CN106187967A - A kind of symmetrical single carbonyl curcumin analog 6b and its preparation method and application - Google Patents
A kind of symmetrical single carbonyl curcumin analog 6b and its preparation method and application Download PDFInfo
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- CN106187967A CN106187967A CN201610561046.XA CN201610561046A CN106187967A CN 106187967 A CN106187967 A CN 106187967A CN 201610561046 A CN201610561046 A CN 201610561046A CN 106187967 A CN106187967 A CN 106187967A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The present invention relates to containing the substituted micromolecular compound with 1,4 diene 3 ketone as parent nucleus of pi-allyl and preparation method and application.Symmetry list carbonyl curcumin analog 6b of the present invention, has good stability, and compound 6b has preferable anti-tumor activity at cellular layer mask, especially to human bile duct cancer, is a clinical anti-cancer little molecule lead compound having very much DEVELOPMENT PROSPECT.
Description
Technical field
The present invention relates to belong to compound medicine field, be specifically related to have antitumor action containing pi-allyl substituted with
1,4-diene-3-ketone structure is the compound of parent nucleus and preparation method and the anticancer usage of this compound.
Background technology
Tumor, is divided into benign tumor and malignant tumor.In China, according to investigation display, just there are average every day 8550 people dead
In cancer.Current Cancer Treatment Regimens is mainly treated and the most popular immunity by chemotherapy, radiotherapy, operation, targeted drug
Therapeutic Method.Traditional therapeutic modality such as chemotherapy, radiotherapy injure too big for cancer patient, easily cause hypoimmunity,
The symptoms such as alopecia.For targeted drug, although at present application is more, but for some specific cancer types, as pulmonary carcinoma,
Breast carcinoma, cancer of pancreas etc. can not reach the effect of radical cure, and even some targeted drug medications there will be resistance to the most in the patient
The phenomenon of medicine.Therefore exploitation new type anticancer medicine remains the important task faced at present.
Curcumin, is the main active in Turmeric, Radix Curcumae and Rhizoma Curcumae.In recent years, pharmaceutical research finds Rhizoma Zingiberis Recens
Flavin has antitumor, antiinflammatory, the multiple pharmacological effect such as antibacterial, and curcumin has come into multinomial II phase clinical experiment in the U.S.
Stage.But, the beta-diketon structure parent nucleus of curcumin itself is highly unstable, causes it by decomposing quickly in human body.
Research finds, after beta-diketon structure parent nucleus makes into Isosorbide-5-Nitrae-diene-3-ketone parent nucleus, the stability of compound is greatly improved.
In the natural plants that some are traditional, it has been found that some natural plants molecule such as honokiol etc. containing allylic structure has
There is preferable anti-tumor activity.Therefore, on the basis of promoting compound stability, introduce pi-allyl alternatively base, find
Compound 6b.Compound 6b has preferable anti-tumor activity at cellular layer mask, and especially to human bile duct cancer, be one has out very much
The clinical anti-cancer little molecule lead compound of the prospect of sending out.
Summary of the invention
For the problem of above-mentioned existence, an object of the present invention is to provide one substituted with Isosorbide-5-Nitrae-two containing pi-allyl
Alkene-3-ketone is the micromolecular compound of parent nucleus.
The two of the purpose of the present invention are to provide a kind of containing substituted with 1,4-diene-3-ketone as parent nucleus little point of pi-allyl
The preparation method of sub-compound.
The three of the purpose of the present invention are to provide a kind of containing substituted with 1,4-diene-3-ketone as parent nucleus little point of pi-allyl
The purposes of sub-compound antitumor.
To achieve these goals, the technical solution used in the present invention is: a kind of symmetrical single carbonyl curcumin analog 6b,
There is following structural formula (1),
Compound 6b is:
Double (3-pi-allyl-4-phenol methylene) dihydro-2H-pyrans-4 (3H)-one of (3E, 5E)-3,5-
(3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)dihydro-2H-pyran-4(3H)-
one。
The preparation method of a kind of symmetrical single carbonyl curcumin analog 6b, prepares as follows:
A kind of symmetrical single carbonyl curcumin analog 6b application in preparing antitumor drug.
Utilize 4stability determination to have rated compound 6b and (be called for short PBS, PH=with curcumin at phosphate buffer
7.4) steadiness in, finds that compound 6b has (details are shown in embodiment 2) more more preferable than curcumin chemical stability.Carefully
In born of the same parents' aspect, experimental evaluation compound 6b is on the impact of human bile duct carcinoma RBE cell survival rate and IC50The mensuration of value, finds
Human bile duct carcinoma RBE cell is had more more preferable fragmentation effect than curcumin by compound 6b, its IC to RBE cell50Value
About about 15 μMs.
Beneficial effect: symmetry list carbonyl curcumin analog 6b of the present invention, has good stability, and compound 6b is carefully
Born of the same parents' aspect has preferable anti-tumor activity, especially to human bile duct cancer, is that a clinical anti-cancer having very much DEVELOPMENT PROSPECT is little
Molecule lead compound.
Accompanying drawing explanation
Fig. 1 is the stability curve figure of curcumin；
Fig. 2 is the stability curve figure of the compounds of this invention 6b；
Fig. 3 is the compound 6b survival rate block diagram to human bile duct carcinoma RBE cell；
Fig. 4 is the compound 6b IC50 value block diagram to human bile duct carcinoma RBE cell.
Detailed description of the invention
Embodiment
The preparation of compound b6:
The preparation of intermediate 2: weigh 10g hydroxy benzaldehyde (1) in reaction bulb, adds proper amount of acetone and dissolves raw material,
Weigh 10g potassium carbonate again, under the conditions of oil bath, be slowly added into 14ml allyl bromide, bromoallylene, be finally slowly added to 10g potash solid, 65 DEG C
Being stirred at reflux 18 hours, TLC monitors reaction.Reaction is spin-dried for acetone after terminating, and with water/ethyl acetate extraction product, removes carbonic acid
Potassium, is spin-dried for ethyl acetate layer, wet method dress post, petroleum ether: ethyl acetate=10:1 crosses post, obtains water white transparency and reset raw material midbody
2 (4-allyloxy benzaldehydes).
The preparation of intermediate 3: weighing 3g and reset raw material, add 5ml N, N-diethylaniline, balloon leads to N2, reaction unit
Vacuum filtration 5 minutes, removes the dissolved oxygen in reactant liquor, and under the conditions of sand-bath, (200 DEG C) are stirred at reflux 5 hours, and TLC monitoring is anti-
Should.Reaction terminates rear reaction system and is cooled to room temperature, direct wet method dress post, and silica gel column chromatography purification obtains green rearrangement product i.e.
Intermediate 3-pi-allyl-4-hydroxy benzaldehyde (3).
The preparation of compound 6b: weigh 150mg intermediate 3 and 60.5mg tetrahydro pyrone respectively in the ratio of 2:1, respectively
It is loaded in reaction bulb and large-scale EP pipe, adds appropriate glacial acetic acid, lead to 5 minutes hydrogen chloride gas respectively, it was observed that rearrangement product is molten
Liquid reddens.Tetrahydro pyrone solution is slowly dropped in rearrangement product solution, reaction 48 hour is stirred at room temperature, keep reaction bulb
Sealing to be got well, and TLC monitors reaction.After reaction terminates, use saturated NaHCO3Regulation solution PH is to 7-8, by water/ethyl acetate extraction
Taking, collect ethyl acetate layer, be spin-dried for ethyl acetate, dry method upper prop, silica gel column chromatography purification obtains yellow end-product 6b (gross production rate
About 35%).
Essential information and the nuclear magnetic resonance map data of compound 6b are as follows:
(3E,5E)-3,5-Bis(3-allyl-4-hydroxybenzylidene)dihydro-2H-pyran-4(3H)-
one(6b)
Double (3-pi-allyl-4-phenol methylene) dihydro-2H-pyrans-4 (3H)-one of (3E, 5E)-3,5-
Yellow power.Yield:40%.m.p:162.3-165.0 DEG C.1H NMR(600MHz,DMSO-d6)δ
(ppm): 10.07 (2H, s, Ar-OH), 7.55 (2H, s, H-β, H-β '), 7.15 (2H, d, J=8.4Hz, H-6, H-6'), 7.13
(2H, s, H-2, H-2'), 6.90 (2H, d, J=8.4Hz, H-5, H-5'), 6.01-5.94 (2H, m, A, B-ArCH2 CH=CH2),
5.08-5.03(4H,m,A,B-ArCH2CH=CH 2),4.85(4H,s,CH 2-O-CH 2), 3.31 (4H, d, J=6.6Hz, A, B-
ArCH 2CH=CH2).13C NMR(150MHz,DMSO-d6)δ(ppm):184.3,156.7×2,136.6×2,135.0×2,
132.8×2,130.5×2,130.5×2,126.6×2,125.4×2,115.7×2,115.3×2,67.7×2,33.5×
2.ESI-MS,m/z:387.1[M-H]-.calcd for C25H24O4:388.16
Compound 6b and the Stability Determination of curcumin
Compound dissolution, in DMSO, is configured to the DMSO solution of 1mM concentration.Take the DMSO solution of 20 μ l compounds, add
Enter the PBS solution of 980 μ l, obtain the solution after diluting 50 times, take appropriate solution, with microplate reader measure compound 0min,
The absorbance size of 5min, 10min, 15min, 20min, 25min different time points (wave-length coverage 250nm-600nm is set,
Every 5nm).By the data that obtain in Excel form, the stability curve figure of compound 6b and curcumin can be obtained (see figure
1, Fig. 2).
The anti-tumor activity checking of compound 6b on cellular level
Cell is cultivated and is administered
Containing 5%CO237 DEG C of environment under, cell is incubated in RPMI 1640 culture medium containing 10% hyclone.Change
Compound 6b is dissolved in DMSO, is configured to the storing solution of 50 μ g/ml and is stored in-20 DEG C of refrigerators.Dosage control 0,5,
7.5,10 μM 4 concentration.It is molten for the end less than 0.1% that each working solution concentration basal medium makes DMSO concentration
Liquid.It is not added with the cell group of compound as negative control group, gives the group of 20 μMs of curcumins as positive controls.
Compound 6b anti-human cholangiocarcinoma cell proliferation assay
RBE cell is incubated in 96 orifice plates (5000 cells/well) of RPMI 1640 culture medium comprising 10%FBS,
Cell gives the compound of variable concentrations after growing 24 hours.Fresh MTT (5mg/ml) solution of PBS preparation joins each
In hole.First a ceremonial jade-ladle, used in libation crystal is formed in living cells, and after dissolving with the DMSO solution of 150 μ L, the absorbance of compound is used under 490nm
Microplate reader measures.The IC of compound50Value can use Graphpad Prism 5.0 computed in software to go out, and (cell experiment result is shown in Fig. 3, figure
4, wherein Fig. 4 unit is um).
Claims (3)
1. a symmetrical single carbonyl curcumin analog 6b, has following structural formula (1),
The preparation method of symmetrical single carbonyl curcumin analog 6b the most according to claim 1, it is characterised in that by following step
Rapid prepared:
Symmetrical single carbonyl curcumin analog 6b application in preparing antitumor drug the most according to claim 1 or claim 2.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040176384A1 (en) * | 1999-12-03 | 2004-09-09 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| WO2012021692A1 (en) * | 2010-08-11 | 2012-02-16 | Rutgers, The State University Of New Jersey | Curcumin analogs and methods of use thereof |
| CN103936667A (en) * | 2014-03-31 | 2014-07-23 | 中山大学 | Novel 3, 5-bis(aryl-methyne)-1-methylpiperidine-4-ketone compound as well as synthetic method and application thereof in preparation of anti-cancer medicines |
| CN105541700A (en) * | 2016-01-22 | 2016-05-04 | 温州医科大学 | Mono-carbonyl curcumin analogue containing piperidone structure and application |
-
2016
- 2016-07-14 CN CN201610561046.XA patent/CN106187967A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040176384A1 (en) * | 1999-12-03 | 2004-09-09 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| WO2012021692A1 (en) * | 2010-08-11 | 2012-02-16 | Rutgers, The State University Of New Jersey | Curcumin analogs and methods of use thereof |
| CN103936667A (en) * | 2014-03-31 | 2014-07-23 | 中山大学 | Novel 3, 5-bis(aryl-methyne)-1-methylpiperidine-4-ketone compound as well as synthetic method and application thereof in preparation of anti-cancer medicines |
| CN105541700A (en) * | 2016-01-22 | 2016-05-04 | 温州医科大学 | Mono-carbonyl curcumin analogue containing piperidone structure and application |
Non-Patent Citations (3)
| Title |
|---|
| ARDESHIR KHAZAEI ET AL.: "Quantitative structureeactivity relationship of the curcumin-related compounds using various regression methods", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
| HEPING ZHU ET AL.: "Synthesis and optimization of novel allylated mono-carbonyl analogs of curcumin (MACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI) in rats", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| STEVEN KOPROWSKI ET AL.: "Curcumin-mediated regulation of Notch1/hairy and enhancer of split-1/survivin: molecular targeting in cholangiocarcinoma", 《JOURNAL OF SURGICAL RESEARCH》 * |
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