CN107739381A - Curcuma zedoary 01 derivatives and its application in antineoplastic is prepared - Google Patents
Curcuma zedoary 01 derivatives and its application in antineoplastic is prepared Download PDFInfo
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- CN107739381A CN107739381A CN201710983039.3A CN201710983039A CN107739381A CN 107739381 A CN107739381 A CN 107739381A CN 201710983039 A CN201710983039 A CN 201710983039A CN 107739381 A CN107739381 A CN 107739381A
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- alkyl
- derivatives
- curcuma zedoary
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- alkoxy
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- 0 CC(C)[C@](C[C@]([C@@](C)CC1)([C@]1(C)*(C1)=C)O)C1O Chemical compound CC(C)[C@](C[C@]([C@@](C)CC1)([C@]1(C)*(C1)=C)O)C1O 0.000 description 2
- DDRPCXLAQZKBJP-UHFFFAOYSA-N NCc1ccc[o]1 Chemical compound NCc1ccc[o]1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
Abstract
Application the present invention relates to curcuma zedoary 01 derivatives and its in antineoplastic is prepared.By carrying out structural modification to curcuma zedoary 01 derivatives, amine is further introduced by Mannich reaction after the hydroxy position of rcumenol introduces chaff amine fragment, obtains a series of curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, hydrate, solvate or prodrug with formula (I) structure for having no document report.Being tested by Bioactivity confirms, these new curcuma zedoary 01 derivatives have inhibitory activity to cervical carcinoma, liver cancer, lung cancer etc. respectively, and most compound activity is significantly higher than its parent rcumenol.In addition, the polarity of the curcuma zedoary 01 derivatives of overwhelming majority synthesis is significantly increased compared to rcumenol, according to the similar principle that mixes, prove that the curcuma zedoary 01 derivatives solubility of synthesis is higher than parent compound rcumenol to a certain extent, preparation research is preferably carried out for it, performance drug effect provides main theoretical basis of the reform of Chinese economic structure.
Description
Technical field
The present invention relates to pharmaceutical technology field, more precisely say be rcumenol derivative, the preparation side of curcuma zedoary 01 derivatives
The purposes of method and curcuma zedoary 01 derivatives.It is that structural modification is carried out to the monomer rcumenol with antitumor activity, obtains a series of
The curcuma zedoary 01 derivatives of better efficacy.
Background technology
Tumour serious threat the life of the mankind and health, the death rate are number two, and is only second to the painstaking effort of the death rate first
Pipe disease.IARC's prediction is following 20 years or so, and the case that cancer is died from the whole world will rise to annual 13000000,
It is newly-increased to rise to annual 22000000 with cases of cancer.Tumour will turn into significant problem, situation in future in control and prevention of disease
Also become increasingly severeer, the number of the infected to or so the year two thousand fifty is expected that 23,830,000 people will be risen to, and death toll will rise to
16000000 people.Shown according to items investigation, be substantially higher in the cancer morbidity and cancer mortality of developing country in prosperity
Country.Industrialization, urbanization, modernization and the quickening of IT application process, bad life style, environment are promoted along with China
The situation that the problems such as pollution and aged number are continuously increased faces malignant tumour is more severe.China suffers from the disease of malignant tumour
There may be 286 people morbidity in every 100,000 people of people.180 people, which are there are about, in every 100,000 people dies from malignant tumour.Current China is frequently-occurring
Cancer is the cancers such as stomach cancer, lung cancer, liver cancer, colon cancer, breast cancer and the cancer of the esophagus.Stomach cancer, lung cancer, liver cancer, colon cancer, breast cancer
This six kinds of cancer patients account for more than the sixty percent of malignant tumor patient total number of persons with the cancer of the esophagus.Wherein liver cancer, lung cancer morbidity rate are continuous
Rise and be significantly higher than the global average level incidence of disease.
In recent years, Chinese medicine is by feat of its multicomponent, Mutiple Targets, too many levels effect and advantage obtains to human injury is small etc.
The extensive attention of medical personal.There is very extensive bioactive substance in Chinese herbal medicine and plant medicines natural products.
These natural products toxic side effects are small, good with people's histocompatbility.So the antineoplastic for extracting to obtain in Chinese medicine can
It is effective to mitigate adverse reaction.In addition, the resource of these natural products is extremely abundant, can be greatly reduced the treatment of tumor patient into
This.The one of value is mentioned that, found at present in Chinese herbal medicine with the small antineoplastic of unique effect, toxic side effect and its
The research work of ancillary drug has been achieved for a series of achievement, is improving the quality of life of tumour patient, is extending neoplastic disease
The life of people and success rate of raising treatment tumor patient etc. all achieve significant effect.
One of the important substance of rcumenol as Curcuma Aromatic Oil, it is many currently for its antitumor pharmacological action
Research, related research shows that curcuma zedoary can not only be directed to a variety of cancer cells and produce the effect directly destroyed, and can strengthen
Body immune system specificity, so that body obtains obvious anticarcinogenic effect, but because rcumenol water solubility is poor, makes it
Clinical practice is restricted.
The content of the invention
An object of the present invention is using rcumenol as lead compound, according to the design feature of rcumenol in itself, to it
Hydroxyl sites carry out structural modification, synthesize a series of new curcuma zedoary 01 derivatives.
The second object of the present invention is a series of new antineoplastics with more preferable pharmacological activity of synthesis.
The third object of the present invention is to provide using these compounds as effective medicinal active ingredient and is used for antitumor
Medicine.
The fourth object of the present invention is to provide these compounds process for production thereof.
The present invention to its structure modify the compound of synthesis, its structural formula such as formula using rcumenol as lead compound
(Ⅰ)
Wherein, L isR is selected from-NR1R2。
R1And R2It is identical or different, separately selected from hydrogen, C1-C10Alkyl, C3-C7Cycloalkyl, optionally by 1-3 phase
Same or different R3Substituted C1-C10Alkyl, optionally the identical or different R by 1-33Substituted C3-C7Cycloalkyl；
Or R1And R2With forming 5-10 circle heterocycles bases together with the nitrogen-atoms connected with them, the heterocyclic radical except with R1
And R2Outside the nitrogen-atoms of connection, optionally containing the 1-4 hetero atoms for being selected from N, O and S, optionally by 1-3 identical or different R4Take
Generation；
R3For C1-C6Alkyl, C1-C4Alkoxy, halogen, hydroxyl, cyano group, carboxyl, ester group or NR5R6；
R4For C1-C6Alkyl, C1-C4Alkoxy, halogen, hydroxyl C1-C6Alkyl, C1-C4Alkoxy C1-C6Alkyl, carboxyl, ester
Base, aryl, aralkyl, aryloxy group, aralkoxy, heteroaryl, CONR5R6Or NR5R6；
R5And R6It is identical or different, separately selected from hydrogen, C1-C6Alkyl or C3-C7Cycloalkyl.
Preferably, R1And R2It is identical or different, separately selected from hydrogen, C1‐C4Alkyl, C3‐C4Cycloalkyl, optionally by 1-
3 identical or different R3Substituted C1‐C4Alkyl, optionally the identical or different R by 1-33Substituted C3‐C4Cycloalkyl；
Or R1And R2With forming 5-6 circle heterocycles bases together with the nitrogen-atoms connected with them, the heterocyclic radical except with R1With
R2Outside the nitrogen-atoms of connection, optionally containing the 1-2 hetero atoms for being selected from N, O and S, optionally by 1-3 identical or different R4Take
Generation；
R3For C1-C3Alkyl, C1-C3Alkoxy, halogen, hydroxyl, cyano group, carboxyl, ester group or NR5R6；
R4For C1-C3Alkyl, C1-C3Alkoxy, halogen, hydroxyl C1-C3Alkyl, C1-C3Alkoxy C1-C3Alkyl, carboxyl, ester
Base, aryl, aralkyl, CONR5R6Or NR5R6；
R5And R6It is identical or different, separately selected from hydrogen, C1-C3Alkyl, C3-C4Cycloalkyl.
It is furthermore preferred that described aryl is selected from phenyl, xenyl, naphthyl；Or aryl optionally by 1,2 or 3 independently
Selected from C1‐C3Alkyl, C1‐C3Alkoxy, halogen, cyano group, morpholinyl, piperidyl, the substituent of trifluoromethyl or trifluoromethoxy
Substitution；
Described aralkyl is selected from-(CH2) n- aryl.
It is furthermore preferred that described aryl is selected from phenyl；Or aryl optionally by 1,2 or 3 independently selected from C1‐C3Alkyl,
C1‐C3The substituent substitution of alkoxy, halogen, morpholinyl, piperidyl, trifluoromethyl or trifluoromethoxy；
Described aralkyl is selected from-(CH2) n- aryl, n 1-3.
The present invention, the preparation method of curcuma zedoary 01 derivatives：Using chaff amine and rcumenol as initiation material, by chloroacetylation,
It is as follows into ether, Mannich reaction synthesising target compound, synthetic route：
According to above route of synthesis, the curcuma zedoary 01 derivatives of following structures can be obtained
The beneficial effects of the invention are as follows：By carrying out structural modification to curcuma zedoary 01 derivatives, in the hydroxy position of rcumenol
Introduce after chaff amine fragment and amine is further introduced by Mannich reaction, obtain a series of rcumenols for having no document report and derive
Thing.Being tested by Bioactivity confirms, these new curcuma zedoary 01 derivatives have to cervical carcinoma, liver cancer, lung cancer etc. respectively
Inhibitory activity, most compound activity are significantly higher than its parent rcumenol.In addition, the rcumenol of overwhelming majority synthesis derives
The polarity of thing is significantly increased compared to rcumenol, according to the similar principle that mixes, proves the rcumenol synthesized to a certain extent
Derivative solubility is higher than parent compound rcumenol, preparation research is preferably carried out for it, performance drug effect provides basic theories
Foundation.
Embodiment
Hereinafter, the present invention is illustrated according to specific embodiment.But the present invention is not limited to these embodiments.
The preparation of the curcuma zedoary 01 derivatives of embodiment 1
Preparation scheme is as follows：
1st, chaff amine (25mmol), puts in eggplant-shape bottle, and thereto plus dry tetrahydrofuran, triethylamine (75mmol) are used as and tie up acid
Agent adds, and is placed in magnetic agitation, the tetrahydrofuran containing chloracetyl chloride (37.5mmol) is slowly added dropwise under room temperature condition thereto
Solution is simultaneously stirred continuously, and 1h is added dropwise, and continues to react at room temperature, and after the completion of question response, it is molten to remove reaction using vacuum rotary steam
Agent tetrahydrofuran, appropriate amount of water is added, ethyl acetate extracts 3 times, combined ethyl acetate layer, saturated sodium-chloride water solution backwash, nothing
Water magnesium sulfate is dried in right amount, is filtered after 1h, is concentrated under reduced pressure to give sepia crude product, after vacuum drying chamber is dried, is obtained compound
1, direct plunge into and react in next step.
2nd, rcumenol (5mmol) is added in eggplant-shape bottle, adds dry tetrahydrofuran and be stirred to dissolve, weigh sodium hydride
(7.5mmol), add heat temperature raising backflow 2h after condensation, drying tube, slightly cold to cool, the compound 1 of addition previous step synthesis
After (6mmol), continue heat temperature raising backflow, the monitoring reaction of TLC methods.After the completion of question response, experiment post processing is carried out：Decompression rotation
Boil off except appropriate amount of water after reaction dissolvent tetrahydrofuran, is added, ethyl acetate extracts 3 times, combined ethyl acetate layer, saturated sodium-chloride
Aqueous solution backwash, anhydrous magnesium sulfate are dried drying, filtered after 1h, vacuum rotary steam obtains sepia crude product, passes through silica gel in right amount
Column chromatography obtains target product MNX-1.
3rd, 4mmol amine is slowly dropped in 10mL glacial acetic acid solutions, after stirring, adds 37% formalin
After 0.32g, 25 DEG C of stirring 30min, MNX-1 (0.3g) is added, continues to stir 4h, the monitoring reaction of TLC methods under the conditions of 25 DEG C.Treat
After completion of the reaction, water is added, 20% sodium hydroxide adjusts pH to 9-11, and dichloromethane 20mL is extracted 3 times, combined dichloromethane layer,
Saturated sodium-chloride water solution backwash dichloromethane layer, anhydrous magnesium sulfate are dried, and are concentrated under reduced pressure to give crude product, further silicagel column
Chromatography purifies to obtain target product MNX-2a~MNX-2n.
Using appropriate raw material and reagent, according to the preparation scheme of above-mentioned curcuma zedoary 01 derivatives, you can institute in table 1 is made
Arrange new curcuma zedoary 01 derivatives.
Table 1
Embodiment 2:Anti tumor activity in vitro is tested
The curcuma zedoary 01 derivatives synthesized in selected part embodiment 1 carry out anti tumor activity in vitro experiment, select respectively
HepG2 (human liver cancer cell), Hela (human cervical carcinoma cell), A549 (human lung carcinoma cell) cell line, using MTT (3- (4,5- bis-
Methylthiazol -2) -2,5- diphenyltetrazolium bromide bromides) reducing process determine rcumenol -3- substituent ethers derivative to three-type-person's cancer
The inhibitory activity of cell line, and drug concentration when inhibiting rate reaches 50%, i.e. IC50 values are calculated, positive control selects 5- fluorine
Uracil.
From the tumour cell of exponential phase, after being digested with pancreatin, the culture mediums of RPMI 1640 are made into 6 × 104/
ML cell suspension, then cell suspension is added in 96 well culture plates, 37 DEG C, 5%CO2Under the conditions of cultivate 24 hours.Will
The medicine of the good various concentrations gradient of configured in advance is added separately in 96 porocyte culture plates, and each concentration gradient sets 3
Parallel hole, 37 DEG C, 5%CO2Under the conditions of cultivate 24 hours after, abandoning supernatant, washed 2 times with PBS, per hole add 10 μ L newly match somebody with somebody
MTT culture mediums, continue culture 3 hours under the conditions of 37 DEG C, abandoning supernatant adds 100 μ LDMSO, after vibration mixes, ELIASA
Optical density (OD values) is determined at 570nm.
Inhibiting rate calculates：
Growth inhibition ratio=(OD controls-OD experiments)/(OD control-OD blank) × 100%
According to drug concentration-growth inhibition ratio curve, IC50 is calculated, as a result such as table 2.
Suppression IC50 (μm ol/L) of the part curcuma zedoary 01 derivatives of table 2 to tumour cell
From table 2, result of the test is it can be clearly seen that the compound of the claimed formula (I) of the present invention has
Good anti tumor activity in vitro, most compounds are better than parent drug rcumenol or positive control drug 5 FU 5 fluorouracil
(5-Fu).Wherein, MNX-2i, MNX-2j are especially pronounced to the inhibitory action of lung cancer A549 cell, compared with parent compound rcumenol
It has been respectively increased 9.5 and 8.1 times.
Although describing the present invention by particular, modification and equivalent variations are for being proficient in this field
It will be apparent from for technical staff, and they are included within the scope of the invention.It would be recognized by those skilled in the art that enter one
Step further investigation according to the ordinary technical knowledge of this area and is used on the premise of the above-mentioned basic fundamental thought of the present invention is not departed from
With means, can also there are the modification, replacement or change of diversified forms to its content.It is all to be realized based on the above of the present invention
Technology belongs to the scope of the present invention.
Claims (8)
1. one kind have formula (I) structure curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, hydrate, solvate or
Prodrug：
Wherein, L isR is selected from-NR1R2,
R1And R2It is identical or different, separately selected from hydrogen, C1-C10Alkyl, C3-C7It is cycloalkyl, optionally identical or not by 1-3
Same R3Substituted C1-C10Alkyl, optionally the identical or different R by 1-33Substituted C3-C7Cycloalkyl；
Or R1And R2With forming 5-10 circle heterocycles bases together with the nitrogen-atoms connected with them, the heterocyclic radical except with R1And R2Even
Outside the nitrogen-atoms connect, optionally containing the 1-4 hetero atoms for being selected from N, O and S, optionally by 1-3 identical or different R4Substitution；
R3For C1-C6Alkyl, C1-C4Alkoxy, halogen, hydroxyl, cyano group, carboxyl, ester group or NR5R6；
R4For C1-C6Alkyl, C1-C4Alkoxy, halogen, hydroxyl C1-C6Alkyl, C1-C4Alkoxy C1-C6Alkyl, carboxyl, ester group,
Aryl, aralkyl, aryloxy group, aralkoxy, heteroaryl, CONR5R6Or NR5R6；
R5And R6It is identical or different, separately selected from hydrogen, C1-C6Alkyl or C3-C7Cycloalkyl.
2. curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, water according to claim 1 with formula (I) structure
Compound, solvate or prodrug, it is characterised in that
R1And R2It is identical or different, separately selected from hydrogen, C1-C4Alkyl, C3-C4Cycloalkyl is optionally identical or not by 1-3
Same R3Substituted C1-C4Alkyl, optionally the identical or different R by 1-33Substituted C3-C4Cycloalkyl；
Or R1And R2With forming 5-6 circle heterocycles bases together with the nitrogen-atoms connected with them, the heterocyclic radical except with R1And R2Even
Outside the nitrogen-atoms connect, optionally containing the 1-2 hetero atoms for being selected from N, O and S, optionally by 1-3 identical or different R4Substitution；
R3For C1-C3Alkyl, C1-C3Alkoxy, halogen, hydroxyl, cyano group, carboxyl, ester group or NR5R6；
R4For C1-C3Alkyl, C1-C3Alkoxy, halogen, hydroxyl C1-C3Alkyl, C1-C3Alkoxy C1-C3Alkyl, carboxyl, ester group,
Aryl, aralkyl, CONR5R6Or NR5R6；
R5And R6It is identical or different, separately selected from hydrogen, C1-C3Alkyl, C3-C4Cycloalkyl.
3. curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, water according to claim 2 with formula (I) structure
Compound, solvate or prodrug, it is characterised in that：
Described aryl is selected from phenyl, xenyl, naphthyl；Or aryl optionally by 1,2 or 3 independently selected from C1‐C3Alkyl,
C1‐C3The substituent substitution of alkoxy, halogen, cyano group, morpholinyl, piperidyl, trifluoromethyl or trifluoromethoxy；
Described aralkyl is selected from-(CH2) n- aryl.
4. curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, water according to claim 3 with formula (I) structure
Compound, solvate or prodrug, it is characterised in that
Described aryl is selected from phenyl；Or aryl optionally by 1,2 or 3 independently selected from C1-C3Alkyl, C1-C3Alkoxy, halogen
The substituent substitution of element, morpholinyl, piperidyl, trifluoromethyl or trifluoromethoxy；
Described aralkyl is selected from-(CH2) n- aryl, n 1-3.
5. curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, water according to claim 1 with formula (I) structure
Compound, solvate or prodrug, it is characterised in that there is following structural formula：
6. curcuma zedoary 01 derivatives with formula (I) structure described in claim any one of 1-5 and its pharmaceutically acceptable
Salt, hydrate, solvate or prodrug are applied in antineoplastic is prepared.
7. application according to claim 6, it is characterised in that curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, water
The application of compound, solvate or prodrug as active ingredient in antitumor monomer medicine or pharmaceutical composition is prepared.
8. application according to claim 6, it is characterised in that described tumour is selected from cervical carcinoma, liver cancer or lung cancer.
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| CN201710983039.3A CN107739381B (en) | 2017-10-20 | 2017-10-20 | Curcumenol derivative and application thereof in preparation of antitumor drugs |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109223711A (en) * | 2018-09-19 | 2019-01-18 | 辽宁大学 | The method of film hydration method control curcuma zedoary 01 derivatives PEG-PLA micellar particle size |
| CN110604732A (en) * | 2019-09-20 | 2019-12-24 | 浙江工业大学 | Application of curcumenol derivative in preparation of medicine for treating colorectal cancer |
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| CN106632383A (en) * | 2016-11-21 | 2017-05-10 | 辽宁大学 | Curcumenol derivative as well as preparation method and application thereof in antitumor drugs |
| CN106674242A (en) * | 2016-11-21 | 2017-05-17 | 辽宁大学 | Curcumol derivatives with anti-tumor activity, and preparation method and application of curcumol derivatives |
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2017
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| CN106632383A (en) * | 2016-11-21 | 2017-05-10 | 辽宁大学 | Curcumenol derivative as well as preparation method and application thereof in antitumor drugs |
| CN106674242A (en) * | 2016-11-21 | 2017-05-17 | 辽宁大学 | Curcumol derivatives with anti-tumor activity, and preparation method and application of curcumol derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109223711A (en) * | 2018-09-19 | 2019-01-18 | 辽宁大学 | The method of film hydration method control curcuma zedoary 01 derivatives PEG-PLA micellar particle size |
| CN110604732A (en) * | 2019-09-20 | 2019-12-24 | 浙江工业大学 | Application of curcumenol derivative in preparation of medicine for treating colorectal cancer |
| CN110604732B (en) * | 2019-09-20 | 2022-10-14 | 浙江工业大学 | Application of curcumenol derivative in preparation of medicine for treating colorectal cancer |
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