CN107652261B - Calycosin derivative and synthetic method thereof - Google Patents
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Abstract
The invention discloses a calycosin derivative and a synthesis method thereof, wherein the derivative is prepared by dissolving a compound 1 and a compound 2 in an organic solvent, reacting under an alkaline condition to obtain an intermediate product 3, and then dissolving the intermediate product 3 and a compound 4 in the organic solvent, reacting under the alkaline condition to obtain a target crude product, the applicant finds that the derivative can promote the proliferation of human umbilical vein endothelial cells under a lower concentration to generate a good vascular protection effect, can be applied to the preparation of ER α agonists and GPR30 agonists, and has an inhibitory effect on MCF-7 cells under a low concentration (10 mu M). The structures of the compound 1, the compound 2, the intermediate product 3 and the compound 4 related in the derivative and the synthesis method thereof are respectively as follows:
Description
Technical Field
The invention relates to a calycosin derivative and a synthesis method thereof, belonging to the technical field of medicines.
Background
The radix astragali is dried root of Astragalus membranaceus (Fisch.) Bge. belonging to Leguminosae family perennial herbaceous plant Astragalus membranaceus (Fisch.) Bge. According to the pharmacopoeia, astragalus root has sweet taste and mild nature, and has the efficacies of tonifying qi and invigorating yang, benefiting wei and defensive qi, strengthening exterior, improving cardiac function, expanding coronary artery, promoting urination and detumescence, supporting sore and promoting granulation, resisting bacteria, resisting virus, resisting fatigue, resisting aging, promoting hematopoiesis, protecting liver and the like.
Calycosin (calycosin) is an isoflavone compound extracted and separated from radix astragali (Ma Xiaofeng et al, research on flavone components in Mongolian radix astragali, Chinese herbal medicine, vol. 36, 9 th, 9.2005, p1293-1296), and its structural formula is shown as follows:
the existing research shows that calycosin has the effects of resisting oxidative stress, resisting virus, regulating apoptosis and the like, but has the defects that the effective concentration is higher, the target point is undefined, and the calycosin (less than 16 mu M) with low concentration can promote the proliferation of ER positive breast cancer cells MCF-7; although high concentration of calycosin (>20 μ M) can inhibit proliferation of ER-positive breast cancer cells MCF-7 and T47D, it has no effect on proliferation of ER-negative breast cancer cells MDA-MB-435s (Zhouyiming, Chengjian, effect of calycosin with different concentrations on ER-positive breast cancer cells and mechanism research thereof, proceedings of the eleventh national chemotherapeutics and pharmacology workshop of Chinese Pharmacology, 7/1/2012, p 322-323).
Disclosure of Invention
The invention aims to provide a calycosin derivative which has a novel structure, can promote the proliferation of human umbilical vein endothelial cells at a lower concentration and has an inhibition effect on MCF-7 cells, and a synthesis method thereof.
The calycosin derivative has a compound shown in the following formula (I) or pharmaceutically acceptable salt thereof:
the chemical name of the compound represented by the formula (I) is: 3- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -7- (2-morpholinoethoxy) -4H-benzopyran-4-one, molecular weight 510.6.
The invention also provides a synthesis method of the compound, which comprises the following steps:
1) dissolving a compound 1 and a compound 2 in an organic solvent, adjusting the pH value of the system to be more than 8, then reacting under the condition of heating or not heating, and recovering the solvent from the reactant to obtain an intermediate product 3;
2) dissolving the intermediate product 3 and the compound 4 in an organic solvent, adjusting the pH value of the system to be more than 8, then reacting under the condition of heating or not heating, and recovering the solvent from the reactant to obtain a crude product of the target product;
the structures of compound 1, compound 2, intermediate 3 and compound 4 above are as follows:
in steps 1) and 2) of the above synthesis method, the organic solvent may be one or a combination of two or more selected from acetone, N-Dimethylformamide (DMF), chloroform and dichloromethane, preferably acetone or DMF, the amount of the organic solvent is determined according to the need, and is usually suitable for dissolving the raw materials for the reaction, specifically, in step 1), the amount of the organic solvent is calculated by adding 6-12m L to 1mmol of compound 1, and in step 2), the amount of the organic solvent is calculated by adding 6-12m L to 1mmol of intermediate product 3.
In step 1) of the above synthesis method, the molar ratio of compound 1 to compound 2 is a stoichiometric ratio, and the molar ratio of intermediate 3 to compound 4 is a stoichiometric ratio, but in actual practice, compound 2 and compound 4 may be in slight excess.
In steps 1) and 2) of the above synthesis method, the reaction is preferably carried out under heating, which can achieve a higher yield than when carried out without heating. When the reaction is carried out under heating, it is preferable that the reaction is carried out at a temperature of 63 ℃ to the boiling point of the organic solvent.
In steps 1) and 2) of the above synthesis method, whether the reaction is complete or not can be detected by tracking with T L C.
In steps 1) and 2) of the above synthesis method, the pH of the system is usually adjusted by using an alkaline substance, specifically, one or a combination of two or more of common alkaline substances selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, and preferably, a weakly alkaline substance such as triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate and the like. In the present application, it is preferable to use the alkaline substance as a solution prepared with water.
In steps 1) and 2) of the above synthesis method, the pH of the system is preferably adjusted to 8 to 12.
In step 1) of the above synthesis method, in order to reduce the impurities introduced into step 2) and simultaneously improve the purity of the crude target product, it is preferable to purify intermediate product 3 obtained in step 1) and then use it in the operation described in step 2). The purification can be a conventional purification operation in the prior art, in the application, the intermediate product 3 is preferably subjected to silica gel column chromatography and then used in the step 2), and in the chromatography process, the used eluent is prepared from a solvent with a volume ratio of 1: 15-2 of ethyl acetate and petroleum ether, further preferably in a volume ratio of 1: 10-4 of ethyl acetate and petroleum ether, more preferably in a volume ratio of 1:4 ethyl acetate and petroleum ether.
The above synthesis process produces a crude compound of formula (I) which can be purified by conventional purification methods to increase the purity of the compound of formula (I). The purification is usually carried out by silica gel column chromatography, specifically, the crude product of the target product is subjected to silica gel column chromatography, and the silica gel column chromatography is carried out by using a solvent prepared from the following components in a volume ratio of 1: eluting with 5-0.25% ethyl acetate and petroleum ether, and evaporating the eluent to remove solvent to obtain purified target product. The volume ratio of the ethyl acetate and the petroleum ether composing the eluent is preferably 1: 1-0.25.
Compared with the prior art, the calycosin derivative with a novel structure and the synthesis method thereof are provided, the calycosin derivative can promote the proliferation of human umbilical vein endothelial cells under a lower concentration, generates a good vascular protection effect, can be applied to the preparation of ER α and GPR30 agonists, and simultaneously has an inhibitory effect on MCF-7 cells under a low concentration (10 mu M).
Drawings
FIG. 1 is a graph showing the dose-response curves of HUVECs in endothelial cells and MCF-7 in breast cancer cells with different concentrations of the target compound of the present invention and calycosin @ p <0.05 vs control and @ p <0.05 vs 10. mu.M of the target compound;
FIG. 2 is a bar graph of HUVECs with the cooperation of the target compounds of the present invention with the ER α inhibitor MPP, the GPR30 inhibitor G15, @ p <0.05 vs control, and @ p <0.05 vs 10. mu.M target compounds.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
The following examples were synthesized to give the title compounds according to the following synthetic routes:
wherein, the chemical name of the compound 1 is: 7-hydroxy-3- (3-hydroxy-4-methoxy) -4H-benzopyran-4-one, compound 2 has the chemical name: 1, 2-dibromoethane, intermediate 3, has the chemical name: 7- (2-bromoethoxy) -3- (3- (2-bromoethoxy) -4-methoxyphenyl) -4H-chromen-4-one, compound 4 having the chemical name: morpholine; the chemical name of compound 5 is: 3- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -7- (2-morpholinoethoxy) -4H-benzopyran-4-one.
Example 1
1) Dissolving 7-hydroxy-3- (3-hydroxy-4-methoxy) -4H-benzopyran-4-ketone (300mg) and 1, 2-dibromoethane in acetone 13m L according to a molar ratio of 1: 8, then adjusting the pH of the system to 10 by triethylamine, reacting for 8H at room temperature, after the reaction is finished, drying in a rotary manner, adding 200ml of ethyl acetate into the obtained residue, washing with water 300m L x 3 for three times, then drying with anhydrous sodium sulfate, and purifying by silica gel column (eluent is ethyl acetate/petroleum ether 1:4 in volume ratio) to obtain an intermediate product 3 (yield is 60%);
2) intermediate 3(100mg) and morpholine were dissolved in 10m L acetone at a molar ratio of 1: 1 and reacted with triethylamine at room temperature for 6h, after completion of the reaction, 150ml ethyl acetate was added to the residue, washed three times with 200m L x 3 water, dried over anhydrous sodium sulfate, and purified on a silica gel column (eluent ethyl acetate/petroleum ether at a volume ratio of 1: 3) to give a yellow solid product (yield 55%).
The yellow solid product obtained in this example was characterized by nmr, and its hydrogen and carbon spectra were as follows:
1H NMR(400MHz,dmso)8.43(s,1H),7.98(d,J＝8.9Hz,1H),7.17(d,J＝9.9Hz,2H),7.12(d,J＝8.4Hz,1H),7.05(d,J＝9.0Hz,1H),6.97(d,J＝8.5Hz,1H),4.21(t,J＝5.6Hz,2H),4.06(t,J＝5.8Hz,2H),3.75(s,4H),3.54(d,J＝4.2Hz,10H),2.77–2.61(m,5H),2.46(d,J＝1.5Hz,17H).
13C NMR(151MHz,DMSO)174.43(s),162.73(s),157.19(s),153.54(s),148.75(s),147.33(s),126.77(s),124.20(s),123.19(s),121.42(s),117.43(s),114.98(s),114.15(s),111.71(s),100.97(s),66.40–65.74(m),56.73(d,J＝45.7Hz),55.50(s),54.74(s),53.45(d,J＝15.0Hz).
therefore, the yellow solid product obtained in this example can be determined to be the target compound of the present application, and the structural formula of the yellow solid product is shown as the following formula (I):
example 2
Example 1 was repeated, except that: the organic solvent in steps 1) and 2) was changed to DMF. The product was obtained as a yellow solid (yield 55%).
The yellow solid product obtained in this example was characterized by nmr and identified as the target compound of the present application.
Example 3
Example 1 was repeated, except that: the organic solvent in steps 1) and 2) was changed to chloroform. The product was obtained as a yellow solid (yield 20%).
The yellow solid product obtained in this example was characterized by nmr and identified as the target compound of the present application.
Example 4
Example 1 was repeated, except that: the organic solvent in steps 1) and 2) was changed to dichloromethane. The product was obtained as a yellow solid (yield 25%).
The yellow solid product obtained in this example was characterized by nmr and identified as the target compound of the present application.
Example 5
Example 1 was repeated, except that: changing the reaction mode in the step 1) into reflux reaction, and changing the reaction time into 4 h; the reaction mode in the step 2) is changed into reflux reaction, and the reaction time is changed into 3 h. The product was obtained as a yellow solid (yield 50%).
The yellow solid product obtained in this example was characterized by nmr and identified as the target compound of the present application.
Example 6
Example 1 was repeated, except that: the reaction in the step 1) is changed to be carried out at the temperature of 60 ℃, and the reaction time is changed to be 6 hours; the reaction mode in the step 2) is changed to be carried out at the temperature of 65 ℃, and the reaction time is changed to be 4 h. The product was obtained as a yellow solid (yield 60%).
The yellow solid product obtained in this example was characterized by nmr and identified as the target compound of the present application.
The applicant finds in research that the target compound of the invention can promote the proliferation of human umbilical vein endothelial cells and has an inhibition effect on MCF-7 cells at a lower concentration, and the following are specific experiments:
example 1: method for detecting endothelial cell proliferation by MTT method
All data in this experiment are expressed as mean + -SEM, statistical comparisons were performed using one-way analysis of variance and Tukey's test for group comparisons.
1.1) test drugs: the target compound (hereinafter, CAG002 will be referred to simply as "CAG") prepared by the method of example 1 of the present invention was dissolved in DMSO to prepare a stock solution with a concentration of 100mM, and stored at 4 ℃ for further use.
1.2) reagents Kaighn 'S modification of Ham' S F12medium (F-12K), Calf serum (FBS), charcoal/dextran treated Calf serum (CS-FBS), Phosphate Buffered Saline (PBS), penicillin-streptomycin (P/S) and 0.25% (W/V) Trypsin/1 mM EDTA (Trypsin-EDTA) were purchased from Invitrogen (USA.) endothelial cell auxin (ECGS), heparin, ER α specific inhibitor (MPP), GPR30 inhibitor G15 was purchased from Sigma (St L ouis, MO.) MTT assay kit supplied by Roche (Mennheim, Germany.).
1.3) cell culture human umbilical vein endothelial cells (HUVEC-12, ATCC, Manassas) were cultured with F-12K containing 2mM L-glutamic acid, 100U/ml penicillin, 100. mu.g/ml streptomycin, 100. mu.g/ml heparin, 30. mu.g/ml ECGS and 10% FBS at 37 ℃ with 5% CO2Culturing in incubator, and culturing breast cancer cell MCF-7 with 1640 medium (containing 10% fetal calf serum, 100U/ml penicillin and 100 μ g/ml streptomycin) at 37 deg.C and 5% CO2Culturing in an incubator. The day before the experiment was changed to a depoisoning medium containing 1% CS-FBS without phenol red, and the experiments were all performed in depoisoning medium.
1.4) Experimental methods and results:
taking HUVECs and MCF-7 growing to 90% of fusion, washing, digesting and preparing into cell suspension. After counting, press 1x104Perwell in 96-well plates. After the cells are completely attached to the wall for 24h, the upper layer of culture solution is removed, and 100. mu.l of low serum phlegmatizer culture solution (0.5% CS-FBS) is added to each well for 24h of culture to synchronize the cell state. The experimental group is provided with CAG002 (1-25 μ M) drug-adding groups with different concentrations, each group has 9 multiple holes, and low serum culture solution containing drugs is added into each hole according to 200 μ l. Two groups of controls were set simultaneously, the blank control was 0.1% DMSO culture medium and the positive control was 10 μ M calycosin.
MTT results show that CAG002 can promote the proliferation of HUVECs in a dose-dependent manner. Wherein, when the drug concentration is 10 μ M, the proliferation effect is most obvious, compared with a blank control, the proliferation rate reaches 50.67% (p is less than 0.05), the inhibition effect on MCF-7 is achieved under the same concentration, the inhibition rate is 9.64%, and the proliferation rate of a positive group is 25.74%. The effect of different concentrations of CAG002 on the proliferation of HUVECs and MCF-7 is shown in FIG. 1.
In an inhibitor experiment, HUVECs are pretreated for 1 hour by using ER α inhibitor MPP and GPR30 inhibitor G15(100nM), a culture solution containing the inhibitor is removed, a culture solution containing a medicament (10 mu M) is added, the culture is continued for 48 hours, and MTT detection results show that a histogram of HUVECs under the combined action of CAG002, ER α inhibitor MPP and GPR30 inhibitor G15 is shown in figure 2. from figure 2, 10 mu M CAG002 can obviously promote the proliferation of HUVECs, the proliferation rate reaches 48.65 percent, 100nM MPP and G15 can obviously reduce the proliferation of HUVECs induced by 10 mu MCAG002, compared with a dosing group, the cell proliferation rate of the G15 group is reduced by 29.38 percent (p is less than 0.05), and the cell proliferation rate of the MPP group is reduced by 22.54 percent.
1.5) conclusion:
the results of the above experiments show that CAG002 is more capable of promoting endothelial cell proliferation than calycosin and appears to inhibit breast cancer cell growth at the same concentration, and therefore CAG002 is more promising as an estrogen substitute than calycosin.
MTT experiments show that CAG002 can promote HUVEC proliferation with the most obvious effect at 10 mu M, and ER α inhibitor MPP and GPR30 inhibitor G15 can both obviously reduce CAG 002-mediated HUVEC proliferation, thus suggesting that CAG002 can promote vascular endothelial cell proliferation through GPR30 and ER α.
Claims (8)
1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
2. a method of synthesizing the compound of claim 1, wherein: the method comprises the following steps:
1) dissolving a compound 1 and a compound 2 in an organic solvent, adjusting the pH value of the system to be more than 8, then reacting under the condition of heating or not heating, and recovering the solvent from the reactant to obtain an intermediate product 3;
2) dissolving the intermediate product 3 and the compound 4 in an organic solvent, adjusting the pH value of the system to be more than 8, then reacting under the condition of heating or not heating, and recovering the solvent from the reactant to obtain a crude product of the target product;
the structures of compound 1, compound 2, intermediate 3 and compound 4 above are as follows:
3. the method of synthesis according to claim 2, characterized in that: in the steps 1) and 2), the organic solvent is one or a combination of more than two selected from acetone, N-dimethylformamide, chloroform and dichloromethane.
4. The method of synthesis according to claim 2, characterized in that: in steps 1) and 2), the pH of the system is adjusted by using an alkaline substance.
5. The method of synthesis according to claim 2, characterized in that: in steps 1) and 2), the pH of the system was adjusted to 8-12.
6. The method of synthesis according to any one of claims 2-5, characterized in that: in step 1), the intermediate product is purified and then used for subsequent operations.
7. The method of synthesis according to claim 6, characterized in that: the purification is to carry out silica gel column chromatography on the intermediate product, and the intermediate product is purified by a reaction product prepared by mixing the raw materials in a volume ratio of 1: 15-2 of ethyl acetate and petroleum ether, evaporating the eluent to remove the solvent, and obtaining a purified intermediate product for subsequent operation.
8. The method of synthesis according to any one of claims 2-5, characterized in that: further comprises a purification step of a crude product of the target: specifically, the prepared crude target product is subjected to silica gel column chromatography, and the silica gel column chromatography is performed by using a silica gel column chromatography method, wherein the silica gel column chromatography is performed by using a silica gel column chromatography method, and the silica gel column chromatography method comprises the following steps of: eluting with 5-0.25% ethyl acetate and petroleum ether, and evaporating the eluent to remove solvent to obtain purified target product.
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| CN111166738B (en) * | 2020-01-10 | 2022-06-14 | 桂林医学院 | Application of calycosin derivative in preparation of medicine for inhibiting endothelial cell proliferation |
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