CN106543155A - As the chalcone and flavone derivative of aurora kinase inhibitors - Google Patents
As the chalcone and flavone derivative of aurora kinase inhibitors Download PDFInfo
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- CN106543155A CN106543155A CN201610850932.4A CN201610850932A CN106543155A CN 106543155 A CN106543155 A CN 106543155A CN 201610850932 A CN201610850932 A CN 201610850932A CN 106543155 A CN106543155 A CN 106543155A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
Inhibitory action of the present invention with regard to the design of a class chalcone and flavone derivative of formula I (I 1 and I 2) and II (II 1 and II 2), synthesis and its to BTAK.The compound can adjust the function of the target spot of the signal path of aurora kinase and its correlation, and then affect cell cycle and proliferation process, to treating cancer and the disease related to cancer.
Description
Technical field：The present invention relates to drug world, more particularly, is related to the chalcone as aurora kinase inhibitors
And flavone derivative and its application on medicine is prepared.
Background technology：Cell propagation is the basis of biology growing, development and heredity.Mitosiss are cell division cycle
A stage, at this stage, cell experienced the maturation of centrosome and separate, the pyknosis of chromosome, bipolar spindle
Formation separate with assembling, chromosome and the process such as cytokinesiss.Research shows in mitotic this series of event
In, aurora kinase plays important regulating and controlling effect.Cancerous cell is a kind of cell of variation, with the unlimited life that normal cell does not have
The characteristics of long, conversion and transfer.Research show aurora kinase in kinds of tumor cells in specificity overexpression, including colon
Cancer, hepatocarcinoma, breast carcinoma, pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, head cancer, neck cancer, cervical cancer and ovarian cancer etc..Suppress it is a kind of or while
Suppress various aurora kinases suppress cell propagation and inducing cell apoptosis in kinds of tumor cells system.
Have now been found that suppression aurora kinase energy arresting cell cycle and promote programmed cell death by apoptosis.
Therefore, the inhibitor of aurora kinase causes anti-cancer agent research as the exploitation of antitumor drug and pays high attention to.Have at present
More than preclinical or clinical investigation phase of 30 kinds of aurora kinase inhibitors in medicine.They by specific hydrogen bond with
The key amino acid of aurora kinase active site region is combined.The other parts of molecule can be distributed in other areas of avtive spot
Domain, or the effect by intermolecular weak interaction force and between solvent and be dispersed in the inactive area of BTAK
Domain.Herba Lycopi's Huang frangula-emodin and luteolin are two natural flavone compounds, are found to have the suppression of preferable aurora kinase B
System activity.Our early-stage Study finds that multiple flavone compounds of Flos Eriocauli are respectively provided with preferably suppression with B to BTAK
System activity.
Deepen continuously with the research of structure activity relationship recently as the pharmacological action of flavone compound, find its antitumor
Activity has obvious dependency with its structure.There is natural flavonoid compound stronger anti-cancer and cancer-preventing to act on, typically by with
Lower three kinds of approach:(1) flavone compound can change gene expression, adjust tumor cell proliferation, thus inducing tumor cell
Apoptosis；(2) flavone compound can also pass through the key enzyme activity in suppression cell signaling processes, act on tumor thin
Born of the same parents, such as protein kinase, tyrosine protein kinase etc.；(3) to carcinogenesis carcinogenic factor.The antitumor of natural flavonoid compound is lived
Property is related to its free radical resisting ionization.2,3 double bonds of natural flavonoid compound C rings, phenolic hydroxyl group substitute mode and number
Its anticancer effect is affected all.As flavone compound metabolite in vivo, some structure activity relationships etc. are still not clear.And it is yellow
The signaling molecule characteristic of ketone compounds increasingly comes important.We should utilize prior art and means constantly to study its pharmacology
Effect essence, strengthens the comprehensive profit of natural flavonoid compound by changing active group, regulation and control metabolism, change dissolubility etc.
With value.
Chalcone is the class native compound being widely present in the various plants such as Radix Glycyrrhizae, Flos lupuli (Flos Humuli Lupuli) and thorn bean, is had
There is extensive pharmacologically active.Research shows that chalcone compounds can cause cell cycle arrest and induce in the retardance phase
Apoptosis of tumor cells and suppress the propagation of tumor cell.Jong Min Lee et al. (Cancer Letters 354 (2014)
348-354) find that some simple chalcone compounds and its derivant can effectively suppress the activity of aurora kinase, and
And it is higher to the inhibitory activity of BTAK.Thus chalcone compounds are carried out with structure of modification, it is most likely that find new
The inhibitor of the active preferably BTAK of chalcones.
The content of the invention：
Goal of the invention：The present invention is with regard to a kind of flavone derivative and its medicine in the inhibitory action for preparing BTAK
The application of thing.The compound can adjust the function of the target spot of the signal path of aurora kinase and its correlation, and then affect thin
Born of the same parents' cycle and proliferation process, to treating cancer and the disease related to cancer.
Technical scheme：
As the chalcone and flavone derivative of aurora kinase inhibitors, it is characterised in that：The derivant is molecular formula
Compound shown in I-1, I-2 and molecule formula II -1, II -2：
In above-claimed cpd：R1 is to form ehter bond with 3 ' or 4 ' positions in flavone female ring；R2 for can with flavone parent nucleus on 6
Bit amino forms the substituent group of amide or sulfonamide.
Described chalcone and flavone derivative as aurora kinase inhibitors, it is characterised in that：The molecular formula
Compound described in I-1 is the one kind in following compound：
Compound described in molecular formula I-2 is the one kind in following compound：
Described chalcone and flavone derivative as aurora kinase inhibitors, it is characterised in that：The molecular formula
Compound described in II -1 is the one kind in following compound：
Compound described in the molecule formula II -2 is the one kind in following compound：
Described chalcone and flavone derivative as aurora kinase inhibitors, it is characterised in that：Also include described
Compound pharmaceutically acceptable salt, hydrate or solvate.
Application of the described compound in the medicine for suppressing BTAK activity is prepared, it is characterised in that：The suppression
The medicine of BTAK activity is a kind of medicine of the function inhibitio growth of cancer cells by mediating BTAK.
Application of the described compound in the medicine for suppressing BTAK activity is prepared, it is characterised in that：The cancer is thin
Born of the same parents' species is included to Non-small cell lung carcinoma A549 cells, human hepatoma HepG2 cell, human breast carcinoma MCF-7 and human leukemia
K562 cells.
Application of the described compound in the medicine for suppressing BTAK activity is prepared, it is characterised in that：The chemical combination
Thing is further used in combination with one or more cytotoxic agent；The cytotoxic agent is that vinblastine, doxorubicin, Changchun are new
One or more in alkali and paclitaxel.
The preparation method of described chalcone and flavone derivative as aurora kinase inhibitors, it is characterised in that：
The method for preparing the compound expressed by I-1, I-2 molecular formula is comprised the following steps：
(1) to added with drying tube CaCl2100ml single-necked flasks in add 4g paeonol and 30ml glacial acetic acid, with 0 DEG C
Deca concentrated nitric acid 15ml while stirring in ice-water bath；
(2) continue reaction 24h in 20 DEG C；
(3) reactant mixture is added in the frozen water of 1000ml, stirring separates out yellowish flocculent deposit, after decompression sucking filtration
Filtration cakes torrefaction is obtained into crude product；
(4) poured into after the acetone solution by the crude product with 50ml again in the frozen water of 1000ml and stirred, separate out white flock
Precipitation, the white solid after the sucking filtration that reduces pressure are 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones；Reaction equation is：
(5) take 10mM vanillin with 20ml being dried DMF dissolving after, add 50mM K2CO3, the stirring reaction at 50 DEG C
After 30min, 4- (2- chloroethyls) morpholines of Deca 10.5mM, after reaction terminates reactant liquor are poured in 80 DEG C of reaction overnights
In 200ml water, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated is obtained slightly produces
Product, Jing silica gel column chromatography purification obtain product；
(6) with 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones and 3- methoxyl group -4- ethyl morpholine benzaldehydes as raw material, with
4:1 EtOH/H2O is solvent, and Jing Claisen-Schmidt condensations reaction in the basic conditions generates chalcone；Reaction equation is：
(7) in DMSO/I2/H2SO4In system, with (6), the chalcone of synthesis obtains corresponding Huang as raw material oxidation closed loop
Ketone compounds；Reaction equation is：
(8) using sodium hydrosulfite as reducing agent, the nitro flavone in (7) is reduced to into amino flavone in ethanolic aqueous system；
Decompression after reaction terminates steams ethanol, adds excessive hydrochloric acid heating excessive sodium hydrosulfite is reacted completely；Reaction equation is：
(9) the amino flavone 10mM synthesized in taking previous step is dissolved in the DMF of 30ml dryings, adds the K2CO3 of 50mM,
The ethyl chloride of 15mM is added at 0 DEG C, stirring reaction is warmed to room temperature overnight；Reactant liquor is poured into after terminating by question response
In 400ml water, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated is obtained slightly produces
Product, Jing silica gel column chromatography purification obtain product and obtain the compound representated by formula I；Reaction equation is as follows：
The method for preparing the compound expressed by II-1, II-2 molecular formula is comprised the following steps：
(1) 4g paeonol and 30ml glacial acetic acid are added in the 100ml single-necked flasks added with drying tube CaCl2, with 0 DEG C
Side stirring in ice-water bath becomes slowly Deca concentrated nitric acid 15ml：
(2) continue reaction 24h in 20 DEG C；
(3) reactant mixture is added in the frozen water of 1000ml, stirring separates out yellowish flocculent deposit, after decompression sucking filtration
Filtration cakes torrefaction is obtained into crude product；
(4) poured into after the acetone solution by the crude product with 50ml again in the frozen water of 1000ml and stirred, separate out white flock
Precipitation, the white solid after the sucking filtration that reduces pressure are 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones；Reaction equation is：
(5) take 10mM vanillin with 20ml being dried DMF dissolving after, add 50mM K2CO3, the stirring reaction at 50 DEG C
After 30min, 4- (2- chloroethyls) morpholines of Deca 10.5mM, after reaction terminates reactant liquor are poured in 80 DEG C of reaction overnights
In 200ml water, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated is obtained slightly produces
Product, Jing silica gel column chromatography purification obtain product；
(6) with 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones and 3- methoxyl group -4- ethyl morpholine benzaldehydes as raw material,
Claisen-Schmidt condensations generate chalcone；Reaction equation is：
(7) with (6), the chalcone of synthesis utilizes Zn/NH4Cl as reducing agent as raw material, with 2% TPGS-750-M's
Aqueous solution is solvent, and the nitro of the chalcone is reduced into amino.Reaction equation is as follows：
(8) the chalcone 5mM for taking synthesis in (7) is dissolved in the dichloromethane of 40ml, and the pyridine of addition 8mM is at 0 DEG C
The ethyl chloride of 7.5mM is added, stirring reaction is warmed to room temperature overnight；To be carried out with silica gel column chromatography after reactant liquor solvent evaporated
Purification obtains the compound representated by formula II；Reaction equation is as follows：
Advantage and effect：The compound of the present invention can adjust the work(of the target spot of the signal path of aurora kinase and its correlation
Can, and then cell cycle and proliferation process are affected, to treating cancer and the disease related to cancer.
Specific embodiment：
Design, synthesis and its suppression to BTAK with regard to formula I (I -1 and I -2) flavone derivative of the invention is made
With.The compound can adjust the function of the target spot of the signal path of aurora kinase and its correlation, and then affect cell cycle
And proliferation process, to treating cancer and the disease related to cancer.
Flavone analog derivative (I -1 and I -2) of the present invention with regard to formula I.
R1 be with flavone female ring 3 ' or 4 ' to form ehter bond.R2 for can with flavone parent nucleus on 6 be amino formed amide
Or the substituent group of sulfonamide.
It is below the compound described in the present invention I -1：
It is below the compound described in the present invention I -2：
The synthetic route of the compound described in formula I：
With paeonol and vanillin as initiation material, paeonol is with HNO3/CH3COOH(V:V=1:3) at room temperature to 5
Carry out nitrification and introduce nitro.And vanillin is then in K2CO3As acid binding agent with R1 groups into ether.The two is in KOH/EtOH-H2O(4:
1) by aldol condensation synthesizing chalcone under the conditions of, then in DMSO/I2Cyclization synthesis chromocor compound under the conditions of/H2SO4.Will
Flavone compound 6 introduces nitro to carry out amide-type replacement after sodium hydrosulfite reduction.Synthetic route is as follows：
The present invention with regard to formula II (II -1 and II -2) a class chalcones derivant design, synthesis and its to aurora swash
The inhibitory action of enzyme A.The compound can adjust the function of the target spot of the signal path of aurora kinase and its correlation, Jin Erying
Cell cycle and proliferation process are rung, to treating cancer and the disease related to cancer.
R1 be with flavone female ring 3 ' or 4 ' to form ehter bond.R2 for can with flavone parent nucleus on 6 be amino formed amide
Or the substituent group of sulfonamide.
It is below the compound described in the present invention II -1：
It is below the compound described in the present invention II -2：
The synthetic route of the compound described in formula II：
All compounds of the present invention, can suppress BTAK activity in effective dosage ranges well, its
These compounds are characterised by by mediating the function of BTAK, to Non-small cell lung carcinoma A549 cells, human liver cancer
HepG2 cells, human breast carcinoma MCF-7 and K562 cell are respectively provided with significant Developing restraint effect.
The compound of the present invention can be applied together with cytotoxic agent in pharmacy procedure, can be remarkably reinforced cytotoxicity
The Cytostatic to tumor cell effect of agent.The cytotoxic agent for being adapted to be used together with aurora kinase inhibitors of the invention it is non-
The example of restriction includes:Vinblastine (vinblastin), doxorubicin (doxorubicin), vincristine (vincristine)
With paclitaxel (paclitaxel).
The method of the compound representated by synthetic molecules formula I
To added with drying tube (CaCl2) 100ml single-necked flasks in add 4g paeonol and 30ml glacial acetic acid, with 0 DEG C
Side stirring in ice-water bath becomes slowly Deca concentrated nitric acid 15ml.After completion of dropping, continue reaction 24h in 20 DEG C.After reaction terminates, will
Reactant mixture is added in the frozen water of 1000ml, and stirring separates out yellowish flocculent deposit, after decompression sucking filtration obtains filtration cakes torrefaction
Crude product.To be poured into after acetone solution of the crude product with 50ml again in the frozen water of 1000ml and stirred, separate out white flock precipitate,
White solid after decompression sucking filtration is 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones.
Take 10mM vanillin with 20ml being dried DMF dissolving after, add 50mM K2CO3, the stirring reaction at 50 DEG C
After 30min, slowly 4- (2- chloroethyls) morpholines of Deca 10.5mM, after reaction terminates reactant liquor are fallen in 80 DEG C of reaction overnights
Enter in 200ml water, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated is obtained slightly
Product, Jing silica gel column chromatography purification obtain product.
With 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones and 3- methoxyl group -4- ethyl morpholine benzaldehydes as raw material, with 4:1
EtOH/H2O is solvent, and Jing Claisen-Schmidt condensations in the basic conditions generate chalcone.Reaction equation descends institute as follows
Show：
In DMSO/I2/H2SO4In system, the chalcone synthesized with 21 obtains corresponding flavonoid as raw material oxidation closed loop
Compound.Reaction equation is as follows：
Using excessive sodium hydrosulfite as reducing agent, the nitro flavone in 22 is reduced to into amino in ethanolic aqueous system yellow
Ketone.Decompression after reaction terminates steams ethanol, adds excessive hydrochloric acid heating excessive sodium hydrosulfite is reacted completely.Reaction equation is such as
Under：
Take the amino flavone (10mM) synthesized in 23 and be dissolved in the K2CO3 that 50mM is added in the DMF of 30ml dryings, after 0 DEG C
The ethyl chloride of lower addition 15mM, is warmed to room temperature stirring reaction overnight.Question response pours reactant liquor into 400ml water after terminating
In, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated obtains crude product, Jing silicon
It is gel column chromatography eluting that product obtains the compound representated by a formula I.Reaction equation is as follows：
The method of the compound representated by synthetic molecules formula II
4g paeonol and 30ml glacial acetic acid are added in the 100ml single-necked flasks added with drying tube (CaCl2), with 0 DEG C
Side stirring in ice-water bath becomes slowly Deca concentrated nitric acid 15ml.After completion of dropping, continue reaction 24h in 20 DEG C.After reaction terminates, will
Reactant mixture is added in the frozen water of 1000ml, and stirring separates out yellowish flocculent deposit, after decompression sucking filtration obtains filtration cakes torrefaction
Crude product.To be poured into after acetone solution of the crude product with 50ml again in the frozen water of 1000ml and stirred, separate out white flock precipitate,
White solid after decompression sucking filtration is 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones.
Take 10mM vanillin with 20ml being dried DMF dissolving after, add 50mM K2CO3, the stirring reaction at 50 DEG C
After 30min, slowly 4- (2- chloroethyls) morpholines of Deca 10.5mM, after reaction terminates reactant liquor are fallen in 80 DEG C of reaction overnights
Enter in 200ml water, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated is obtained slightly
Product, Jing silica gel column chromatography purification obtain product.
With 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones and 3- methoxyl group -4- ethyl morpholine benzaldehydes as raw material,
Claisen-Schmidt condensations generate chalcone.Reaction equation is lower shown as follows：
The chalcone synthesized with 28 utilizes Zn/NH4Cl as reducing agent as raw material, with the water-soluble of 2% TPGS-750-M
Liquid is solvent (plus a small amount of DMF hydrotropies), and the nitro of the chalcone is reduced into amino.Reaction equation is as follows：
Take the chalcone (5mM) synthesized in 28 to be dissolved in the dichloromethane of 40ml, add the pyridine of 8mM to add at 0 DEG C
Enter the ethyl chloride of 7.5mM, be warmed to room temperature stirring reaction overnight.To be carried out with silica gel column chromatography after reactant liquor solvent evaporated pure
Change to obtain compound representated by a formula II.Reaction equation is as follows：
Anti tumor activity in vitro
Detect all compounds related in the invention to A549, HepG2, MCF-7 and K562 cell using mtt assay
Inhibited proliferation.Take the logarithm A549, HepG2, MCF-7 and K562 cell of trophophase, adjustment density to 1 × 105mL-1,
96 orifice plates are inoculated in, 100 μ L/ holes are separately added into certain density flavone and chalcones derivant and incubator after culture 12h
After middle process 48h, the 20 μ L of MTT of 5g/L are added to continue incubation 4h per hole, except K562 cells need to be gone with 96 orifice plate centrifuges
Outside supernatant, remaining cell can direct reject supernatant, add the DMSO vibration 5min of 150 μ L, determine OD with microplate reader
490nm values, reflect survivaling cell quantity indirectly with OD 490nm.Suppression ratio of each acute drug to cell can be speculated accordingly.
In the analysis, to totally 32 compounds are determined in I -1, I -2, II -1 and II -2.As a result find overall
For, and the compound phase ratio in I formula, the majority of compounds representated by II formula all have more preferable proliferation inhibition activity, IC50
Between 70 to 500nM, and the IC of the majority of compounds representated by I formula50Value is then between 400 to 900nM.Additionally, II
In compound representated by formula, I -2 is generally good with II -1 apoplexy due to endogenous wind than I -1 with the activity of II -2 class compound, and this is probably
Because I -2 and the macoradical of II -2 class compound, 3 ' position replace the replacement for comparing 4 ' positions to be more beneficial for the raising of its antiproliferative activity.
But the impact on this position of substitution does not have so obvious in I formula compound in the compound representated by II formula.I -1 pair
The proliferation inhibition activity of above-mentioned four kinds of cell lines is as shown in the table：
The proliferation inhibition activity of I -2 pair of above-mentioned four kinds of cell line is as shown in the table：
The proliferation inhibition activity of II -1 pair of above-mentioned four kinds of cell line is as shown in the table：
The proliferation inhibition activity of II -2 pair of above-mentioned four kinds of cell line is as shown in the table：
The sensitization that the compound of the present invention is applied together with cytotoxic agent.32 compounds in the present invention with
Associated with cytotoxic agent, sensitization is investigated.The infinite example of the cytotoxic agent being used together includes:Changchun
Alkali (vinblastin), doxorubicin (doxorubicin), vincristine (vincristine) and paclitaxel
(paclitaxel)。
HepG2/S and HepG2/ADM cells after recovery are transferred in culture dish, (5% in 37 DEG C of incubators, is cultivated
90%), every other day CO2, relative humidity change culture fluid.When cell covers with 80-90% of bottle wall or so, cell is seeded to into 96
In orifice plate, cell density is controlled 8 × 103Cells/ holes or so.HepG2/S and HepG2/ADM cells are trained with this understanding
Support, but in order to ensure the drug resistance of HepG2/ADM cells, in incubation, need to add 1000ng/mL's in culture fluid
Doxorubicin hydrochloride, to maintain the drug resistance of cell, tests first 2 weeks and is discontinued.After being inoculated in the cell continuation culture 24h of 96 orifice plates,
Compound and vinblastine, doxorubicin, vincristine and paclitaxel in the addition present invention.Put 37 DEG C, 5%CO2In incubator
Culture 24h.Add MTT (5mg/mL) 20 μ L, continuation that 4h is incubated in incubator per hole.Supernatant discarded, adds 150 μ L per hole
DMSO, determines light absorption value (OD values) at 490nm.The cytostatic IC of ADM are calculated respectively50, and calculate by following equation
Drug resistance multiple (Resistant fold)：Drug resistance multiple (Resistant fold, RF)=persister IC50/ sensitive strain IC50。
In the analysis, to totally 32 compounds are determined in I -1, I -2, II -1 and II -2.As a result find I -1 with
Compound in I -2 has preferable sensitization to doxorubicin, its reversing drug resistance index between 15 to 50, to other three
The reversing drug resistance index of medicine is then between 10 to 30.Compound in II -1 and II -2 also has preferable sensitization, and which is inverse
Turn Resistance index between 5 to 45.
BTAK inhibitory activity
Whether its anti-tumor activity is played by suppressing BTAK to inquire into the derivant.We have studied which right
The impact of BTAK enzyme activity.Using CycLex Aurora-A kinase Assay/Inhibitor Screening
Kit test kits, are evaluated to the aurora kinase inhibitory activity of above-mentioned two flavone derivative.
In the analysis, to totally 32 compounds are determined in I -1, I -2, II -1 and II -2.As a result find I formula with
32 kinds of compounds representated by II formula have good inhibiting effect, IC to BTAK50Between 20nM to 200nM.Its
In compound in I -2 than I -1 in compound can preferably suppress the activity of BTAK.And the change in II -1 and II -2
Though compound activity also have certain difference, its difference be far from I -1 with I -2 it is obvious.Speculate in the compound representated by I formula
In, the rigidity of flavone parent nucleus is larger, have impact on the combination of the substituent group and BTAK of 3 ', 4 ' positions.And looking in II formula
You weaken as larger therefore on its 3 ', 4 ' position the substituent group of flexibility is relative with the impact of the combination of BTAK ketone.
Whole features disclosed in this specification can be in any combination.For identical, suitable, or similar purpose, this theory
Each feature disclosed in bright book can be replaced by another kind of feature.Therefore, unless otherwise specified, otherwise disclosed each
Feature is only the example of general suitable or similar characteristics.
From description above, those skilled in the art can readily determine that the essential feature of the present invention, and not carry on the back
In the case of the spirit and scope of the present invention, the present invention can be variously modified and be modified, with suitable for various uses
With situation.Therefore other specific embodiments are also within the scope of claim.
Conclusion：The present invention is derivative with a class chalcone and flavonoid of II (II -1 and II -2) with regard to formula I (I -1 and I -2)
The design of thing, synthesis and its inhibitory action to BTAK.The compound can adjust the letter of aurora kinase and its correlation
The function of the target spot of number path, and then affect cell cycle and proliferation process, to treating cancer and related to cancer
Disease.
Claims (8)
1. as the chalcone and flavone derivative of aurora kinase inhibitors, it is characterised in that：The derivant is molecular formula I-
1st, I-2 and the compound shown in molecule formula II -1, II -2：
In above-claimed cpd：R1 is to form ehter bond with 3 ' or 4 ' positions in flavone female ring；R2 is can be with 6 ammonia on flavone parent nucleus
Base forms the substituent group of amide or sulfonamide.
2. the chalcone and flavone derivative as aurora kinase inhibitors according to claim 1, it is characterised in that：
Compound described in molecular formula I-1 is the one kind in following compound：
Compound described in molecular formula I-2 is the one kind in following compound：
3. the chalcone and flavone derivative as aurora kinase inhibitors according to claim 1, it is characterised in that：
Compound described in the molecule formula II -1 is the one kind in following compound：
Compound described in the molecule formula II -2 is the one kind in following compound：
4. the chalcone and flavone derivative as aurora kinase inhibitors according to any one of claims 1 to 3, its
It is characterised by：Also include the compound pharmaceutically acceptable salt, hydrate or solvate.
5. a kind of compound as described in any one of Claims 1 to 4 prepare suppress BTAK activity medicine in should
With, it is characterised in that：The medicine for suppressing BTAK activity is a kind of function inhibitio cancer by mediating BTAK
The medicine of cell growth.
6. application of the compound according to claim 5 in the medicine for suppressing BTAK activity is prepared, its feature exist
In：The cancerous cell species include to Non-small cell lung carcinoma A549 cells, human hepatoma HepG2 cell, human breast carcinoma MCF-7 and
K562 cell.
7. application of the compound according to claim 5 in the medicine for suppressing BTAK activity is prepared, its feature exist
In：The compound is further used in combination with one or more cytotoxic agent；The cytotoxic agent is vinblastine, how soft
Than one or more in star, vincristine and paclitaxel.
8. a kind of preparation side of chalcone and flavone derivative as aurora kinase inhibitors as claimed in claim 1
Method, it is characterised in that：
The method for preparing the compound expressed by I-1, I-2 molecular formula is comprised the following steps：
(1) to added with drying tube CaCl2100ml single-necked flasks in add 4g paeonol and 30ml glacial acetic acid, the frozen water with 0 DEG C
Deca concentrated nitric acid 15ml while stirring in bath；
(2) continue reaction 24h in 20 DEG C；
(3) reactant mixture is added in the frozen water of 1000ml, stirring separates out yellowish flocculent deposit, will filter after decompression sucking filtration
Cookiess are dry to obtain crude product；
(4) poured into after the acetone solution by the crude product with 50ml again in the frozen water of 1000ml and stirred, separate out white flock precipitate,
White solid after decompression sucking filtration is 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones；Reaction equation is：
(5) take 10mM vanillin with 20ml being dried DMF dissolving after, add 50mM K2CO3, stirring reaction 30min at 50 DEG C
Afterwards, 4- (2- chloroethyls) morpholines of Deca 10.5mM pour reactant liquor into 200ml water in 80 DEG C of reaction overnights after reaction terminates
In, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated obtains crude product, Jing silicon
It is gel column chromatography eluting to obtain product；
(6) with 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones and 3- methoxyl group -4- ethyl morpholine benzaldehydes as raw material, with 4:1
EtOH/H2O is solvent, and Jing Claisen-Schmidt condensations reaction in the basic conditions generates chalcone；Reaction equation is：
(7) in DMSO/I2/H2SO4In system, with (6), the chalcone of synthesis obtains corresponding flavonoid as raw material oxidation closed loop
Compound；Reaction equation is：
(8) using sodium hydrosulfite as reducing agent, the nitro flavone in (7) is reduced to into amino flavone in ethanolic aqueous system；Reaction
Decompression after end steams ethanol, adds excessive hydrochloric acid heating excessive sodium hydrosulfite is reacted completely；Reaction equation is：
(9) the amino flavone 10mM synthesized in taking previous step is dissolved in the DMF of 30ml dryings, adds the K2CO3 of 50mM, after
The ethyl chloride of 15mM is added at 0 DEG C, stirring reaction is warmed to room temperature overnight；Question response pours reactant liquor into 400ml after terminating
In water, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated obtains crude product, Jing
Silica gel column chromatography purification obtains product and obtains the compound representated by formula I；Reaction equation is as follows：
The method for preparing the compound expressed by II-1, II-2 molecular formula is comprised the following steps：
(1) addition 4g paeonol and 30ml glacial acetic acid, the frozen water with 0 DEG C in the 100ml single-necked flasks added with drying tube CaCl2
Side stirring in bath becomes slowly Deca concentrated nitric acid 15ml：
(2) continue reaction 24h in 20 DEG C；
(3) reactant mixture is added in the frozen water of 1000ml, stirring separates out yellowish flocculent deposit, will filter after decompression sucking filtration
Cookiess are dry to obtain crude product；
(4) poured into after the acetone solution by the crude product with 50ml again in the frozen water of 1000ml and stirred, separate out white flock precipitate,
White solid after decompression sucking filtration is 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones；Reaction equation is：
(5) take 10mM vanillin with 20ml being dried DMF dissolving after, add 50mM K2CO3, stirring reaction 30min at 50 DEG C
Afterwards, 4- (2- chloroethyls) morpholines of Deca 10.5mM pour reactant liquor into 200ml water in 80 DEG C of reaction overnights after reaction terminates
In, respectively with ethyl acetate extraction, saturated common salt water washing and anhydrous sodium sulfate drying after, solvent evaporated obtains crude product, Jing silicon
It is gel column chromatography eluting to obtain product；
(6) with 2- hydroxyl -4- methoxyl group -5- nitro-acetophenones and 3- methoxyl group -4- ethyl morpholine benzaldehydes as raw material,
Claisen-Schmidt condensations generate chalcone；Reaction equation is：
(7) with (6), the chalcone of synthesis utilizes Zn/NH4Cl as reducing agent as raw material, with the water-soluble of 2% TPGS-750-M
Liquid is solvent, and the nitro of the chalcone is reduced into amino.Reaction equation is as follows：
(8) the chalcone 5mM for taking synthesis in (7) is dissolved in the dichloromethane of 40ml, adds the pyridine of 8mM to add at 0 DEG C
The ethyl chloride of 7.5mM, is warmed to room temperature stirring reaction overnight；Purification will be carried out with silica gel column chromatography after reactant liquor solvent evaporated
Obtain the compound representated by formula II；Reaction equation is as follows：
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| CN112300002A (en) * | 2020-10-26 | 2021-02-02 | 安徽工业大学 | Preparation method of 5-nitro paeonol and 5-nitro paeonol hydrazone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755541A (en) * | 2014-02-19 | 2014-04-30 | 厦门大学 | Chalcone derivative as well as preparation method and application thereof |
| CN105153089A (en) * | 2015-07-23 | 2015-12-16 | 广西师范学院 | Derivative with 5,2'-dihydroxy-4'-methoxy-3-geranyl flavone skeleton and preparation method therefor and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755541A (en) * | 2014-02-19 | 2014-04-30 | 厦门大学 | Chalcone derivative as well as preparation method and application thereof |
| CN105153089A (en) * | 2015-07-23 | 2015-12-16 | 广西师范学院 | Derivative with 5,2'-dihydroxy-4'-methoxy-3-geranyl flavone skeleton and preparation method therefor and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| KASAHARA, AKIRA: ""Studies of flavanones. XXIX. Syntheses and resolution of 6-amino-7-methoxyflavanones"", 《NIPPON KAGAKU ZASSHI》 * |
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| CN112300002A (en) * | 2020-10-26 | 2021-02-02 | 安徽工业大学 | Preparation method of 5-nitro paeonol and 5-nitro paeonol hydrazone |
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