CN109734658A - A kind of curcumin derivate and its preparation method and application - Google Patents
A kind of curcumin derivate and its preparation method and application Download PDFInfo
- Publication number
- CN109734658A CN109734658A CN201910019941.2A CN201910019941A CN109734658A CN 109734658 A CN109734658 A CN 109734658A CN 201910019941 A CN201910019941 A CN 201910019941A CN 109734658 A CN109734658 A CN 109734658A
- Authority
- CN
- China
- Prior art keywords
- structure shown
- compound
- preparation
- cell
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a kind of curcumin derivates with structure shown in Formulas I and its application, belong to technical field of medicine synthesis, curcumin derivate provided by the invention is inhibited to Ovarian Cancer Cells HO-8910PM, cancer cell is killed and inducing cell apoptosis, bis- (4- halogen-benzylidene) the piperidin-4-one hydrochlorides of curcumin derivate (3E, 5E) -3,5- provided by the invention, bioavailability is high, can be used for preparing the drug of ovarian cancer resistance.The present invention also provides the preparation method of the curcumin derivate with structure shown in Formulas I, the curcumin derivate purity that preparation method provided by the invention is prepared is up to 99% or more.
Description
Technical field
The present invention relates to technical field of medicine synthesis, in particular to a kind of curcumin derivate and preparation method thereof and answer
With.
Background technique
Disease incidence of the oophoroma in female sex organ malignant tumour accounts for third position, but to occupy gynaecology pernicious for case fatality rate
Tumour is the first.Currently, the treatment of oophoroma mainly has operation and post-surgical chemotherapy, postoperative chemotherapy is with chemotherapeutics such as cis-platinums
It is main.Chemotherapy is one of the important means for the treatment of oophoroma, and chemotherapy resistance is the main reason for influencing ovarian cancer patients prognosis.Research
Show proto-oncogene of the Yap as oophoroma, cell is more also easy to produce drug resistance to cis-platinum and taxol when height expression, in nucleus
The distribution of Yap is higher, and patient's prognosis is poorer, in addition, cell migration and invasive ability enhancing when Yap high is expressed.So with
Hippo-Yap can effectively treat oophoroma as target spot.
Liu-ChittendenY people filters out the porphins such as Verteporfin (VP), haematoporphyrin (HP) and protoporphyrin IX (PPIX)
Inhibitor for treating cancer of the quinoline compound as Yap, but these drugs have very big side effect.
Curcumin is a kind of plant polyphenol extracted from turmeric rhizome, safe and non-toxic, is easy to extract.In recent years, to ginger
The research of flavine is more and more, also more and more deep.The study found that curcumin has anti-inflammatory, anti-oxidant, anti-aging, treatment fertilizer
Fat, diabetes, Parkinson's disease, Alzheimer's disease, the biological functions such as antitumor, chemotherapy.US National tumour institute is by it
It is classified as third generation cancer chemoprevention medicine.There are also the study found that addition curcumin is capable of the generation of pre- preventing tumor in diet.Currently,
The Mechanism Study of turmeric extract for treating tumour is very extensive.Curcumin can reduce Bcl-2, increases Bax and promotes apoptosis of tumor cells,
Increase P53 and causes Apoptosis.Curcumin can also promote Apoptosis by increasing the protein expression of Caspase family.More
Importantly, curcumin can increase ovarian cancer cell to the sensibility of cis-platinum, inducible resistance ovarian cellular apoptosis.But
Curcumin is insoluble in water, and trap is low, and is metabolized and eliminates fast, so its bioavailability is very low, therefore limits it and is made extensively
With.
Summary of the invention
In view of this, the present invention provides it is an object of that present invention to provide curcumin derivate and its preparation method and application
Curcumin bioavailability it is high.
The present invention provides a kind of curcumin derivates with structure shown in Formulas I:
The R is Cl or Br or F.
The present invention provides the preparation methods of the above-mentioned curcumin derivate with structure shown in Formulas I, comprising the following steps:
1) by the compound with structure shown in Formula II, the compound with formula III structure, alkali metal hydroxide and first
Aldol condensation reaction is carried out after alcohol mixing, obtains the compound with structure shown in formula IV；The chemical combination with formula III structure
R is Cl, Br or F in object；
3) after mixing the compound with structure shown in formula IV obtained in the step 1) with methylene chloride, it is passed through chlorine
Change hydrogen and carry out acid-base reaction, obtains the curcumin derivate with structure shown in Formulas I.
Preferably, the compound in the step 1) with structure shown in Formula II, compound and alkali with formula III structure
The mass ratio of the material of metal hydroxides is 1:2:7.5.
Preferably, alkali metal hydroxide is potassium hydroxide or sodium hydroxide in the step 1).
Preferably, the temperature of the step 1) Aldol condensation reaction is room temperature, time 12h.
Preferably, the mass ratio of the material of the compound with structure shown in formula IV in the step 2) and hydrogen chloride is 1:1
~3.
Preferably, the temperature of acid-base reaction is 4 DEG C in the step 2), time 30min.
The present invention also provides the above-mentioned curcumin derivates with structure shown in Formulas I in the drug for preparing ovarian cancer resistance
Application, the drug of the ovarian cancer resistance is as including having the curcumin derivate of structure shown in Formulas I and its is pharmaceutically acceptable
Carrier be prepared.
Preferably, the form of the preparation of the medicine of the ovarian cancer resistance includes solid pharmaceutical preparation or liquid preparation.
Preferably, the solid pharmaceutical preparation includes tablet, sustained release tablets, controlled release tablet, capsule, dripping pill, pellet, powder or particle
Agent；The liquid preparation include suspension, emulsion, oral solution, the aqueous or oily solution of sterilizing, aseptic powder injection, liposome or
Emulsion.
Advantageous effects: the present invention provides a kind of curcumin derivates with structure shown in Formulas I and its application, originally
It is inhibited to Ovarian Cancer Cells HO-8910PM to invent the curcumin derivate provided, and inducing cell apoptosis
Kill cancer cell, bis- (4- halogen-benzylidene) the piperidin-4-one salt of curcumin derivate (3E, 5E) -3,5- provided by the invention
Hydrochlorate, piperidine structure increase its bioavilability, can be used for preparing the drug of ovarian cancer resistance.
The present invention also provides the preparation method of the curcumin derivate with structure shown in Formulas I, system provided by the invention
The curcumin derivate purity that Preparation Method is prepared is up to 99% or more.
Detailed description of the invention:
Fig. 1 is the HPLC-PDA measurement result of target product obtained in embodiment 1；
Fig. 2 is the HPLC-ELSD measurement result of the target product in embodiment 1 after purification；
Fig. 3 is the HPLC-MS measurement result of the target product in embodiment 1 after purification；
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of the target product in embodiment 1 after purification；
Fig. 5 is that target product compound 4 obtained in the embodiment 1 of various concentration and curcumin effect HO-8910PM are thin
Born of the same parents for 24 hours after survival rate figure；Wherein (a) is compound 4 and curcumin obtained in embodiment 1 that concentration is 0~120 μm of ol/L
Function cells for 24 hours after survival rate figure, be (b) enlarged drawing of 4 curve of compound at 0~3 μm ol/L sections of abscissa in (a)；
Fig. 6 is after target product compound 4 obtained in 1 μm of ol/L embodiment 1 acts on HO-8910PM cell 12 hours
Apoptosis rate；
Fig. 7 is that target product compound 4 obtained in the embodiment 1 of various concentration acts on HO-8910PM cell 12 hours
The albumen of YAP2, bone-marrow-derived lymphocyte tumor 2 (BCL-2), big tumor suppression kinases 1 (LATS1) and BCL-2 related protein X (BAX) afterwards
It is horizontal；
Fig. 8 is that target product compound 4 obtained in the embodiment 1 of various concentration acts on HO-8910PM cell 12 hours
The messenger RNA (mRNA) of YAP2 gene is horizontal afterwards；
Fig. 9 is that target product compound 4 obtained in 1 μm of ol/L embodiment 1 acts on HO-8910PM cell 0,6,12 and 24
The mRNA level in-site of apoptosis rate Yap-2 gene after hour.
Specific embodiment
The present invention provides a kind of curcumin derivates with structure shown in Formulas I:
The R is Cl, Br or F.
The present invention provides the preparation methods of the above-mentioned curcumin derivate with structure shown in Formulas I, comprising the following steps:
1) by the compound with structure shown in Formula II, the compound with formula III structure, alkali metal hydroxide and first
Aldol condensation reaction is carried out after alcohol mixing, obtains the compound with structure shown in formula IV；The chemical combination with formula III structure
R is Cl, Br or F in object；
2) after mixing the compound with structure shown in formula IV obtained in the step 1) with methylene chloride, it is passed through chlorine
Change hydrogen and carry out acid-base reaction, obtains the curcumin derivate with structure shown in Formulas I；It is described that there is formula III structure
Compound in R be Cl, Br or F.
The present invention is by the compound with structure shown in Formula II, the compound with formula III structure, alkali metal hydroxide
Aldol condensation reaction is carried out with after methanol mixing, obtains the compound with structure shown in formula IV.
In the present invention, the compound with structure shown in Formula II, compound and alkali metal with formula III structure
The mass ratio of the material of hydroxide is preferably 1:2:7.5.In the present invention, the methanol is solvent, use of the present invention to methanol
Amount is not particularly limited, and selects dosage well known to those skilled in the art.
In the present invention, the alkali metal hydroxide is preferably potassium hydroxide or sodium hydroxide.
In the present invention, the temperature of the Aldol condensation reaction is preferably room temperature；The time of the Aldol condensation reaction is excellent
It is selected as 12h.In the present invention, the Aldol condensation reaction preferably carries out under agitation, and the present invention does not have stirring condition
Particular determination selects stirring condition well known to those skilled in the art.
The present invention is to the compound with structure shown in Formula II, the compound with formula III structure, alkali metal hydroxide
It is not particularly limited with the method for methanol mixing, selects mixed method well known to those skilled in the art.The present invention is preferred
First to mix compound, alkali metal hydroxide and methanol with formula III structure under condition of ice bath, alkali gold is then added
Belong to hydroxide.
It in the present invention, further preferably successively include that water quenching reaction, methylene chloride extraction is added after the Aldol condensation reaction
It takes, the drying of saturated common salt water washing and anhydrous sodium sulfate.
The present invention is not particularly limited the method for adding water quenching reaction, selects method well known to those skilled in the art i.e.
It can.
In the present invention, the methylene chloride extraction obtains preferably to adding products therefrom after water quenching reaction to extract
To organic phase.The present invention is not particularly limited the method and number of extraction, and this field is selected to seem method known to personnel
With number.
In the present invention, the saturated common salt water washing preferably carries out salt to gained organic phase after methylene chloride extraction
Water washing obtains organic phase.The present invention is not particularly limited the method for saturated common salt water washing, selects those skilled in the art
Well known method.
In the present invention, the anhydrous sodium sulfate it is dry preferably to gained organic phase after saturated common salt water washing successively into
Row is dry and organic solvent is evaporated off, and obtains the compound with structure shown in formula IV.
After obtaining the compound of structure shown in formula IV, the present invention will obtain compound with structure shown in formula IV with
It after methylene chloride mixing, is passed through hydrogen chloride gas and carries out acid-base reaction, obtain having the curcumin of structure shown in Formulas I derivative
Object；R is Cl, Br or F in the compound with formula III structure.
In the present invention, there is the compound of structure shown in formula IV and the mass ratio of the material of hydrogen chloride is preferably 1:1.
The rate that the present invention is passed through the hydrogen chloride gas is not particularly limited, and is selected well known to those skilled in the art
Rate.
In the present invention, the temperature of the acid-base reaction is preferably 4 DEG C, and the time of the acid-base reaction is preferred
For 30min.
It in the present invention, further include successively being spin-dried for tying again with methanol by gained reaction solution after the acid-base reaction
Crystalline substance obtains the curcumin derivate with structure shown in Formulas I.
In the present invention, the temperature being spin-dried for is preferably room temperature.The present invention is not particularly limited the method being spin-dried for, choosing
Method is spin-dried for well known to those skilled in the art.
The present invention is not particularly limited the method for recrystallizing methanol, and methanol well known to those skilled in the art is selected to tie again
Brilliant method.
The present invention is not particularly limited the method that solvent is evaporated off, and selects method well known to those skilled in the art.
The present invention also provides the above-mentioned curcumin derivates with structure shown in Formulas I in the drug for preparing ovarian cancer resistance
Application, the drug of the ovarian cancer resistance is as including having the curcumin derivate of structure shown in Formulas I and its is pharmaceutically acceptable
Carrier be prepared.
In the present invention, the form of the preparation of the medicine of the ovarian cancer resistance preferably includes solid pharmaceutical preparation or liquid preparation.
In the present invention, the solid pharmaceutical preparation preferably includes tablet, sustained release tablets, controlled release tablet, capsule, dripping pill, pellet, powder
Or granule；The liquid preparation preferably includes suspension, emulsion, oral solution, the aqueous or oily solution of sterilizing, aseptic powder
Needle, liposome or emulsion.
For a better understanding of the present invention, below with reference to the embodiment content that the present invention is furture elucidated, but it is of the invention
Content is not limited solely to the following examples.
Embodiment 1
1) sodium hydroxide (7.5 moles) is added portionwise to the first of compound 1 (1 mole) and compound 2 (2 moles) under ice bath
In alcoholic solution, ice bath is removed, is stirred overnight at room temperature；Add water quenching reaction after overnight, is extracted 2 to 3 times with methylene chloride, merging
Organic phase saturated common salt water washing, it is dry with anhydrous sodium sulfate, obtain compound 3；
2) 3 adding into dichloromethane of compound that will be obtained is passed through hydrogen chloride gas 30min, (gas usage under ice bath
Abundance is greater than 1mol), then reaction solution is spin-dried for, with methanol crystallization up to target product curcumin derivate.Synthesis is anti-
Answer path as follows:
The HPLC-PDA measurement result of target product obtained in embodiment 1 as shown in Figure 1, peak value 1.768 peak area
Value is 98.667%, shows that the purity of target product is 98.667%.
After purification to the further methanol crystallization of target product, HPLC-ELSD is carried out containing measurement to target product after purification
Determine result as shown in Fig. 2, peak value 1.891 peak area value be 100%, illustrate that the purity of target product after purification reaches
100%.
HPLC-MS and magnetic resonance detection result to target product after purification distinguish as shown in Figure 3 and Figure 4, HPLC-
Peak value under MS positive ion mode is 344, consistent with the relative molecular mass (344.23) of compound 4.
Curcumin derivate obtained in embodiment 1 (a kind of curcumin derivate with structure shown in Formulas I, R Cl,
Hereinafter referred to as compound 4) influence to HO-8910PM cellular morphology:
Cell culture processes are as follows: HO-8910PM cell strain is incubated at the cell culture medium containing 10% import fetal calf serum
(DMEM) in, separately plus l-GLUTAMINE (L-glutamine) 300mg 1.5g/L sodium bicarbonate (NaHCO3) and antibiotic
(100U penicillin and 100mg/L streptomysin).Cell is placed in 37 degrees Celsius, saturated humidity, contains 5%CO2In the incubator of gas
Culture.
Cell propagating method is as follows:
A. 80% or so is grown in inverted phase contrast microscope observation cell, can passed on.It is super with ultraviolet light irradiation before passage
Net workbench is more than half an hour, and with 75% alcohol wipe workbench and both hands.
B. the old culture solution in culture bottle is sucked with pipette tips, is cleaned 2 times with phosphate buffer (PBS).
C. pancreatin 2mL/1mL (75cm is added2/25cm2Culture bottle) it is digested, static about 3 minutes, and be inverted frequently
It is observed under phase contrast microscope, when cytoplasm bounces back, when iuntercellular no longer connects in blocks, appropriate serum-containing medium is added and terminates pancreas egg
The effect of white enzyme.
D. the cell digested is blown and beaten into cell suspension with dropper, is sucked into 15mL centrifuge tube, be centrifuged 5 minutes 1000
Turn.
E. liquid is discarded supernatant, is washed twice with phosphate buffer (PBS), liquid is finally discarded supernatant, 5mL culture solution is added,
It is gently blown and beaten with pipette tips to cell suspension, 1:2~1:3 is distributed into new culture bottle, adds appropriate culture solution and relays in incubator
Continuous culture, obtains the cell of logarithmic growth phase.
Morphological observation: by the cell inoculation of logarithmic growth phase in culture dish, two groups, one group are divided into after being incubated overnight
Without any processing, as a control group, the compound 4 of 2 μm of ol/L concentration of another group of addition is handled, and 4 solvent of compound is diformazan
Base sulfoxide (DMSO) observes cell shape as experimental group under inverted phase contrast microscope respectively after 6 hours, 12 hours, 24 hours
State changes and records.
By microscopically observation it is found that cellular control unit adherent growth, flanking cell fusion in flakes, cell in similar round or
Shuttle shape, volume is larger, and arrangement is close, and the smooth of the edge, cytoplasm is full, and the structure outlines such as nuclear membrane, kernel are obvious, and cell growth is fast
Speed.Experimental group cell density gradually decreases over time, and the speed of growth is obviously slowed to and almost stagnated, and cell gradually falls off
And it floats in culture solution；Cell volume reduces, after birth shrinkage, at small circular or irregular form, common fine granularity intracellular
Substance；Drug treating time is longer, and morphological changes of cell is more obvious.Illustrate that compound 4 can promote Ovarian Cancer Cells HO-
8910PM cell volume reduces to induce its apoptosis.
Cytotoxicity test (methyl- azoles salt method, i.e. mtt assay):
A. cell bottle logarithmic growth phase in above-mentioned cell passage assays is digested to single cell suspension, is pressed after cell count
Be inoculated in 96 orifice plates according to 8000/ hole, every hole adds the 100 corresponding culture mediums of μ L, routine culture in 37 degrees Celsius, contain 5%CO2Gas
Incubator in, as experimental group.
B. negative control group (have cell not dosing, but add 0.1%DMSO drug solvent) is set, blank control group (has cell
Not dosing, also not solubilizer), it is other identical as the processing step of experimental group.
C.24 after hour observe cell adherent growth it is good, be separately added into experimental group orifice plate concentration be 0.1 μm of ol/L,
0.25 μm of ol/L, 0.5 μm of ol/L, 1 μm of ol/L, 2 μm of ol/L compounds 4, every hole set 3 repeating holes.
D. 96 orifice plates moved into 37 degrees Celsius after dosing, contain 5%CO2Continue culture 24 hours in the incubator of gas.
E. every hole adds 20 μ L of MTT liquid (5mg/mL) at the end of every group of experiment, and 37 degrees Celsius, contain 5%CO2The culture of gas
After case continues culture 4 hours, supernatant is sucked, every hole adds 80 μ LDMSO, shakes on shaking table 10 minutes.Then it is detected in microplate reader
Absorbance (OD) value in every hole in wavelength 450.
F. absorption values are subtracted the blank control wells degree that is averaged is cell MTT detection data, with nonlinear regression
Method calculates half lethal concentration (IC50).
Fig. 5 be compound 4 and curcumin function cells obtained in the embodiment 1 of various concentration for 24 hours after survival rate figure.
Wherein (a) be compound 4 obtained in embodiment 1 that concentration is 0~120 μm of ol/L and curcumin function cells for 24 hours after deposit
Motility rate figure is (b) enlarged drawing of 4 curve of compound at 0~3 μm ol/L sections of abscissa in (a).As shown in Figure 5, survival rate point
It Wei 90%, 80%, 60%, 50% and 40%.The curcumin derivate of various concentration is thin to Ovarian Cancer Cells HO-8910PM
The growth of born of the same parents has inhibiting effect, and it is about 50 μm of ol/L, compound 4 that curcumin, which acts on 24 hours IC50 of HO-8910PM cell,
Acting on 24 hours IC50 of HO-8910PM cell is about 1 μm of ol/L, it follows that compound 4 induces ovarian cancer cell HO-
The ability of 8910PM apoptosis increases nearly 50 times than curcumin.Various concentration and different time processing group after two-way analysis of variance
Between difference there is statistical significance (P < 0.05), compound 4 to the growth inhibition effect of HO-8910PM in time-concentration according to
Rely.
Cellular cycle and apoptosis test: with logarithmic growth phase HO-8910PM cell, the cell of suitable density is inoculated in 6 holes
Plate after cultivating 24 hours in cell incubator, is added after 1 μm of ol/L compound 4 acts on HO-8910PM cell 2,6 and 12 hours
Cell is collected by centrifugation in pancreatin digestion, and PBS washes 3 centrifugations, after 70% 4 DEG C of ethyl alcohol fixed cell pellet overnights are added into cell precipitation
2 centrifugations are washed with PBS again, are protected from light culture 30 minutes for 37 degrees Celsius after addition 250 μ L, 100 μ g/mLRNase.50 μ g/mL are added
Propidium iodide (PI) coloring agent room temperature be protected from light the variation of Flow cytometry cell cycle after 30 minutes.Same procedure
Cell is collected, cell, which is resuspended, with 1x combination buffer makes cell concentration 1 × 106/mL.Take 100 μ L cell suspensions into new pipe
And 5 μ L fluorescein isothiocynate cardiolipin binding proteins 5 (FITC Annexin V) and 5 μ L PI, after mixing gently, room are added
Temperature is protected from light 15min, and flow cytometry as early as possible is added after 400 μ L 1X combination buffers in every pipe.
As analysis result it is found that 0.5 μm of ol/L, 1 μm of ol/L and 2 μm of ol/L embodiment 1 obtained in compound 4 stimulate
It HO-8910PM cell 24 hours, observes under ordinary optical microscope, 0.5 μm of ol/L compound 4 acts on HO-8910PM cell 24
After hour, cell is without significant change, after compound 5 obtained in 1 μm of ol/L embodiment 1 acts on HO-8910PM cell 12 hours,
There is empty balloon-shaped in cytoplasm, and then leads to Apoptosis (as shown in Figure 6), the experimental results showed that, compound 4 induces HO-
8910PM Apoptosis is obvious with drug concentration increase.
HO-8910PM apoptosis is induced in order to study certain density compound 4, flow cytometer detection instrument detects chemical combination
Object 4 acts on HO-8910PM cell apoptosis assay and cell cycle variation.Apoptosis the experimental results showed that, 1 μm of ol/L compound 4 is made
After HO-8910PM cell 12 hours, compared with the control group, apoptosis phase cell obviously increases (as shown in Figure 7).Flow cytometry
After the cell cycle is detected the results show that 1 μm of ol/L compound 4 acts on HO-8910PM cell 12 hours, compared with the control group, add
There is apparent apoptotic peak in the medicine group cell cycle.In addition, compared with the control group, the dosing group appearance apparent G2/M phase is detained (such as
Shown in Fig. 8).Apoptosis experiment and cell cycle the experimental results showed that, compared with the control group, 1 μm of ol/L compound 4 acts on HO-
Can induce cell apoptosis after 8910PM cell 12 hours: cytoplasmic vacuoles sample changes, and apoptosis phase cell increased significantly, cell week
There is apparent apoptotic peak and leads to the delay of G2/M phase in phase.
The pharmacological mechanism of curcumin derivate obtained in embodiment 1 is tested:
With logarithmic growth phase HO-8910PM cell, appropriate cell density is inoculated with into 6cm culture dish, is placed in cell culture
After being cultivated 24 hours in case, 0.5 μm of ol/L, 1 μm of ol/L, 2 μm of ol/L compounds 4 are added and act on 12 hours collection cells；1μ
Mol/L compound 4 collects cell after acting on 0.25,0.5,1,2,4,6,12 and 24 hour.A part for extract nucleus and
Suppressor proteins albumen uses Western blot measurement LATS1, YAP2, BAX, BCL-2 and actin β (ACTB) in
Ginseng.Another part extracts RNA with TRIZOL method, and with the expression quantity of real time fluorescent quantitative (qPCR) measurement Yap2 gene, phosphoric acid is sweet
Oily aldehyde dehydrogenase (Gapdh) is used as internal reference.
As seen from the experiment, 0.5 μm of ol/L, 1 μm of ol/L and 2 μm of ol/L compound 4 stimulate cell 12 hours after, egg
White western blot test detects protein expression.The results show that compound 4 can reduce Yap2 albumen, increase the table of Lats1 albumen
It reaches, further, it is also possible to reduce Bcl-2 albumen, increases the expression of the apafls such as Bax albumen, and be in dose-dependant
(as shown in Figure 7).It is direct reduction Yap2 gene level to further study compound 4 to reduce Yap2 protein expression, still
Influence protein translation link.QPCR detection compound 4 stimulates the variation of Yap2mRNA level after cell, knot under same experimental conditions
Fruit shows, increases as 4 drug concentration of compound increases with stimulation time, Yap2mRNA level gradually decreases (such as Fig. 8 and Fig. 9
It is shown).The result shows that compound 4 promotes Apoptosis by reducing Yap2 albumen and gene level.
Embodiment 2
1) sodium hydroxide (7.5 moles) is added portionwise to the first of compound 5 (1 mole) and compound 6 (2 moles) under ice bath
In alcoholic solution, ice bath is removed, is stirred overnight at room temperature；Add water quenching reaction after overnight, is extracted 2 to 3 times with methylene chloride, merging
Organic phase saturated common salt water washing, it is dry with anhydrous sodium sulfate, obtain compound 7；
3) 7 adding into dichloromethane of compound that will be obtained is passed through hydrogen chloride gas 30min, (gas usage under ice bath
Abundance is greater than 1mol), then reaction solution is spin-dried for, with methanol crystallization up to target product curcumin derivate 8.Synthesis is anti-
Answer path as follows:
Embodiment 3
1) compound 9 (1 mole) and compound 10 (2 moles) is added portionwise in sodium hydroxide (7.5 moles) under ice bath
In methanol solution, ice bath is removed, is stirred overnight at room temperature；After overnight plus water quenching reaction is merged with methylene chloride extraction 2 to 3 times
Organic phase saturated common salt water washing, it is dry with anhydrous sodium sulfate, obtain compound 11；
4) 11 adding into dichloromethane of compound that will be obtained is passed through hydrogen chloride gas 30min under ice bath, and (gas is used
Amount is sufficient to be greater than 1mol), then reaction solution is spin-dried for, with methanol crystallization up to target product curcumin derivate 12.It closes
It is as follows at response path:
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, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of curcumin derivate with structure shown in Formulas I:
The R is Cl or Br or F.
2. a kind of preparation method of the curcumin derivate described in claim 1 with structure shown in Formulas I, including following step
It is rapid:
1) compound with structure shown in Formula II, the compound with formula III structure, alkali metal hydroxide and methanol are mixed
Aldol condensation reaction is carried out after conjunction, obtains the compound with structure shown in formula IV；In the compound with formula III structure
R is Cl, Br or F；
2) 13 object of chemical combination with structure shown in formula IV obtained in the step 1) 2 is mixed with methylene chloride after, be passed through chlorine
Change hydrogen and carry out acid-base reaction, obtains the curcumin derivate with structure shown in Formulas I.
3. preparation method according to claim 2, which is characterized in that the change with structure shown in Formula II in the step 1)
The mass ratio of the material for closing object, the compound with formula III structure and alkali metal hydroxide is 1:2:7.5.
4. preparation method according to claim 2, which is characterized in that alkali metal hydroxide is hydrogen-oxygen in the step 1)
Change potassium or sodium hydroxide.
5. according to preparation method described in claim 2~4 any one, which is characterized in that the step 1) condensation is anti-
The temperature answered is room temperature, time 12h.
6. preparation method according to claim 2, which is characterized in that the change with structure shown in formula IV in the step 2)
The mass ratio of the material for closing object and hydrogen chloride is 1:1~3.
7. the preparation method according to claim 2 or 6, which is characterized in that the temperature of acid-base reaction in the step 2)
Degree is 4 DEG C, time 30min.
8. curcumin derivate the answering in the drug for preparing ovarian cancer resistance described in claim 1 with structure shown in Formulas I
With, which is characterized in that the drug of the ovarian cancer resistance as include have structure shown in Formulas I curcumin derivate and its pharmaceutically
Acceptable carrier is prepared.
9. application according to claim 8, which is characterized in that the form of the preparation of the medicine of the ovarian cancer resistance includes solid
Preparation or liquid preparation.
10. application according to claim 9, which is characterized in that the solid pharmaceutical preparation include tablet, sustained release tablets, controlled release tablet,
Capsule, dripping pill, pellet, powder or granule；The liquid preparation include suspension, emulsion, oral solution, sterilizing it is aqueous or oily
Property solution, aseptic powder injection, liposome or emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910019941.2A CN109734658A (en) | 2019-01-09 | 2019-01-09 | A kind of curcumin derivate and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910019941.2A CN109734658A (en) | 2019-01-09 | 2019-01-09 | A kind of curcumin derivate and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109734658A true CN109734658A (en) | 2019-05-10 |
Family
ID=66364124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910019941.2A Pending CN109734658A (en) | 2019-01-09 | 2019-01-09 | A kind of curcumin derivate and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109734658A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303019A (en) * | 2020-04-16 | 2020-06-19 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Piperidone curcumin analogue as well as preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011005790A1 (en) * | 2009-07-06 | 2011-01-13 | The Ohio State University Research Foundation | Compositions and methods for inhibition of cancers |
| CN102477012A (en) * | 2011-07-21 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human |
| CN102477013A (en) * | 2011-07-28 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
| CN103222970A (en) * | 2013-04-10 | 2013-07-31 | 温州医学院 | Application of asymmetric single-carbonyl curcumin analogues in preparing antitumor medicines |
| US8722707B1 (en) * | 2009-07-06 | 2014-05-13 | The Ohio State University | Compositions and methods for inhibition of smooth muscle cell proliferation and neointimal hyperplasia |
| CN106214677A (en) * | 2016-07-20 | 2016-12-14 | 温州医科大学 | The application in preparing antitumor drug of a kind of substituted single carbonyl curcumin compounds containing pi-allyl |
-
2019
- 2019-01-09 CN CN201910019941.2A patent/CN109734658A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011005790A1 (en) * | 2009-07-06 | 2011-01-13 | The Ohio State University Research Foundation | Compositions and methods for inhibition of cancers |
| US8722707B1 (en) * | 2009-07-06 | 2014-05-13 | The Ohio State University | Compositions and methods for inhibition of smooth muscle cell proliferation and neointimal hyperplasia |
| CN102477012A (en) * | 2011-07-21 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human |
| CN102477013A (en) * | 2011-07-28 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
| CN103222970A (en) * | 2013-04-10 | 2013-07-31 | 温州医学院 | Application of asymmetric single-carbonyl curcumin analogues in preparing antitumor medicines |
| CN106214677A (en) * | 2016-07-20 | 2016-12-14 | 温州医科大学 | The application in preparing antitumor drug of a kind of substituted single carbonyl curcumin compounds containing pi-allyl |
Non-Patent Citations (4)
| Title |
|---|
| DIMMOCK, J. R.等: "Cytotoxic Evaluation of Some 3,5-diarylidene-4-piperidones and Various Related Quaternary Ammonium Compounds and Analogs", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| SINGARAM, KULATHOORAN等: "Synthesis and antimicrobial activity of new 3,5-diarylidene-4-piperidone derivatives", 《JOURNAL OF THE SERBIAN CHEMICAL SOCIETY》 * |
| TAN, KHENG-LIN等: "Curcumin Analogues with Potent and Selective Anti-proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co-repressor (N-CoR) Protein as a Basis for Selective Activity", 《CHEMMEDCHEM》 * |
| WEI, XINGCHUAN等: "Synthesis and evaluation of curcumin-related compounds for anticancer activity", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303019A (en) * | 2020-04-16 | 2020-06-19 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Piperidone curcumin analogue as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11484550B2 (en) | Pharmaceutical composition for improving health, cure abnormalities and degenerative disease, achieve anti-aging effect of therapy and therapeutic effect on mammals and method thereof | |
| CN101255119B (en) | Novel tetrahydro curcumin derivatives and salt | |
| Basak et al. | Liposome encapsulated curcumin-difluorinated (CDF) inhibits the growth of cisplatin resistant head and neck cancer stem cells | |
| Zahran et al. | Design, synthesis and antitumor evaluation of novel thalidomide dithiocarbamate and dithioate analogs against Ehrlich ascites carcinoma-induced solid tumor in Swiss albino mice | |
| US20160151415A1 (en) | Pharmaceutical composition for improving health, cure abnormalities and degenerative disease, achieve anti-aging effect of therapy and therapeutic effect on mammals and method thereof | |
| CN106581690B (en) | Tumor microenvironment stimulates degradable amphipathic block HPMA polymeric drug delivery system and preparation method thereof | |
| Hakimuddin et al. | Treatment of mcf-7 breast cancer cells with a red grape wine polyphenol fraction results in disruption of calcium homeostasis and cell cycle arrest causing selective cytotoxicity | |
| CN103002895A (en) | Method for treating hematological cancers | |
| CN109734658A (en) | A kind of curcumin derivate and its preparation method and application | |
| Jiang et al. | The paradigm-shifting idea and its practice: from traditional abortion Chinese medicine Murraya paniculata to safe and effective cancer metastatic chemopreventives | |
| CN104337803B (en) | Isodon xerophilus B prime xerophilusin B application in preparation suppression tumor growth product | |
| Tan et al. | Gypensapogenin H suppresses tumor growth and cell migration in triple-negative breast cancer by regulating PI3K/AKT/NF-κB/MMP-9 signaling pathway | |
| CN110452163A (en) | A kind of application of the preparation method of curcumin derivate and its anti-prostate cancer | |
| Ong et al. | The anticancer effect of protein-extract from Bidens alba in human colorectal carcinoma SW480 cells via the reactive oxidative species-and glutathione depletion-dependent apoptosis | |
| CN108938638A (en) | ZINC62678696 inhibits the purposes of hepatic fibrosis medicines in preparation | |
| CN104725372B (en) | Tetracyclic indole alkaloid derivative as well as preparation method and application thereof | |
| CN105388294B (en) | Application of mitochondrion three-function enzyme alpha subunit in preparing AA005 medicine target for inhibiting lipid accumulation | |
| CN102727505A (en) | Application of salidroside in preventing and treating amyotrophy diseases | |
| CN107569451B (en) | A kind of synthesis and its application of the degradable nano magnesia metal micelle complex of gene target | |
| RU2454232C2 (en) | Application of triindolyl methane derivatives as anticancer drugs | |
| CN115057798B (en) | Fluorescent probe, preparation method and application thereof | |
| CN103864720A (en) | Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application | |
| CN110124057A (en) | A kind of anti-tumor drug or pharmaceutical carrier of the cyclodextrin comprising glutamine modification | |
| Jeon et al. | Anti-platelet activity of tissue-cultured mountain ginseng adventitious roots in human whole blood | |
| CN112941027B (en) | Human keratinocyte malignant transformation cell strain caused by dimethylarsinic acid and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190510 |