CN106543155B - Chalcone and flavonoid derivative as aurora kinase inhibitor - Google Patents

Chalcone and flavonoid derivative as aurora kinase inhibitor Download PDF

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CN106543155B
CN106543155B CN201610850932.4A CN201610850932A CN106543155B CN 106543155 B CN106543155 B CN 106543155B CN 201610850932 A CN201610850932 A CN 201610850932A CN 106543155 B CN106543155 B CN 106543155B
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aurora kinase
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cancer
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赵庆春
范艳华
许永男
周志鹏
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General Hospital of the Northern War Zone of the Chinese People's Liberation Army
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    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D295/00—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
    • 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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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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Abstract

The invention relates to design and synthesis of chalcone and flavonoid derivatives shown in formulas I (I-1 and I-2) and II (II-1 and II-2) and an inhibition effect of the chalcone and the flavonoid derivatives on aurora kinase A. The compounds are capable of modulating the function of targets of aurora kinases and their associated signaling pathways, thereby affecting cell cycle and cell proliferation processes for the treatment of cancer and cancer-related diseases.

Description

Chalcone and flavonoid derivative as aurora kinase inhibitor
The technical field is as follows: the invention relates to the field of medicines, in particular to chalcone and flavonoid derivatives serving as aurora kinase inhibitors and application of the derivatives in preparation of medicines.
Background art: cell proliferation is the basis for the growth, development and inheritance of an organism. Mitosis is a phase of the cell division cycle in which cells undergo the processes of centrosome maturation and separation, chromosome condensation, bipolar spindle formation and assembly, chromosome separation and cytokinesis. Studies have shown that aurora kinases play an important regulatory role in this series of events in mitosis. Cancer cells are a variant of cells with unlimited growth, transformation and metastasis that normal cells do not have. Research shows that aurora kinase is specifically over-expressed in various tumor cells, including colon cancer, liver cancer, breast cancer, lung cancer, pancreatic cancer, prostatic cancer, head cancer, neck cancer, cervical cancer, ovarian cancer and the like. Inhibition of one or more aurora kinases simultaneously inhibits cell proliferation and induces apoptosis in a variety of tumor cell lines.
It has now been found that inhibition of aurora kinase can arrest the cell cycle and promote programmed cell death by apoptosis. Therefore, the development of inhibitors of aurora kinase as antitumor drugs has attracted a great deal of attention in the research of new antitumor drugs. Over thirty aurora kinase inhibitors are currently in the preclinical or clinical research phase of medicine. They bind to key amino acids in the region of the aurora kinase active site via specific hydrogen bonds. Other parts of the molecule may be distributed in other regions of the active site or dispersed in the inactive region of aurora kinase a by weak interaction between molecules and interaction with a solvent. The eupatorium and luteolin are two natural flavonoid compounds and are found to have better inhibition activity of aurora kinase B. Previous researches find that a plurality of flavonoids compounds of the pipewort have good inhibitory activity on aurora kinase A and aurora kinase B.
In recent years, with the continuous and deep research on the relationship between the pharmacological action and the structure-activity of flavonoid compounds, the antitumor activity of the flavonoid compounds is found to have obvious correlation with the structure of the flavonoid compounds. The natural flavonoid compound has stronger anticancer and cancer-preventing functions, and generally adopts three ways of (1) the flavonoid compound can change gene expression and regulate the proliferation of tumor cells, thereby inducing the apoptosis of the tumor cells; (2) the flavonoids can also act on tumor cells by inhibiting the activity of key enzyme in the process of cell signal transduction, such as protein kinase, tyrosine protein kinase and the like; (3) against carcinogenic factors. The antitumor activity of natural flavonoid compounds is related to the effect of the natural flavonoid compounds on resisting free radical ions. The anticancer effect of the natural flavonoid compound is influenced by the double bonds at 2 and 3 positions of C ring and the substitution mode and number of phenolic hydroxyl. The metabolites and some structure-activity relationships of the flavonoids in vivo are not clear. And the signal molecular properties of flavonoids are becoming more and more important. The pharmacological action essence of the natural flavonoid compound is continuously researched by utilizing the prior art and means, and the comprehensive utilization value of the natural flavonoid compound is enhanced by changing active groups, regulating metabolism, changing solubility and the like.
Chalcone is a natural compound widely existing in various plants such as liquorice, hops and spine beans, and has wide pharmacological activity. Research shows that chalcone compounds can lead to cell cycle arrest and induce tumor cell apoptosis in the arrest stage so as to inhibit the proliferation of tumor cells. Jong Min Lee et al (Cancer Letters 354(2014)348 and 354) found that some simple chalcone compounds and derivatives thereof can effectively inhibit the activity of aurora kinase, and have higher inhibition activity on aurora kinase A. Therefore, the structural modification of the chalcone compound is carried out, and a new chalcone aurora kinase A inhibitor with better activity is possibly discovered.
The invention content is as follows:
the purpose of the invention is as follows: the invention relates to a flavonoid derivative and application thereof in preparing a drug with an aurora kinase A inhibiting effect. The compounds are capable of modulating the function of targets of aurora kinases and their associated signaling pathways, thereby affecting cell cycle and cell proliferation processes for the treatment of cancer and cancer-related diseases.
The technical scheme is as follows:
chalcone and flavonoid derivatives as aurora kinase inhibitors, characterized in that: the derivatives are compounds shown in molecular formulas I-1 and I-2 and molecular formulas II-1 and II-2:
Figure BDA0001120910050000031
in the above compounds: r1 is an ether bond with the 3 'or 4' position on the flavone mother ring; r2 is substituted by a group which can form amide or sulfonamide with 6-site amino on a flavone mother nucleus.
The chalcone and flavonoid derivative used as the aurora kinase inhibitor is characterized in that: the compound of the formula I-1 is one of the following compounds:
Figure BDA0001120910050000041
the compound of the formula I-2 is one of the following compounds:
Figure BDA0001120910050000042
。
the chalcone and flavonoid derivative used as the aurora kinase inhibitor is characterized in that: the compound shown in the formula II-1 is one of the following compounds:
Figure BDA0001120910050000051
。
the compound shown in the molecular formula II-2 is one of the following compounds:
Figure BDA0001120910050000052
。
the chalcone and flavonoid derivative used as the aurora kinase inhibitor is characterized in that: also included are pharmaceutically acceptable salts, hydrates or solvates of the compounds.
The application of the compound in preparing a medicine for inhibiting the activity of aurora kinase A is characterized in that: the drug inhibiting aurora kinase A activity is a drug inhibiting the growth of cancer cells by mediating the function of aurora kinase A.
The application of the compound in preparing a medicine for inhibiting the activity of aurora kinase A is characterized in that: the cancer cell types comprise human non-small cell lung cancer A549 cells, human liver cancer HepG2 cells, human breast cancer MCF-7 cells and human leukemia K562 cells.
The application of the compound in preparing a medicine for inhibiting the activity of aurora kinase A is characterized in that: the compounds are further used in combination with one or more cytotoxic agents; the cytotoxic agent is one or more of vinblastine, doxorubicin, vincristine and paclitaxel.
The preparation method of the chalcone and the flavonoid derivative used as the aurora kinase inhibitor is characterized by comprising the following steps:
the method for preparing the compounds expressed by the formulas I-1 and I-2 comprises the following steps:
(1) to the addition of a drying tube CaCl24g of paeonol and 30ml of glacial acetic acid are added into a 100ml single-neck flask, and 15ml of concentrated nitric acid is added dropwise while stirring in an ice water bath at the temperature of 0 ℃;
(2) continuously reacting for 24 hours at the temperature of 20 ℃;
(3) adding the reaction mixture into 1000ml of ice water, stirring to separate out light yellow flocculent precipitate, decompressing, filtering, and drying a filter cake to obtain a crude product;
(4) dissolving the crude product with 50ml of acetone, pouring into 1000ml of ice water, stirring, separating out white flocculent precipitate, and performing vacuum filtration to obtain a white solid which is 2-hydroxy-4-methoxy-5-nitroacetophenone; the reaction formula is as follows:
Figure BDA0001120910050000061
(5) dissolving 10mM vanillin in 20ml dry DMF, adding 50mM K2CO3Stirring and reacting at 50 ℃ for 30min, then dropwise adding 10.5mM 4- (2-chloroethyl) morpholine, reacting at 80 ℃ overnight, after the reaction is finished, pouring the reaction solution into 200ml of water, extracting with ethyl acetate, washing with saturated saline solution and drying with anhydrous sodium sulfate, evaporating the solvent to obtain a crude product, and purifying by silica gel column chromatography to obtain a product;
Figure BDA0001120910050000071
(6) 2-hydroxy-4-methoxy-5-nitroacetophenone and 3-methoxy-4-ethylmorpholine benzaldehyde are taken as raw materials, and 4:1 EtOH/H is taken as2O is a solvent, and chalcone is generated by a claisen-Schmidt condensation reaction under an alkaline condition; the reaction formula is as follows:
Figure BDA0001120910050000072
(7) in DMSO/I2/H2SO4In the system, the chalcone synthesized in (6)Ketone is taken as a raw material, and corresponding flavonoid compounds are obtained through oxidation and ring closure; the reaction formula is as follows:
Figure BDA0001120910050000073
(8) reducing the nitroflavone in the step (7) into the amino flavone in an ethanol water system by taking sodium hydrosulfite as a reducing agent; after the reaction is finished, decompressing and steaming out ethanol, adding excessive hydrochloric acid and heating to ensure that excessive sodium hydrosulfite completely reacts; the reaction formula is as follows:
Figure BDA0001120910050000074
(9) dissolving the amino flavone 10mM synthesized in the previous step in 30ml of dry DMF, adding 50mM K2CO3, adding 15mM ethylsulfonyl chloride at 0 ℃, raising the temperature to room temperature, and stirring for reaction overnight; after the reaction is finished, pouring the reaction liquid into 400ml of water, extracting by ethyl acetate, washing by saturated saline solution and drying by anhydrous sodium sulfate, evaporating the solvent to obtain a crude product, and purifying by silica gel column chromatography to obtain a product, namely the compound represented by the formula I; the reaction formula is as follows:
Figure BDA0001120910050000081
the method for preparing the compounds expressed by the molecular formulas II-1 and II-2 comprises the following steps:
(1) 4g of paeonol and 30ml of glacial acetic acid are added into a 100ml single-neck flask which is provided with a drying tube CaCl2, and 15ml of concentrated nitric acid is slowly added into the flask while stirring in an ice-water bath at the temperature of 0 ℃:
(2) continuously reacting for 24 hours at the temperature of 20 ℃;
(3) adding the reaction mixture into 1000ml of ice water, stirring to separate out light yellow flocculent precipitate, decompressing, filtering, and drying a filter cake to obtain a crude product;
(4) dissolving the crude product with 50ml of acetone, pouring into 1000ml of ice water, stirring, separating out white flocculent precipitate, and performing vacuum filtration to obtain a white solid which is 2-hydroxy-4-methoxy-5-nitroacetophenone; the reaction formula is as follows:
Figure BDA0001120910050000082
(5) dissolving 10mM vanillin in 20ml dry DMF, adding 50mM K2CO3, stirring and reacting at 50 ℃ for 30min, then dropwise adding 10.5mM 4- (2-chloroethyl) morpholine, reacting at 80 ℃ overnight, after the reaction is finished, pouring the reaction solution into 200ml of water, extracting with ethyl acetate, washing with saturated saline solution and drying with anhydrous sodium sulfate, evaporating the solvent to dryness to obtain a crude product, and purifying by silica gel column chromatography to obtain a product;
Figure BDA0001120910050000083
(6) 2-hydroxy-4-methoxy-5-nitroacetophenone and 3-methoxy-4-ethylmorpholine benzaldehyde are used as raw materials, and are subjected to Claisen-Schmidt condensation to generate chalcone; the reaction formula is as follows:
Figure BDA0001120910050000091
(7) and (3) taking the chalcone synthesized in the step (6) as a raw material, reducing the nitro group of the chalcone into an amino group by taking Zn/NH4Cl as a reducing agent and taking a 2% TPGS-750-M aqueous solution as a solvent. The reaction formula is as follows:
Figure BDA0001120910050000092
(8) dissolving 5mM of chalcone synthesized in the step (7) in 40ml of dichloromethane, adding 8mM of pyridine, adding 7.5mM of ethylsulfonyl chloride at 0 ℃, raising the temperature to room temperature, and stirring for reacting overnight; evaporating the solvent of the reaction solution to dryness, and purifying by silica gel column chromatography to obtain a compound represented by a formula II; the reaction formula is as follows:
Figure BDA0001120910050000093
。
the advantages and effects are as follows: the compounds of the invention are capable of modulating the function of targets of aurora kinases and their associated signaling pathways, thereby affecting the cell cycle and cell proliferation processes for the treatment of cancer and cancer-related diseases.
The specific implementation mode is as follows:
the invention relates to design and synthesis of flavonoid derivatives shown in formula I (I-1 and I-2) and inhibition effect of the flavonoid derivatives on aurora kinase A. The compounds are capable of modulating the function of targets of aurora kinases and their associated signaling pathways, thereby affecting cell cycle and cell proliferation processes for the treatment of cancer and cancer-related diseases.
The invention relates to flavonoid derivatives (I-1 and I-2) shown in formula I.
Figure BDA0001120910050000101
R1 is an ether bond with 3 'or 4' on the flavone mother ring. R2 is substituted by a group which can form amide or sulfonamide with 6 on the flavone parent nucleus.
The following are compounds described in I-1 of the present invention:
Figure BDA0001120910050000102
the following are compounds described in I-2 of the present invention:
Figure BDA0001120910050000111
a synthetic route to compounds described by formula i:
using paeonol and vanillin as starting materials, and HNO as the paeonol3/CH3The nitro group was introduced by nitration of the 5-position with COOH (V: V ═ 1:3) at room temperature. And vanillin is at K2CO3As an acid-binding agent to form ether with the R1 group. Both in KOH/EtOH-H2Synthesis of chalcones by aldol condensation under O (4:1) conditions, followed by DMSO/I2Cyclizing and synthesizing the flavone compound under the condition of H2SO 4. Introducing nitro into 6-position of the flavonoid compound, reducing the flavonoid compound with sodium hydrosulfite, and then substituting with amides. Synthetic routeAs follows:
Figure BDA0001120910050000112
the invention relates to design and synthesis of chalcone derivatives of formula II (II-1 and II-2) and inhibition effect thereof on aurora kinase A. The compounds are capable of modulating the function of targets of aurora kinases and their associated signaling pathways, thereby affecting cell cycle and cell proliferation processes for the treatment of cancer and cancer-related diseases.
R1 is an ether bond with 3 'or 4' on the flavone mother ring. R2 is substituted by a group which can form amide or sulfonamide with 6 on the flavone parent nucleus.
The following are compounds described in the invention II-1:
Figure BDA0001120910050000121
the following are compounds described in the invention II-2:
Figure BDA0001120910050000122
a synthetic route to compounds described by formula ii:
Figure BDA0001120910050000131
all the compounds of the invention can well inhibit the activity of aurora kinase A within the effective dose range, and are characterized in that the compounds have obvious growth inhibition effect on human non-small cell lung cancer A549 cells, human liver cancer HepG2 cells, human breast cancer MCF-7 cells and human leukemia K562 cells by mediating the function of aurora kinase A.
The compound of the invention can be applied together with a cytotoxic agent in the process of pharmacy, and can obviously enhance the tumor cell proliferation inhibition effect of the cytotoxic agent. Non-limiting examples of cytotoxic agents suitable for use with the aurora kinase inhibitors of the present invention include vinblastine (vinblastin), doxorubicin (doxorubicin), vincristine (vincristine) and paclitaxel (paclitaxel).
Process for the synthesis of compounds of formula I
To the drying tube (CaCl)2) 4g of paeonol and 30ml of glacial acetic acid are added into a 100ml single-neck flask, and 15ml of concentrated nitric acid is slowly added into the flask with stirring in an ice water bath at the temperature of 0 ℃. After the addition, the reaction was continued at 20 ℃ for 24 hours. After the reaction is finished, adding the reaction mixture into 1000ml of ice water, stirring to separate out light yellow flocculent precipitate, decompressing and filtering, and drying a filter cake to obtain a crude product. Dissolving the crude product with 50ml acetone, pouring into 1000ml ice water, stirring, precipitating white flocculent precipitate, and vacuum filtering to obtain white solid 2-hydroxy-4-methoxy-5-nitroacetophenone.
Figure BDA0001120910050000141
Dissolving 10mM vanillin in 20ml dry DMF, adding 50mM K2CO3After the reaction is finished, pouring the reaction liquid into 200ml of water, extracting by ethyl acetate, washing by saturated saline solution and drying by anhydrous sodium sulfate respectively, evaporating the solvent to obtain a crude product, and purifying by silica gel column chromatography to obtain the product.
Figure BDA0001120910050000142
2-hydroxy-4-methoxy-5-nitroacetophenone and 3-methoxy-4-ethylmorpholine benzaldehyde are taken as raw materials, and 4:1 EtOH/H is taken as2O is used as a solvent, and chalcone is generated by Claisen-Schmidt condensation under alkaline conditions. The reaction formula is shown below:
Figure BDA0001120910050000143
in DMSO/I2/H2SO4In the system, with 21 as raw material to obtain corresponding flavonoid compound through oxidation ring closure. The reaction formula is shown as follows:
Figure BDA0001120910050000144
excess sodium hydrosulfite is used as a reducing agent, and nitroflavone in 22 is reduced into aminoflavone in an ethanol water system. After the reaction is finished, the ethanol is evaporated under reduced pressure, and the excessive sodium hydrosulfite is added and heated to completely react. The reaction formula is as follows:
Figure BDA0001120910050000151
the aminoflavone synthesized in 23 (10mM) was dissolved in 30ml of dry DMF, and 50mM K2CO3 was added, followed by addition of 15mM ethylsulfonyl chloride at 0 ℃ and stirring overnight at room temperature. And after the reaction is finished, pouring the reaction solution into 400ml of water, extracting by using ethyl acetate, washing by using saturated saline solution and drying by using anhydrous sodium sulfate respectively, evaporating the solvent to obtain a crude product, and purifying by using silica gel column chromatography to obtain the compound represented by the formula I. The reaction formula is as follows:
Figure BDA0001120910050000152
process for synthesizing compounds of formula II
4g of paeonol and 30ml of glacial acetic acid were added to a 100ml single-neck flask equipped with a drying tube (CaCl2), and 15ml of concentrated nitric acid was added slowly while stirring in an ice-water bath at 0 ℃. After the addition, the reaction was continued at 20 ℃ for 24 hours. After the reaction is finished, adding the reaction mixture into 1000ml of ice water, stirring to separate out light yellow flocculent precipitate, decompressing and filtering, and drying a filter cake to obtain a crude product. Dissolving the crude product with 50ml acetone, pouring into 1000ml ice water, stirring, precipitating white flocculent precipitate, and vacuum filtering to obtain white solid 2-hydroxy-4-methoxy-5-nitroacetophenone.
Figure BDA0001120910050000153
Dissolving 10mM vanillin in 20ml dry DMF, adding 50mM K2CO3, stirring and reacting at 50 ℃ for 30min, slowly and dropwise adding 10.5mM 4- (2-chloroethyl) morpholine at 80 ℃ for overnight reaction, pouring the reaction solution into 200ml of water after the reaction is finished, extracting with ethyl acetate, washing with saturated saline solution and drying with anhydrous sodium sulfate respectively, evaporating the solvent to obtain a crude product, and purifying by silica gel column chromatography to obtain the product.
Figure BDA0001120910050000161
2-hydroxy-4-methoxy-5-nitroacetophenone and 3-methoxy-4-ethylmorpholine benzaldehyde are used as raw materials, and are subjected to Claisen-Schmidt condensation to generate chalcone. The reaction formula is shown below:
Figure BDA0001120910050000162
the nitro group of the chalcone synthesized in the step 28 is reduced into an amino group by taking the chalcone as a raw material, Zn/NH4Cl as a reducing agent and a 2% TPGS-750-M aqueous solution as a solvent (a small amount of DMF is added for dissolving assistance). The reaction formula is as follows:
Figure BDA0001120910050000163
chalcone (5mM) synthesized in 28 was dissolved in 40ml dichloromethane, 8mM pyridine was added thereto, 7.5mM ethylsulfonyl chloride was added at 0 deg.C, and the reaction was stirred at room temperature overnight. Evaporating the solvent of the reaction solution to dryness, and purifying by silica gel column chromatography to obtain a compound represented by a formula II. The reaction formula is as follows:
Figure BDA0001120910050000164
in vitro antitumor Activity
MTT method is used for detecting all related compound pairs A549, HepG2 and MC in the inventionProliferation inhibition of F-7 and K562 cells A549, HepG2, MCF-7 and K562 cells in logarithmic growth phase were taken and density was adjusted to 1 × 105mL-1Inoculating the cells into a 96-well plate, culturing for 12h, adding flavone and chalcone derivatives with certain concentration into the 96-well plate, treating the cells in an incubator for 48h, adding 20 mu L of MTT (methyl thiazolyl tetrazolium) with the concentration of 5g/L into each well, continuously incubating for 4h, directly discarding the supernatant of the K562 cells except that the K562 cells need to be centrifuged by a 96-well plate centrifuge, adding 150 mu L of DMSO, oscillating for 5min, measuring the OD490nm value by an enzyme-labeling instrument, and indirectly reflecting the number of the surviving cells by OD490 nm. Based on this, the inhibition rate of each concentration of the drug on the cells can be estimated.
In this analysis, a total of 32 compounds I-1, I-2, II-1 and II-2 were determined. As a result, it was found that, in general, most of the compounds represented by the formula II have better proliferation inhibitory activity, IC, than the compounds represented by the formula I50Between 70 and 500nM, and the IC of most compounds represented by formula I50Values were between 400 and 900 nM. Furthermore, of the compounds represented by the formula II, the compounds of the classes I-2 and II-2 generally have better activity than the compounds of the classes I-1 and II-1, probably because the substitution of the bulky group at the 3 '-position of the compounds of the classes I-2 and II-2 favours the increase in their antiproliferative activity over the substitution at the 4' -position. However, the effect of this substitution position is less pronounced in the compounds represented by formula II than in the compounds of formula I. The proliferation inhibitory activities of I-1 on the above four cell lines are shown in the following table:
Figure BDA0001120910050000171
the proliferation inhibitory activities of I-2 on the above four cell lines are shown in the following table:
Figure BDA0001120910050000181
the proliferation inhibitory activities of II-1 on the above four cell lines are shown in the following table:
Figure BDA0001120910050000182
the proliferation inhibitory activities of II-2 on the above four cell lines are shown in the following table:
Figure BDA0001120910050000183
sensitization of a compound of the invention when administered with a cytotoxic agent. The sensitization of 32 compounds of the present invention in combination with cytotoxic agents was examined. Non-limiting examples of cytotoxic agents used together include vinblastine (vinblastin), doxorubicin (doxorubicin), vincristine (vincristine), and paclitaxel (paclitaxel).
Transferring the recovered HepG2/S and HepG2/ADM cells to a culture dish, culturing in an incubator at 37 ℃ (5% CO2 and relative humidity of 90%), replacing culture solution every other day, inoculating the cells to a 96-well plate when the cells grow to be about 80-90% of the bottle wall, and controlling the cell density to be 8 × 103cells/well. HepG2/S and HepG2/ADM cells were cultured under these conditions, but to ensure the resistance of HepG2/ADM cells, 1000ng/mL doxorubicin hydrochloride was added to the culture medium during the culture to maintain the resistance of the cells, and the cells were stopped 2 weeks before the test. After the cells inoculated in the 96-well plate were cultured for 24 hours, the compound of the present invention was added together with vinblastine, doxorubicin, vincristine and paclitaxel. Placing at 37 ℃ and 5% CO2Culturing in an incubator for 24 h. mu.L of MTT (5mg/mL) was added to each well and incubation in the incubator was continued for 4 h. The supernatant was discarded and 150. mu.L of LDMSO was added to each well and the absorbance (OD) was measured at 490 nm. Separate calculation of IC for ADM inhibition of cell growth50And calculating the drug resistance fold (resist fold) according to the following formula: multiple Resistance (RF) strain IC50Sensitive strain IC50。
In this analysis, a total of 32 compounds I-1, I-2, II-1 and II-2 were determined. The results show that the compounds in I-1 and I-2 have better sensitization effect on doxorubicin, and the reversal drug resistance index of the compounds is between 15 and 50, and the reversal drug resistance index of the compounds for other three drugs is between 10 and 30. The compounds in II-1 and II-2 also have better sensitization, and the reversal drug resistance index is between 5 and 45.
Aurora kinase A inhibitory Activity
To investigate whether the derivative exerts its antitumor activity by inhibiting aurora kinase a. We investigated its effect on aurora A enzyme activity. Aurora kinase inhibitory activity of the two flavonoid derivatives is evaluated by using a CycLex Aurora-A kinase Assay/Inhibitor screening kit.
In this analysis, a total of 32 compounds I-1, I-2, II-1 and II-2 were determined. As a result, the 32 compounds represented by the formulas I and II have good inhibition effect on aurora kinase A, IC50Between 20nM and 200 nM. Wherein the compound of I-2 inhibits the activity of aurora A better than the compound of I-1. While the activity of the compounds in II-1 and II-2 is different to a certain extent, the difference is far less obvious than that of I-1 and I-2. It is presumed that in the compounds represented by the formula I, the rigidity of the flavone nucleus is large, and the binding mode of the substituents at the 3 'and 4' positions to aurora kinase A is affected. The chalcone in the formula II has relatively weak influence on the combination mode of substituents at 3 'and 4' positions and aurora kinase A due to larger flexibility.
All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by another feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, other embodiments are within the scope of the following claims.
And (4) conclusion: the invention relates to design and synthesis of chalcone and flavonoid derivatives shown in formulas I (I-1 and I-2) and II (II-1 and II-2) and an inhibition effect of the chalcone and the flavonoid derivatives on aurora kinase A. The compounds are capable of modulating the function of targets of aurora kinases and their associated signaling pathways, thereby affecting cell cycle and cell proliferation processes for the treatment of cancer and cancer-related diseases.

Claims (5)

1. Chalcone and flavonoid derivatives as aurora kinase inhibitors, characterized in that: the derivatives are compounds shown in molecular formulas I-1 and I-2 and molecular formulas II-1 and II-2:
Figure FDA0002461275260000011
in the above compounds: r1 is
Figure FDA0002461275260000012
Forming ether bond with 3 'or 4' position of flavone mother ring; r2 is
Figure FDA0002461275260000013
Can form amide or sulfamide group substitution with 6-site amino on flavone mother nucleus;
the compound of the formula I-1 is one of the following compounds:
Figure FDA0002461275260000021
；
the compound of the formula I-2 is one of the following compounds:
Figure FDA0002461275260000031
；
the compound shown in the formula II-1 is one of the following compounds:
Figure FDA0002461275260000032
；
the compound shown in the molecular formula II-2 is one of the following compounds:
Figure FDA0002461275260000041
。
2. chalcones and flavonoid derivatives as aurora kinase inhibitors according to claim 1, characterized in that: also included are pharmaceutically acceptable salts of the compounds.
3. Use of a compound according to claim 1 for the preparation of a medicament for inhibiting aurora kinase a activity, wherein: the drug inhibiting aurora kinase A activity is a drug inhibiting the growth of cancer cells by mediating the function of aurora kinase A.
4. Use of a compound according to claim 3 for the manufacture of a medicament for inhibiting aurora kinase a activity, wherein: the cancer cell types comprise human non-small cell lung cancer A549 cells, human liver cancer HepG2 cells, human breast cancer MCF-7 cells and human leukemia K562 cells.
5. Use of a compound according to claim 3 for the manufacture of a medicament for inhibiting aurora kinase a activity, wherein: the compounds are further used in combination with one or more cytotoxic agents; the cytotoxic agent is one or more of vinblastine, doxorubicin, vincristine and paclitaxel.
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Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Title
"Studies of flavanones. XXIX. Syntheses and resolution of 6-amino-7-methoxyflavanones";Kasahara, Akira;《Nippon Kagaku Zasshi》;19581231;第79卷;第343-345页 *

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