CN109879808B - Five-membered azole heterocyclic group-containing chalcone derivative and preparation method and medical application thereof - Google Patents
Five-membered azole heterocyclic group-containing chalcone derivative and preparation method and medical application thereof Download PDFInfo
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- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 abstract description 6
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Abstract
Five-membered azole heterocyclic group-containing chalcone derivativeA preparation method and medical application thereof, a five-membered azole heterocyclic chalcone derivative is shown in a general formula (I),
R1is composed of
Or
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a five-membered azole heterocyclic chalcone derivative, a preparation method thereof and application of the derivative as an antitumor medicament.
Background
Protein kinase becomes a hot anticancer target due to regulation of cell cycle physiological process, and an inhibitor of the protein kinase is also an important source of anticancer lead compounds. However, only 30 protein kinase inhibitors are successfully marketed as anticancer drugs, and most of them are forced to stop late-stage research due to low drug-forming defects such as low selectivity and large toxic and side effects, thus becoming one of the major bottlenecks restricting the research and development of anticancer drugs.
The protein kinase CK2 is a serine/threonine protein kinase ubiquitous in eukaryotic cells, is closely related to the pathogenesis of tumors, and has important clinical value and application prospect in the research and development of anti-cancer drugs taking the protein kinase CK2 as a target point. At present, anticancer lead compounds based on CK2 target have complex polycyclic structures, so that great technical challenges are faced for improving the pharmaceutical properties of the anticancer lead compounds through structural optimization. Therefore, the discovery of the novel linear-chain framework anticancer drugs has potential application value.
Chalcone compounds are widely distributed in medicinal plants and synthesized active molecules, show wide biological activity, and become important sources of anticancer lead compounds. On the basis of the preliminary research work of documents, patents and subject groups at home and abroad, the invention optimizes the combination of five-membered azole heterocyclic group of anticancer drug effect fragment aiming at 2-propenone skeleton of chalcone, thereby obtaining novel anticancer chalcone compound
Disclosure of Invention
The invention relates to a chalcone derivative containing a five-membered azole heterocyclic group, a preparation method thereof and application thereof in the field of medicines.
The inventor finds that the 2-propenone skeleton of chalcone completely coincides with the core skeleton region of CX4945 by deeply comparing and analyzing the differences of the binding modes of the natural product chalcone and anticancer active compounds CX-4945 and CK2, and shows that the combination optimization of anticancer pharmacodynamic fragments aiming at the 2-propenone skeleton of the chalcone has stronger rationality and feasibility. By optimizing anti-cancer pharmacodynamic groups with different structures and properties, R in 2-propenone skeleton is finally provided1Five-membered azole heterocyclic group is introduced into the site to obtain the novel compound with anti-tumor cell proliferation activity.
In order to achieve the purpose of the invention, the five-membered azole heterocyclic group-containing chalcone derivative provided by the invention has a compound shown as a general formula (I):
wherein R is1Is composed of
Any one of them.
When R is1Is composed of
When the compound is 4- ((E) -2- ((1H-imidazol-2-yl) carbamoyl) vinyl) benzoic acid (Compound 1)
When R is1Is composed of
When the compound is 4- ((E) -2- (1H-pyrazol-4-yl-carbamoyl) vinyl) benzoic acid (compound 2).
The invention also provides a preparation method of the two five-membered azole heterocyclic chalcone derivatives, and the reaction process of the method is as follows:
R1is composed of
Any one of them.
The specific synthetic steps of the compound provided by the invention are as follows:
(1) dissolving a compound c, EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) and DMAP (4-dimethylaminopyridine) in THF, stirring for reacting for 1-3 hours, adding a compound R1-NH2 into the solution, stirring the obtained system overnight, adding water, filtering the precipitate, and concentrating in vacuum to obtain a compound d;
(2) dissolving the compound d obtained in the step (1) in methanol, adding a LiOH aqueous solution, and stirring for reaction; monitoring the reaction process by thin-layer chromatography, concentrating in vacuum after the reaction is finished, acidifying with dilute hydrochloric acid to adjust the pH value of the solution to be acidic, adding water for suction filtration, drying with anhydrous magnesium sulfate to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain a compound e, namely the five-membered azole heterocyclic group chalcone derivative.
The method comprises the following steps:
in the step (1):
the compounds c, EDCI, DMAP and R1—NH2The molar ratio of (1) to (2: 2-4:1-3: 2-5);
the reaction temperature of the compound c, EDCI and DMAP is controlled between 25 and 30 ℃;
adding compound R to the reaction solution of compounds c, EDCI and DMAP1-NH2Control of reaction temperatureThe temperature is controlled at 25-30 ℃.
In the step (2):
the molar ratio of the compound d to LiOH is 1: 1-3;
the reaction time is controlled to be 2-5 h;
the reaction temperature is controlled at 25-30 ℃;
the concentration of a hydrochloric acid solution used for hydrochloric acid acidification is 10-30%, and the pH of the solution is controlled to be 4-6;
the eluent used for the silica gel column chromatography is methanol and dichloromethane, and gradient elution is adopted, wherein the volume ratio of the methanol to the dichloromethane is 1:8-1: 15.
The application of the five-membered azole heterocyclic group-containing chalcone derivative in preparing an anti-tumor medicament belongs to the protection scope of the invention.
Furthermore, the five-membered azole heterocyclic group-containing chalcone derivative has certain activity of resisting tumor cell proliferation. The tumor cells comprise one or two of lung cancer cells A549 and breast cancer cells MCF-7.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited to the following examples.
The structural formulae of compound 1 and compound 2 referred to in the following examples are as follows:
the reaction steps of the synthesis are as follows (including the synthesis steps from compound a to compound c):
R1is composed of
Any one of them.
Example Synthesis of- ((E) -2- ((1H-imidazol-2-yl) carbamoyl) vinyl) benzoic acid (Compound 1)
(1) Synthesis of p-formyl benzoic acid ester
Weighing Compound a (1g,6.66mmol) dissolved in anhydrous CH3CN (20mL), adding DBU (1.105mL, 7.325mmol), CH3I (0.54mL,8.66mmol), stirred at rt for 2h and monitored by TLC (petroleum ether: ethyl acetate 1: 1). Concentrated in vacuo to give a yellow oily liquid, the residue was dissolved in ethyl acetate and washed with H2O, HCl, saturated NaHCO3The organic phase was washed with brine and MgSO4Drying, removal of the solvent in vacuo, and drying afforded compound b (1.5g, 9.14mmol) as a white solid in 69% yield.
(2) Synthesis of 3- (2- (methoxycarbonyl) phenyl) acrylic acid
A mixture system of p-formylbenzoate b (1.23g,7.5mmol), malonic acid (1.56g,15mmol), pyridine (1.25mL), and piperidine (0.75mL) was weighed, and heated under reflux for 5 hours. The hot mixture was poured into ice water, acidified to pH <2 with dilute hydrochloric acid (10%), the precipitate filtered, washed with water, recrystallized from 95% ethanol, and dried under vacuum to give a pale yellow solid of formula 3 (0.52g) in 34% yield.
(3) Synthesis of methyl 4- ((E) -2- ((1H-imidazol-2-yl) carbamoyl) vinyl) benzoate
3- (2- (methoxycarbonyl) phenyl) acrylic acid (1.03g,5mmol), EDCI (0.95g,5mmol) and DMAP (0.3g,2.45mmol) were dissolved in THF (15mL) and stirred at room temperature, after which the compound 1H-imidazol-2-amine (0.5g,5mmol) was added. The system was stirred at room temperature overnight. The precipitate was filtered with water and concentrated in vacuo to give the crude product, formula 4 (0.695g,5.12mmol) as a white solid in 48% yield.
(4) Synthesis of 4- ((E) -2- ((1H-imidazol-2-yl) carbamoyl) vinyl) benzoic acid
Methyl (4- ((E) -2- ((1H-imidazol-2-yl) carbamoyl) vinyl) benzoate (0.865g,3mmol) was weighed out and dissolved in methanol (15mL), an aqueous solution (15mL) of LiOH (0.252g,6mmol) was added, stirring at room temperature, vacuum concentration was carried out, diluted hydrochloric acid was acidified to pH 5-6, water was added, suction filtration was carried out, and drying was carried out to obtain the objective compound 1(1.07g,3.14mmol) as a white solid in a yield of 65%.1HNMR(400MHz,DMSO-d6) 10.77(d,J＝7.9Hz,1H),6.74(d,J＝3.4Hz,1H,),7.26(d,J＝3.3Hz,1H),12.77 (s,1H),7.41(d,J＝15.7Hz,1H),7.00(d,J＝16.0Hz,1H),7.95(d,J＝8.4Hz,2H), 7.75(d,J＝8.4Hz,2H),12.82(s,1H).HRMS(ESI)calcd for[M+H]+C13H12N3O3 +: 257.0821,found:257.0800.
Example Synthesis of 24- ((E) -2- (1H-pyrazol-4-yl-carbamoyl) vinyl) benzoic acid (Compound 2)
(1) Synthesis of p-formyl benzoic acid ester
P-formylbenzoic acid a (1.2g,8.1mmol) was dissolved in anhydrous CH3CN (24mL), DBU (1.38mL, 8.79mmol), CH were added3I (0.65mL,10.4mmol), stirred at rt for 2h and monitored by TLC (petroleum ether: ethyl acetate 1: 1). Concentrated in vacuo to give a yellow oily liquid, the residue was dissolved in ethyl acetate and washed with H2O, HCl, saturated NaHCO3The organic phase was washed with brine and MgSO4Drying, removal of the solvent in vacuo, and drying afforded p-formylbenzoate (1.8g,10.36mmol) as a white solid in 71% yield.
(2) Synthesis of 3- (2- (methoxycarbonyl) phenyl) acrylic acid
A mixture system of p-formylbenzoate b (1.28g,7.8mmol), malonic acid (1.64g,15.76mmol), pyridine (1.5mL) and piperidine (0.86mL) was weighed and heated under reflux for 5 hours. The hot mixture was poured into ice water, acidified to pH <2 with dilute hydrochloric acid (10%), the precipitate filtered, washed with water, recrystallized from 95% ethanol, and dried under vacuum to give a light yellow solid of formula 3 (0.58g,2.82mmol) in 36% yield.
(3) Synthesis of methyl 4- ((E) -2- (1H-pyrazol-4-yl-carbamoyl) vinyl) benzoate
3- (2- (methoxycarbonyl) phenyl) acrylic acid (1.23g,5.97mmol), EDCI (1g, 5.24mmol) and DMAP (0.35g,2.87mmol) were dissolved in THF (18mL) and stirred at room temperature, after which the compound 1H-pyrazol-4-amine (0.56g,5.6mmol) was added. The system was stirred at room temperature overnight. The precipitate was filtered with water and concentrated in vacuo to give the crude product of formula 4 (0.72g,2.66mmol) as a white solid in 49% yield.
(4) Synthesis of 4- ((E) -2- (1H-pyrazol-4-yl-carbamoyl) vinyl) benzoic acid
Methyl 4- ((E) -2- (1H-pyrazol-4-yl-carbamoyl) vinyl) benzoate (0.88g,0.325mmol) was dissolved in methanol (16mL), and an aqueous solution (16mL) of LiOH (0.28g,6.67mmol) was added, followed by stirring at room temperature. Vacuum concentrating, acidifying with dilute hydrochloric acid to pH 5-6, adding water, vacuum filtering, and drying to obtain white solid (1.17g,3.44mmol) represented by the target product compound 2, with a yield of 66%.1HNMR(400MHz,DMSO-d6)10.07(d,J＝7.9Hz,1H),8.60-8.59(m,2H,),12.51 (s,1H),7.84(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.05(d,J＝15.4Hz,1H),7.65(d,J ＝14.9Hz,1H),13.88(s,1H,).HRMS(ESI)calcd for[M+H]+C13H12N3O3 +:257.0875, found:257.0800.
Example 3 measurement of inhibitory Effect of Compound 1 and Compound 2 on proliferation of Lung cancer cell A549 and Breast cancer cell MCF-7 by CCK-8 method
Preparing lung cancer cell A549 and breast cancer cell MCF-7 in logarithmic cell growth phase into cell suspension with certain concentration, adding 7500 cells per well into 96-well plate, and keeping CO constant at 37 deg.C2The incubator is used for 24 h. Preparing the compounds 1 and 2 into 6-1000 μ M liquid medicine, respectively adding into corresponding 96-well plate, setting negative control and blank control, and culturing for 48 h. CCK-8 reagent was added to each well, and the culture was continued for 4 hours to terminate the culture. The light absorption value is measured by a microplate reader in the wavelength range of 490-570nm, and a curve is drawn to indirectly reflect the survival amount of the cells. As shown in Table 1, Compound 1 inhibits the proliferation of lung cancer cells A54950IC value of 100. mu.M for proliferation of breast cancer cells MCF-750The value was 35.63. mu.M. As shown in Table 2, the IC of compound 2 in proliferation of lung cancer cell A54950IC value of 158. mu.M for proliferation of breast cancer cells MCF-750The value was 79.34. mu.M.
TABLE 1 antitumor cell proliferation Activity (μ M) of Compound 1 and Compound 2
Claims (9)
1. A chalcone derivative containing a five-membered azole heterocyclic group is characterized by being a compound represented by a formula (I):
2. the process for preparing chalcone derivatives with five-membered azole heterocyclic group according to claim 1, wherein the following 2 steps are performed:
the method comprises the following reaction steps:
(1) dissolving compound c, EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) and DMAP (4-dimethylaminopyridine) in THF, reacting for 1-3 hours with stirring, and adding the compound to the solution
Stirring the obtained system overnight, adding water, filtering the precipitate, and concentrating in vacuum to obtain a compound d;
(2) dissolving the compound d obtained in the step (1) in methanol, adding a LiOH aqueous solution, and stirring for reaction; monitoring the reaction process by thin-layer chromatography, concentrating under vacuum after the reaction is finished, acidifying with dilute hydrochloric acid to adjust the pH value of the solution, adding water for suction filtration, drying with anhydrous magnesium sulfate to obtain a crude product, and separating and purifying by silica gel column chromatography to obtain a compound e, namely the five-membered azole heterocyclic group chalcone derivative.
3. The process for producing heterocyclic chalcone derivatives according to claim 2, wherein in step (1), the compounds c, EDCI, DMAP and
mole ofThe ratio is 2:2-4:1-3: 2-5; the temperature of both stirring reactions was controlled at 25-30 ℃.
4. The process for producing a heterocyclic chalcone derivative according to claim 2, wherein the molar ratio of compound d to LiOH in step (2) is 1: 1-3.
5. The process for preparing a chalcone derivative with a heterocyclic group containing a five-membered azole according to claim 2, wherein the stirring reaction temperature in the step (2) is controlled to be 25-30 ℃ and the reaction time is 2-5 hours.
6. The preparation method of the heterocyclic chalcone derivative with a five-membered azole group according to claim 2, wherein the hydrochloric acid solution in the step (2) has a concentration of 10% to 30% by mass; controlling the pH value of the solution to be 4-6.
7. The process for preparing chalcone derivatives having a five-membered azole heterocyclic group according to claim 2, wherein the eluent used in the step (2) is methanol and dichloromethane, and the gradient elution is performed, wherein the volume ratio of methanol to dichloromethane is 1:8-1: 15.
8. The use of the heterocyclic chalcone derivatives with five-membered azoles according to claim 1 for preparing antitumor drugs.
9. The use of the heterocyclic chalcone derivatives with a pentazole group according to claim 8, as an antitumor agent, wherein the tumor cells include one or both of lung cancer cell a549 and breast cancer cell MCF-7.
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