CN112300106B - Protein kinase inhibitor, preparation method and application - Google Patents
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry. The invention discloses a novel protein kinase inhibitor, which has a structural formula shown as a formula I:
wherein R is 1 Represents hydroxyl, carboxyl, amido, hydrogen; r 2 Represents nitro, amino, amido, hydroxyl, sulfydryl, halogen and trifluoromethyl; r 3 Represents alkoxy, hydroxy; ring A represents benzopyrone, 1H-benzo [ d]Imidazole, substituted hydroxy 1H-benzo [ d]Imidazole, benzoxazole, 1H-pyrrolo [2,3-b ]]Pyridine, benzopyrrole, 2, 3-dihydrobenzo [ b ]][1,4]Dioxins, 1H-indazoles; x represents an ester group or an amide group; and the ring B represents a benzene ring, a nitrogen-containing five-membered heterocyclic ring or a nitrogen-containing six-membered heterocyclic ring. The invention obtains a novel protein kinase inhibitor by utilizing a splicing principle, and plays a role in resisting tumors by inhibiting the proliferation of tumor cells and promoting the apoptosis of the tumor cells.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to preparation of a novel protein kinase inhibitor and application of the novel protein kinase inhibitor in the field of antitumor medicines.
Background
Renal Cell Carcinoma (RCC) is refractory to traditional therapies, including radiation and cytokine therapies. The use of molecularly targeted therapies against mTOR, VEGF, and other angiogenic factors has significantly improved the extent of treatment of the disease. However, many current therapies are limited by acquired resistance. In addition, serine-threonine protein kinase is important for activation of various survival signaling pathways, and its catalytic activity is constantly enhanced in various types of tumors including kidney cancer, wherein the use of CK2 inhibitors of serine-threonine protein kinase in RCC has not been developed.
Ellagic acid (Ellagic acid) as CK2 inhibitor with dicumarin structure has strong CK2 inhibition activity and IC 50 =0.04 μ M, and the crystal structure analysis shows that the coumarin structure of ellagic acid occupies the cavity, the 3-hydroxyl group forms a hydrogen bond with K68 in the positive region through the coumarin structure, which is the key of CK2 kinase inhibitory activity, and ellagic acid has certain renal cancer cell inhibitory activity but weak effect (IC) 50 ＝38.6±2.3μM，ACHN)。
The Baylis-Hillman reaction has the characteristics of high selectivity (chemical, regional, diastereomeric and enantiomeric), good atom economy, mild reaction conditions and the like, and the product (Baylis-Hillman adduct) has the characteristic of multiple functional groups, is a good organic synthesis intermediate, is usually used for synthesizing various heterocyclic or carbocyclic skeletons with antitumor activity, and is considered as a way for finding cheap new drugs. Researches show that the Baylis-Hillman adduct also has anti-tumor biological activity, for example, methyl 2- ((4-cyanophenyl) (hydroxy) methyl) acrylate has good proliferation inhibition effect on various tumor cell lines (MCF 7, NCI460, PC-03 and the like), wherein the Baylis-Hillman adduct also has strong inhibition effect on renal cancer cells 786-O, and IC 50 At 2.5. Mu.M, suggesting its potential in the treatment of renal cancer. The analysis of structure-activity relationship shows that the terminal alkene structure and the aromatic benzene ring are necessary functional groups for maintaining antitumor activity, and the hydroxyl position has larger modification space.
Therefore, how to provide a protein kinase inhibitor which can effectively inhibit the activity of RCC is a problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides a novel protein kinase inhibitor based on the crystal structure of the serine-threonine protein kinase CK2 and by utilizing the splicing principle, which plays a role in resisting tumors by inhibiting the proliferation of tumor cells and promoting the apoptosis of the tumor cells.
In order to achieve the purpose, the invention adopts the following technical scheme:
a novel protein kinase inhibitor having the structural formula shown in formula I:
wherein: r 1 Represents hydroxyl, carboxyl, amido, hydrogen;
R 2 represents nitro, amino, amido, hydroxyl, sulfydryl, halogen and trifluoromethyl;
R 3 represents alkoxy, hydroxy;
ring A represents benzopyrone, 1H-benzo [ d ] imidazole, substituted hydroxy 1H-benzo [ d ] imidazole, benzoxazole, 1H-pyrrolo [2,3-b ] pyridine, benzopyrrole, 2, 3-dihydrobenzo [ b ] [1,4] dioxin, 1H-indazole; x represents an ester group, an amide group;
and the ring B represents a benzene ring, a nitrogen-containing five-membered heterocyclic ring and a nitrogen-containing six-membered heterocyclic ring.
The invention also aims to provide a preparation method of the novel protein kinase inhibitor, which comprises the following specific preparation steps: acylating the intermediate by oxalyl chloride or thionyl chloride or reacting the intermediate with a compound shown in a formula XI in an organic solvent by a condensing agent to obtain a target product, namely the compound shown in the formula I;
wherein the compound of formula XI has the following structural formula:
wherein R is 1 Represents hydrogen, halogen, nitro, methoxy, trifluoromethyl, methoxy, methyl; r is 2 Represents a hydrocarbon group; x represents a carbon atom or a nitrogen atom.
Preferably, the intermediate comprises compounds represented by I-X, and each compound has the following structural formula:
wherein R is hydrogen or hydroxy; the above intermediates are commercially available from literature or commercial companies.
Preferably, the condensing agent selected is one selected from the group consisting of Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI).
Preferably, the selected organic solvent is selected from one of dichloromethane, tetrahydrofuran, dioxane or DMF.
Preferably, the reaction conditions are under the protection of nitrogen.
Furthermore, the protein kinase inhibitor prepared by the invention can be applied to preparing a silk-threonine kinase CK2 inhibitor.
Further, the protein kinase inhibitor prepared by the invention can be applied to preparing drugs for inhibiting the activity of tumor cells, including but not limited to: renal cancer cells ACHN, breast cancer cells MCF7, colorectal cancer cell line HCT116 and liver cancer cell line HepG2.
According to the technical scheme, compared with the prior art, the invention has the following beneficial effects:
1. 10 μ M Compound III 2 ，III 3 And III 6 The inhibition effect on the ACHN of renal cancer cells is stronger than that of the compound III 1 And Ellagic acid (Ellagic acid) with a bishydroxycoumarin structure, which indicates that the activity of the compound can be enhanced by an electron-withdrawing substituent on an aromatic ring structure on an alkenoic acid ester side chain, and whether 7-position in the coumarin structure has a hydroxyl group or not, compared with Ellagic acid which is a positive control compound, the 10 mu M target compound has strong inhibitory effect on breast cancer cell MCF7, and the series of compounds also have certain inhibitory activity on proliferation of Hep G2 and HCT116 cells.
2. CK2 Kinase activity was detected using a Kinase-Glo Plus luminescence Kinase assay kit, and its inhibitory activity against CK2 Kinase (65% @ 1. Mu.M, 89% @ 10. Mu.M) and ellagic acid (79% @ 1. Mu.M, 98% @ 10. Mu.M) were comparable.
3. Compound III 6 The treatment group was able to induce ACHN apoptosis and was able to induce apoptosis dose-dependently. With 0.1, 1 and 10. Mu.M of the target compound III6After conditioning ACHN cells, the apoptosis rates were 21.29. + -. 0.9%, 46.58. + -. 0.4% and 65.67. + -. 0.4%, respectively.
4. Molecular docking display, compound III 6 The 7-hydroxycoumarin structure of (a) is a main reason for maintaining kinase inhibitory activity by interacting hydroxyl with a key amino acid residue K68 in a positive region of a CK2 protein and forming hydrogen bond interaction with V116 and N118 in a hinge region through a nitro group.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a drawing of Compound III 6 Apoptotic effects on renal cancer cells ACHN.
FIG. 2 is the drawing of Compound III 6 Molecular docking pattern with the serine-threonine protein kinase CK 2.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Based on the crystal combination mode of the serine/threonine protein kinase CK2 and Ellagicacid, the novel protein kinase inhibitor is obtained by utilizing the splicing principle.
Example 1
In view of the wide variety of protein kinase inhibitors prepared by the invention, the applicant only lists one kind of compounds, and other compounds can achieve the following technical effects, wherein the compound of the formula I-1 is one kind of compounds of the formula I, and the structural formula is as follows:
the specific steps for preparing formula I-1 are as follows:
the I is a compound XI, and the II is a compound II.
R 1 Represents hydrogen, halogen, nitro, methoxy, trifluoromethyl, methoxy, methyl;
R 2 represents a hydrocarbon group;
R 3 hydroxyl and hydrogen.
The preparation method comprises the following steps: dissolving II (compound of formula II) (1 equivalent) in thionyl chloride (1.5mL, 20mmol), heating to 80 ℃ for reaction for 4h, concentrating to remove excessive thionyl chloride, carrying with toluene to dry, adding I (XI) (1 equivalent), adding triethylamine (1 equivalent), stirring at room temperature for 48h, pouring the reaction solution into water for quenching, and using 1 mol. L -1 After washing with hydrochloric acid, the mixture was washed with brine, and the organic phase was dried over anhydrous magnesium sulfate and subjected to column chromatography (PE: EA = 4).
Further, the target compound III is prepared by the preparation method 1 -Ⅲ 6 ：
2- (ethoxycarbonyl) -1-phenylallyl 2-oxo-2H-methylene-3-carboxylate (III) 1 ) Pale yellow solid, yield 63%. 1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝0.6Hz,1H),8.06(s,1H),7.68–7.55(m,4H),7.50–7.29(m,5H),5.22(s,1H),4.36–4.27(m,2H),0.98–0.90(m,3H)；IR(KBr,cm -1 ):v3059,3030,2978,2964,2930,2872,2854,2426,2285,1767,1749,1715,1609,1568,1555,HRMS(ESI)calcd for C 22 H 18 O 6 401.0995[M+H] + ,found 401.1019。
2- (ethoxycarbonyl) -1- (2- (trifluoromethyl) phenyl) allyl 2-oxo-2H-benzyl-3-carboxylate (III) 2 ) Yellow solid, yield 55%. 1 H NMR(400MHz,CDCl 3 )δ8.44(s,1H),8.29–7.61(m,5H),7.46(d,J＝4.6Hz,1H),7.38(s,1H),7.36(s,1H),7.30(s,1H),5.07(s,1H),4.53–3.99(m,2H),1.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ165.86,162.42,156.53,155.21,148.62,142.42,139.96,134.49,132.19,130.63,129.73,129.58,129.35,129.08,128.70,128.07,124.91,117.99,117.82,116.83,61.56,60.30,14.24.IR(KBr,cm -1 ):v3067,3043,2982,2934,1767,1717,1647,1609,1568.HRMS(ESI)calcd for C 23 H 17 F 3 O 6 469.0869[M+Na] + ,found469.0894。
1- (2-chlorophenyl) -2- (ethoxycarbonyl) allyl 2-oxo-2H-benzyl-3-carboxylate (III) 3 ) Yellow solid, yield 57%.1HNMR (400MHz, CDCl) 3 )δ8.42(s,1H),8.14(s,1H),7.67–7.17(m,9H),5.12(s,1H),4.34(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ166.27,162.59,156.66,155.43,155.34,149.23,148.73,142.86,137.28,134.57,133.11,130.78,130.76,129.78,129.68,128.49,127.25,126.31,125.00,117.96,116.97,77.48,77.16,76.84,66.08,61.61,60.71,14.41.IR(KBr,cm -1 ):v3061,2959,2926,2854,1767,1749,1715,1609,1568,1558.HRMS(ESI)calcd forC 22 H 17 ClO 6 435.0616[M+Na] + ,found435.0611。
1- (3-bromophenyl) -2- (ethoxycarbonyl) allyl 2-oxo-2H-methylene-3-carboxylate (III) 4 ) Yellow solid, yield 69%. 1 HNMR(400MHz,CDCl 3 )δ8.53(s,1H),7.88–7.56(m,3H),7.48–7.40(m,1H),7.38–7.30(m,1H),7.21(t,J＝7.9Hz,3H),6.83(s,1H),6.50(s,1H),6.31(dd,J＝1.6,0.9Hz,1H),4.17(q,J＝9.8,7.2Hz,2H),1.23(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ164.73,162.10,156.51,155.43,149.71,149.68,140.01,138.77,134.76,131.72,130.95,130.17,129.76,127.14,126.74,125.00,122.54,117.88,116.89,74.12,61.25,14.13.IR(KBr,cm -1 ):v 3061,2980,2962,2930,2907,2872,1767,1749,1722,1609,1568.HRMS(ESI)calcd forC 22 H 17 BrO 6 479.0101[M+Na] + ,found479.0103。
2- (ethoxy)Carbonyl) -1- (4-methoxyphenyl) allyl 2-oxo-2H-methylene-3-carboxylate (III) 5 ) Yellow solid, yield 44%. 1 HNMR(400MHz,CDCl 3 )δ8.50(s,1H),7.67–7.56(m,2H),7.47–7.41(m,2H),7.39–7.29(m,2H),6.88(s,1H),6.86(t,J＝2.7Hz,2H),6.46(s,1H),6.28(s,1H),4.15(q,J＝5.4Hz,2H),3.78(s,3H),1.23(t,J＝7.1Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ165.04,162.15,159.81,156.56,155.37,149.27,139.43,134.55,129.70,129.66,129.52,126.03,124.91,118.31,117.92,116.86,113.94,74.74,61.05,55.34,14.14.IR(KBr,cm -1 ):v3061,3042,2980,2961,2935,2908,2837,1767,1749,1717,1610,1587,1568,1514.HRMS(ESI)calcd for C 23 H 20 O 7 431.1101[M+Na] + ,found431.1130。
2- (ethoxycarbonyl) -1- (4-nitrophenyl) allyl 7-hydroxy-2-oxo-2H-methylene-3-carboxylate (III) 6 ) The synthesis of 7-hydroxycoumarin replaces salicylaldehyde with 2, 4-dihydroxybenzaldehyde, and the synthesis method is the same as the synthesis of coumarin-3-carboxylic acid to obtain yellow solid with the yield of 51%. 1 HNMR(400MHz,CDCl 3 )δ8.20(d,J＝8.9Hz,4H),7.76(s,3H),7.57(m,J＝8.9,0.6Hz,3H),6.39(s,1H),5.83(t,J＝0.9Hz,1H),5.62(s,1H),4.30(m,2H),1.35(m,3H).IR(KBr,cm -1 ):v3379,3071,2955,2955,2924,2847,1759,1713,1612,1566.MS(ESI)calcd forC 22 H 17 NO 9 438.1[M-H] - ,found438.2。
Example 2
The inhibition effect of the compound on kidney cancer cell line ACHN, breast cancer cell line MCF7, colorectal cancer cell line HCT116 and liver cancer cell line HepG2 is determined by adopting a CCK8 method. Add 100. Mu.L (about 5000 cells) of tumor cell suspension in the logarithmic growth phase of cells to each well of a 96-well plate, incubate the plate in an incubator for 24 hours (37 ℃,5% CO) 2 ) Adding 100 mu L of test compound with the concentration of 10 mu mol/L into each hole, incubating for 72 hours or 96 hours in an incubator, discarding liquid in the hole, adding 10 mu L of CCK-8 solution into each hole in a dark place, incubating for 0.5-4 hours in the incubator, measuring absorbance at the wavelength of 450-570nm by using a microplate reader, and calculating the single concentration (10 mu mol/L) inhibition of the test compound to each tumor cellAnd (5) preparing the rate.
TABLE 1 inhibitory Effect of 10. Mu.M Compounds on tumor cell proliferation
As can be seen from Table 1, 10. Mu.M of Compound III 2 ，III 3 ，III 4 And III 6 The inhibition effect on the ACHN of renal cancer cells is stronger than that of the compound III 1 And Ellagic acid (Ellagic acid) with a bishydroxycoumarin structure, which indicates that the activity of the compound can be enhanced by connecting an electron-withdrawing substituent on an aromatic ring structure on an alkenoic acid ester side chain. When 7-position in the coumarin structure is provided with hydroxyl, the inhibition activity on ACHN is obviously enhanced. Compared with the positive control compound ellagic acid, the target compound has enhanced inhibition effect on breast cancer cells MCF7. In addition, the series of compounds also have certain proliferation inhibition activity on Hep G2 and HCT116 cells.
Further, CK2 Kinase activity was detected using a Kinase-Glo Plus luminescence Kinase assay kit. All enzymatic reactions were carried out at 30 ℃ for 40min. A prepared 50. Mu.L kinase buffer contained 40mM Tris, pH 7.4, 10mM MgCl 2 0.1mg/mL BSA,1mM DTT, 10. Mu.M ATP, kinase and enzyme substrate. Compounds were diluted with 10% DMSO, and then 5 μ L of the dilution was added to 50 μ L of the reaction so that the final concentration of DMSO was 1% in all reactions. The Kinase activity was detected by the Kinase-Glo Plus luminescence Kinase assay kit by quantifying the amount of ATP remaining in the solution after the Kinase reaction. The luminescence value determined correlates with the amount of ATP present and inversely with the amount of kinase activity.
TABLE 2 double concentration of Compound III 6 Inhibitory Activity on CK2 kinase
Further, digesting and inoculating the kidney cancer cells ACHN in logarithmic growth phase into a six-well plate, adding corresponding drug-containing culture media according to group settings after the cells adhere to the wall the next day, and simultaneously setting up a negative control group; after 24h of drug action, the cells were collected by digestion with 0.25% pancreatin (without EDTA); washing the cells twice with PBS (centrifugation 1000rpm,5 min) 5X 10 harvest 5 A cell; adding 500 mu L Binding Buffer suspension cells; adding 5 mu L of annexin V-FITC, mixing uniformly, adding 5 mu L of LPropidium Iodide, and mixing uniformly; reacting at room temperature in dark for 5-15min; detecting the apoptosis condition by using a flow cytometer.
Referring to fig. 1, compound III 6-treated group was able to induce ACHN apoptosis, and was able to induce apoptosis dose-dependently. With 0.1, 1 and 10. Mu.M of the target compound III 6 After ACHN cells are treated, the apoptosis rate is 21.29 +/-0.9%, 46.58 +/-0.4% and 65.67 +/-0.4% respectively.
See FIG. 2, molecular docking showing Compound III 6 The 7-hydroxycoumarin structure of (a) is mainly responsible for maintaining kinase inhibitory activity by interacting hydroxyl with a key amino acid residue K68 in the positive region of the CK2 protein and forming hydrogen bond interactions with V116 and N118 in the hinge region through nitro.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (8)
1. A protein kinase inhibitor having the structural formula shown in formula I:
wherein: r 1 Represents hydroxy, hydrogen;
R 2 represents trifluoromethyl, chlorine, bromine or nitro.
2. The method for preparing a protein kinase inhibitor according to claim 1, comprising the steps of:
acylating the intermediate by oxalyl chloride or thionyl chloride or reacting the intermediate with a compound shown in a formula XI in an organic solvent by a condensing agent to obtain a target product, namely the compound shown in the formula I;
wherein the compound of formula XI has the following structural formula:
wherein R is 2 Represents trifluoromethyl, chlorine, bromine or nitro.
3. The method of claim 2, wherein the intermediate has the following structural formula:
4. the method of claim 2, wherein the condensing agent is selected from the group consisting of Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI).
5. The method of claim 2, wherein the organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, dioxane, and DMF.
6. The method for preparing a protein kinase inhibitor according to any one of claims 2 to 5, wherein the reaction conditions are under nitrogen protection.
7. Use of the protein kinase inhibitor of claim 1 in the preparation of a CK2 inhibitor of a serine-threonine kinase.
8. Use of a protein kinase inhibitor according to claim 1 for the preparation of a medicament for inhibiting the activity of a tumor cell comprising: renal cancer cell ACHN, breast cancer cell MCF7.
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