hydroxy triptolides
During Neurospora crassa to be chosen 250mL triangular flasks (equipped with 60mL potatoes culture medium) from test tube slant, 200rpm, 25
Shaken cultivation adds the ethanol solution of the 14- dehydroxylation -14- methylene triptolide 3 of 200 μ L10mg/mL at DEG C after 1 day
（Containing 10%DMSO）, continue to cultivate 4 days under similarity condition.Filtering fermentation liquor, filtrate are extracted 3 times with isometric ethyl acetate,
Neurospora crassa is then with appropriate ethyl acetate ultrasonic extraction 30 minutes.Merge two-part ethyl acetate, rotary evaporation is removed
Solvent, obtains conversion product residue.The residue is separated through half preparative high-performance liquid chromatographic, collects stream part, 40 °C of removings concentrated under reduced pressure
Solvent, obtains a of 14- dehydroxylation -14- methylene -5- hydroxy triptolides I（0.4mg, yield 20%）.MS(ESI):m/z373
[M+1]+。1H NMR(CD3OD,300MHz):δ5.55(s,1H),5.42(s,1H),4.84-4.80(m,2H),3.90(d,1H,J
=2.7Hz),3.65(d,1H,J=2.7Hz),3.07-3.06(m,1H),2.52-2.43(m,1H),2.28-2.06(m,3H),
1.91-1.81(m,1H),1.32-1.21(m,2H),1.13(s,3H),0.99(d,3H,J=6.3Hz),0.87(d,3H,J=
6.3Hz)。
Embodiment 2
Structural formula（Ⅰb）The preparation of 14- dehydroxylation -14- methylene -15- hydroxy triptolides
Step 1
Structural formula（Ⅰb）The preparation of 14- dehydroxylation -14- methylene -15- hydroxy triptolides
The storing solution of 14- dehydroxylation -14- methylene triptolide 3（50mM）Prepared using methyl alcohol, be finally incubated body
Methanol content is 0.1% in system.Single incubation system volume is 10mL, and medium is 100mM phosphate buffers（PBS, pH7.4）, bag
Include rat liver microsomes body protein, 50 μM of the and of 14- dehydroxylation -14- methylene triptolide 3 of final concentration of 0.5mg/mL
The NADPH of 1mM, 37 °C of water-baths are incubated 2h.With the rat of ethyl acetate extraction 14- dehydroxylation -14- methylene triptolide 3
Hepatomicrosome artemia hatching solution, 40 °C of removing solvents concentrated under reduced pressure, with 5ml methyl alcohol：Water 65：35 dissolvings, the solution prepares efficient through half
Liquid chromatogram is separated, and collects stream part, and 40 °C of removing solvents concentrated under reduced pressure obtain 14- dehydroxylation -14- methylene -15- hydroxyl Thunder Gods
The b of rattan lactone alcohol I（10mg, yield 10%）.MS(ESI):m/z373[M+1]+。1H NMR(CDCl3,400MHz):δ5.82(s,
1H),5.65(s,1H),4.84-4.80(m,2H),3.97(d,1H,J=3.3Hz),3.87(d,1H,J=3.3Hz),3.07-
3.06(m,1H),2.87-2.83(m,1H),2.28-2.08(m,3H),1.97-1.92(m,1H),1.52-1.38(m,2H),
1.35(s,3H),1.34(s,3H),1.09(s,3H).13C NMR(CDCl3,100MHz):δ176.68,164.65,140.77,
125.90,119.11,72.52,72.08,67.01,66.68,64.93,62.58,57.48,42.13,37.30,31.90,
27.28,27.05,25.22,18.51,14.63。
2nd, pharmacodynamic evaluation test example
14- dehydroxylation -14- methylene -5- hydroxy triptolides and embodiment 2 prepared by embodiments of the invention 1
The HOC SK- of 14- dehydroxylation -14- methylene -15- 2 Compounds in vitro cultures of hydroxy triptolide of preparation
The growth inhibition effect research of OV-3 cells.
HOC SK-OV-3 cells are cultivated with the DMEM culture mediums (Gibco, the U.S.) containing 10% hyclone, cultivate bar
Part is 37 DEG C, 5%CO2, tumour cell 0.7x104/ hole is inoculated in 96- orifice plates, and after 24 hours, addition storing solution is dimethyl sulfoxide (DMSO)
Configuration (10-2M), each compound of normal saline dilution, makes final concentration of 10 in culture medium-5、10-6M, acts on 72 hours.Discard
Nutrient solution, cell is fixed with 10% cold trichloroacetic acid, is dyeed with Sulforhodamine B (Sulforhodamine B, SRB) solution, is washed
After removing uncombined SRB, Tris dissolves and protein bound SRB, and ELIASA determines OD values under 560nM wavelength, by following equation
Calculate inhibitory rate of cell growth：Inhibiting rate=(OD valuesControl wells- OD is worthDosing holes)/OD valuesControl wellsx100%.Obtain the 14- of the preparation of embodiment 1
Dehydroxylation -14- methylene -5- hydroxy triptolides（Referring to Fig. 1）14- dehydroxylation -14- the methylenes prepared with embodiment 2
Amount-effect curve of the base -15- hydroxy triptolides in vitro culture HOC's SK-OV-3 Carbazole alkaloids（Referring to Fig. 2）.
14- prepared by 14- dehydroxylation -14- methylene -5- hydroxy triptolides and embodiment 2 prepared by embodiment 1
Dehydroxylation -14- methylene -15- hydroxy triptolides are shown in the growth inhibition effect result of HOC's SK-OV-3 cells
Table 1.
Growth inhibition effect of the compound of table 1. to HOC's SK-OV-3 cells
| Sequence number | Evaluate | |
| Ia | 3000 | Effectively |
| Ib | 390 | Effectively |
The activity data listed in table 1 shows that compound of the invention has effective suppression HOC SK-OV-3 thin
The effect of intracellular growth.
Compound above prepares embodiment and pharmacodynamic evaluation experimental example is merely illustrative the change of present invention offer
Structure of compound and preparation method thereof and the pharmacological results, but this can be made to one skilled in the art a variety of
Modifications and variations, it is all these in the appending claims covering present invention without departing from the spirit and scope of the present invention
Modification.
Claims (4)
1. the double bond shown in formula (Ib) replaces triptolide derivatives：
2. a kind of method that double bond prepared described in claim 1 replaces triptolide derivatives, it is characterised in that structural formula
(Ib) compound is prepared from by following steps shown in：
Step 1：14- dehydroxylations -14- methylene triptolide (3) uses rat liver microsomes in phosphate buffer solution
Albumen is incubated and prepares 14- dehydroxylations -14- methylene -15- hydroxy triptolides (I b).
3. described in claim 1 double bond substitution triptolide derivatives prepare for treating cancer and with cancer phase
Application in the medicine of related disorders.
4. application as claimed in claim 3, wherein the cancer is kidney, breast cancer, lung cancer, malignant mela noma, colon
Cancer, prostate cancer or oophoroma.
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| CN201210380144.5A CN103709227B (en) | 2012-10-09 | 2012-10-09 | Double bond substitution triptolide derivatives and its preparation method and application |
| PCT/CN2013/084291 WO2014056401A1 (en) | 2012-10-09 | 2013-09-26 | Double-bond substituted tripterygium wilfordii lactone derivative and preparation method and use thereof |
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|---|---|---|---|---|
| CN1726025A (en) * | 2002-12-17 | 2006-01-25 | 泛华医药公司 | Triptolide derivatives as immunomodulator and anticancer agents |
| CN101255186A (en) * | 2008-04-10 | 2008-09-03 | 中国科学院上海药物研究所 | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726025A (en) * | 2002-12-17 | 2006-01-25 | 泛华医药公司 | Triptolide derivatives as immunomodulator and anticancer agents |
| CN101255186A (en) * | 2008-04-10 | 2008-09-03 | 中国科学院上海药物研究所 | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 雷公藤甲素和雷公藤内酯酮的生物转化研究;宁黎丽;《中国优秀博硕士学位论文全文数据库（博士）工程科技I辑》;20040915(第03期);B016-33 * |
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Effective date of registration: 20190827 Address after: Room 650-10, Building No. 2, 351 Guoshoujing Road, Shanghai Free Trade Pilot Area, 201203 Patentee after: SHANGHAI HUILUN LIFE SCIENCE & TECHNOLOGY Co.,Ltd. Address before: Room 304-12, 665 Zhangjiang Road, Shanghai Free Trade Pilot Area, Pudong New Area, Shanghai 201210 Patentee before: Shanghai Huilun Pharmaceutical Technology Co.,Ltd. |
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| CP01 | Change in the name or title of a patent holder |
Address after: Room 650-10, Building No. 2, 351 Guoshoujing Road, Shanghai Free Trade Pilot Area, 201203 Patentee after: Shanghai Hui Bio Technology Co.,Ltd. Address before: Room 650-10, Building No. 2, 351 Guoshoujing Road, Shanghai Free Trade Pilot Area, 201203 Patentee before: SHANGHAI HUILUN LIFE SCIENCE & TECHNOLOGY Co.,Ltd. |
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| CP03 | Change of name, title or address |
Address after: 200241 floor 10, building 5, No. 525, Yuanjiang Road, Minhang District, Shanghai Patentee after: Shanghai Huilun Pharmaceutical Co.,Ltd. Address before: Room 650-10, building 2, 351 GuoShouJing Road, Shanghai pilot Free Trade Zone, 201203 Patentee before: Shanghai Hui Bio Technology Co.,Ltd. |