CN106632383B - Curcuma zedoary 01 derivatives and preparation method thereof and the application in antitumor drug - Google Patents
Curcuma zedoary 01 derivatives and preparation method thereof and the application in antitumor drug Download PDFInfo
- Publication number
- CN106632383B CN106632383B CN201611021609.2A CN201611021609A CN106632383B CN 106632383 B CN106632383 B CN 106632383B CN 201611021609 A CN201611021609 A CN 201611021609A CN 106632383 B CN106632383 B CN 106632383B
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- Prior art keywords
- derivatives
- curcuma zedoary
- ethyl acetate
- preparation
- rcumenol
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- WYIWFWTWPUVXLN-OLZZFSTQSA-N CC(C)[C@H](C1)[C@](C2)(Oc3cc(C(OC)=O)nc4ccn[n]34)O[C@@]1([C@@H](C)CC1)[C@@H]1C2=C Chemical compound CC(C)[C@H](C1)[C@](C2)(Oc3cc(C(OC)=O)nc4ccn[n]34)O[C@@]1([C@@H](C)CC1)[C@@H]1C2=C WYIWFWTWPUVXLN-OLZZFSTQSA-N 0.000 description 1
- RCEPFXFCACZUQU-UHFFFAOYSA-N CC1(C)C=Nc2ccn[n]2C(C(C)=C)=C1 Chemical compound CC1(C)C=Nc2ccn[n]2C(C(C)=C)=C1 RCEPFXFCACZUQU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D493/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The present invention discloses a kind of curcuma zedoary 01 derivatives and preparation method thereof and the application in antitumor drug.The curcuma zedoary 01 derivatives of the present invention have the structure of logical formula (I).The curcuma zedoary 01 derivatives with anti-tumor activity of the present invention, based on the chemical constitution of rcumenol, different nitrogenous substituent groups is introduced, has inhibiting effect to the activity of human cervical carcinoma cell, human hepatoma cell and human lung carcinoma cell, there is good antitumor activity.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more precisely say be the derivative of rcumenol, curcuma zedoary 01 derivatives preparation side
The purposes of method and curcuma zedoary 01 derivatives.It is that structural modification is carried out to monomer rcumenol with anti-tumor activity, obtains a series of
The curcuma zedoary 01 derivatives of better efficacy.
Technical background
The hot spot of the antitumor concern as current era medicine sector attracts always countless medicine and pharmacology workers and goes
It explores, research.Currently, treating tumour using Chinese medical extract, make encouraging progress, has sent out in the experimental therapy of tumour
Exhibition foreground is more optimistic.The study found that traditional Chinese medicine monomer has similar costimulatory molecules to act on, using traditional Chinese medicine monomer to tumour cell
Carry out series of biologic structure, it is possible to by enhancing or adding costimulating signal, the effectively antineoplastic immune of excitating organism
Reaction.
The structural formula of rcumenol (Curcumol) is shown in (1-1) that nickname Curcumol, curcumol are colorless needle crystals,
Belong to sesquiterpenoids, is to extract the important monomer composition being isolated from the zedoary volatile oil of curcuma.Cowherb
New anti-tumor Chinese medicine monomer one of of the art alcohol as discovered in recent years, the especially validity and hypotoxicity of Curcumenol medicament,
Its research in oncotherapy is set increasingly to be valued by people.From germplasm resource than being found in more rich natural plants
Antitumor drug with clinical value and commercial value undoubtedly has good development prospect.
Recent study shows that rcumenol has and is acted on compared with powerful antitumor, including cervical carcinoma, gastric cancer, lung cancer, oophoroma, breast
Gland cancer, liver cancer, nasopharyngeal carcinoma, colon cancer and osteosarcoma, pertinent literature show that it can be directed to a variety of cancer cells and have and directly destroy
Effect, and the enhancing of body immune system specificity can be promoted to obtain apparent anticarcinogenic effect.Clinical research also found, rcumenol
It is not only preferable to oncotherapy effect, and adverse reaction is less.Compared with many chemical anti-tumor drugs, whether there is or not mutagenicity,
Efficiently, low toxicity, safe and reliable, clinical application is extensive, it is effective to a variety of diseases the advantages that.
Though rcumenol has antitumor activity, its water solubility is relatively low, and dissolved solution degree is only 0.3%, carries out preparation
Research is more difficult, and bioavilability is not high, and to limit its clinical application, thus it is necessary to carry out structural modification research to it.
Invention content
An object of the present invention is that new rcumenol is synthesized to its structural modification using rcumenol as lead compound
Derivative.
The second object of the present invention is to synthesize a series of new antitumor drugs with more preferable pharmacological activity.
The third object of the present invention is to provide using these compounds as effective medicinal active ingredient and is used for antitumor
Drug.
The present invention carries out its structure the compound of modification synthesis, structural formula such as formula using rcumenol as lead compound
(I)：
Wherein, R is
R1Selected from H, saturation or unsaturated alkyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, nitro, halogen, alkane
Base formoxyl or-CONR2R3。
R2And R3Independently selected from H and alkyl.
Alkyl, which is selected from, has at most 6 carbon atom (C1-C6) straight chained alkyl, 3 to 6 carbon atom (C3-C6) branched alkane
Base, 3 to 7 carbon atom (C3-C7) naphthenic base.
Unsaturated alkyl is selected from 2 to 6 carbon atom (C2-C6) alkenyl or 2 to 6 carbon atom (C2-C6) alkynyl.
Alkoxy is 1 to 6 carbon atom (C1-C6) straight chain O- connections hydrocarbon or 3 to 6 carbon atom (C3-C6) branch
The hydrocarbon of O- connections.
The fourth object of the present invention is there is provided the preparation method of these noval chemical compounds, and above compound is with rcumenol and R-
Cl is Material synthesis, and synthetic route is as follows：
According to the above route of synthesis, suitable raw material and solvent are selected, the curcuma zedoary 01 derivatives of following structures can be obtained：
One or more pharmaceutical carriers or excipients can be added in above-mentioned curcuma zedoary 01 derivatives, be prepared into powder, granule, ball
Agent, capsule, tablet or emulsion are preferably applied to disease treatment.
The invention has the beneficial effects that it has been investigated that, the curcuma zedoary 01 derivatives of synthesis are to cervical carcinoma, liver cancer, lung cancer etc.
With preferable antitumor activity, the antitumoral compounds curcuma zedoary 01 derivatives that the present invention obtains have more preferable antitumor activity
And safety, it is to have very much application value to treat cervical carcinoma, liver cancer, lung cancer in field of medicaments.Synthesized rcumenol spreads out
Biology compares the increase of rcumenol polarity, water-soluble increase, preferably improves drug effect for it, provides basis applied to clinic.
Specific implementation mode
Hereinafter, illustrating the present invention according to specific embodiment.However, the present invention is not limited to these examples, of the invention
Protection domain is not limited with specific implementation mode, but is defined in the claims.
Embodiment 1：The synthesis of curcuma zedoary 01 derivatives
It prepares and leads to method by taking the synthesis of compound BD-1 as an example：
Rcumenol 1.18g (5mmol) is taken, the tetrahydrofuran solution of 30mL dryings is dissolved in, sodium hydride 0.30g is added
(7.5mmol, 60%), in 66-73 DEG C of heating reflux reaction 1h, slightly it is cold cool after, 2- (chloromethyl) imidazo [1,2-a] is added
Pyridine 1.00g (6mmol) continues heat temperature raising, in 66-73 DEG C of back flow reaction 10h, TLC method monitoring reaction.Wait for that reaction finishes
Afterwards, the most reaction dissolvent tetrahydrofurans of revolving removal, are added 30mL water, are extracted 3 times with ethyl acetate 40mL, merge acetic acid
Methacrylate layer, saturated sodium-chloride water solution backwash ethyl acetate layer, anhydrous magnesium sulfate are dried ethyl acetate layer, are filtered after 1h in right amount,
It is concentrated under reduced pressure to give sepia oil product, the light red oil product BD-1 of further silica gel column chromatography separating purification.
Using raw material appropriate and reagent, lead to method according to being prepared described in embodiment 1, you can obtain novel rcumenol in table 1
Derivative.
Table 1
The Anticancer Activity in vitro of 2 curcuma zedoary 01 derivatives of embodiment is studied：
Curcuma zedoary 01 derivatives are measured to Human cervical cancer cell lines HeLa cells using mtt assay, human hepatoma cell line HepG2 is thin
The inhibiting rate of born of the same parents and human lung cancer cell line's A549 cells reaches drug concentration when 50%.
The tumour cell of exponential phase is selected, after being digested with pancreatin, 1640 culture mediums of RPMI are made into 6 × 104/
Then cell suspension is added in 96 well culture plates by the cell suspension of mL, 37 DEG C, is cultivated 24 hours under the conditions of 5%CO2.It will
The drug of the good various concentration gradient of configured in advance is added separately in 96 porocyte culture plates, and each concentration gradient is arranged 3
Parallel hole, 37 DEG C, 5%CO2Under the conditions of cultivate 24 hours after, discard supernatant liquid, washed 2 times with PBS, per hole be added 10 μ L newly match
MTT culture mediums, continue culture 4 hours under the conditions of 37 DEG C, discard supernatant liquid and 100 μ LDMSO are added, after vibrating mixing, microplate reader
Optical density (OD values) is measured 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.
Inhibition IC50 (μm ol/L) of the 2 part curcuma zedoary 01 derivatives of table to tumour cell
As can be seen from Table 2, the antitumor activity relative to rcumenol, most of target compound of synthesis has preferable anti-
Cervical carcinoma HeLa, liver cancer HepG2 and lung cancer A549 activity.
The above embodiment is only exemplary, and the implementation content of the present invention is further described in detail, but not
This should be interpreted as the above-mentioned theme of the present invention range be only limitted to more than example.It would be recognized by those skilled in the art that into one
Step further investigation according to the ordinary technical knowledge of this field and is used under the premise of not departing from above-mentioned basic fundamental thought of the invention
With means, to its content can also there are many modification, replacement or the changes of form.It is all to be realized based on the above of the present invention
Technology all belongs to the scope of the present invention.
Claims (5)
1. curcuma zedoary 01 derivatives and its pharmaceutically acceptable salt, which is characterized in that have the following structure：
2. the preparation method of curcuma zedoary 01 derivatives BD-1 described in claim 1, which is characterized in that method is as follows：Rcumenol is taken,
It is dissolved in dry tetrahydrofuran solution, sodium hydride is added, in 66-73 DEG C of heating reflux reaction 1h, after cooling, 2- (chloromethanes are added
Base) imidazo [1,2-a] pyridine, continues heating reflux reaction 10h, TLC method in 66-73 DEG C and monitors reaction end, wait reacting
After, the most reaction dissolvent tetrahydrofurans of revolving removal are added water, are extracted with ethyl acetate, combined ethyl acetate layer,
Saturated sodium-chloride water solution backwash ethyl acetate layer, anhydrous magnesium sulfate dry ethyl acetate layer, filter, and are concentrated under reduced pressure, silicagel column
Chromatography purifies, and obtains product curcuma zedoary 01 derivatives BD-1.
3. curcuma zedoary 01 derivatives described in claim 1 and its pharmaceutically acceptable salt answering in the preparation of antitumor drugs
With.
4. application according to claim 3, which is characterized in that the tumour is selected from cervical carcinoma, liver cancer or lung cancer.
5. application according to claim 3, which is characterized in that curcuma zedoary 01 derivatives or its pharmaceutically acceptable salt conduct
Active ingredient prepares antitumor monomer medicine or pharmaceutical composition.
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| CN106632383B true CN106632383B (en) | 2018-08-14 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107739381B (en) * | 2017-10-20 | 2020-09-22 | 辽宁大学 | Curcumenol derivative and application thereof in preparation of antitumor drugs |
| CN109331008A (en) * | 2018-12-11 | 2019-02-15 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Application of the rcumenol in the drug of preparation prevention and treatment psoriasis |
| CN114149392B (en) * | 2020-09-07 | 2023-06-06 | 沈阳药科大学 | Curcumene nitrogen-containing derivative, preparation and application thereof |
| CN114149394B (en) * | 2020-09-07 | 2023-06-06 | 沈阳药科大学 | Curcumene derivative and preparation and application thereof |
| CN113181166B (en) * | 2021-05-27 | 2024-01-05 | 澳门科技大学 | Application of curcumenol in preparing anti-lung cancer medicine |
| CN116173159B (en) * | 2021-11-28 | 2024-02-02 | 北京中医药大学东直门医院 | Zedoary turmeric oil sulfonate, and preparation method and application thereof |
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| CN1704417A (en) * | 2004-05-26 | 2005-12-07 | 杭州民生药业集团有限公司 | Novel curcumenol derivatives |
| CN1995056B (en) * | 2006-10-31 | 2011-06-15 | 温州医学院 | Curcumenol glucoside compound and its preparation method and uses |
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Effective date of registration: 20230802 Address after: Room 61, 6th Floor, Building 1, Zone 1, No. 186 South Fourth Ring West Road, Fengtai District, Beijing, 100071 Patentee after: PHARMASEA (BEIJING) PHARMACEUTICAL TECHNOLOGY CO.,LTD. Address before: 110000 58 Shenbei New Area Road South, Shenyang, Liaoning. Patentee before: LIAONING University |