CN110483465B - Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction - Google Patents

Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction Download PDF

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CN110483465B
CN110483465B CN201910793375.0A CN201910793375A CN110483465B CN 110483465 B CN110483465 B CN 110483465B CN 201910793375 A CN201910793375 A CN 201910793375A CN 110483465 B CN110483465 B CN 110483465B
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延玺
于渼璇
宋静磊
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Abstract

The invention provides a genistein derivative shown as a formula (I), wherein R is pyridyl, aldehyde group, hydroxyethyl and tert-butyloxycarbonyl. Compared with the prior art, the genistein derivative provided by the invention has a good growth inhibition effect on various tumor cells, and particularly has higher growth inhibition activity on five tumor cells, namely A549 cells, Hela cells, MCF-7 cells, SH-SY5Y cells and HepG2 cells when R is a pyridine substituent.

Description

Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a genistein derivative, and a preparation method and application thereof.
Background
Nowadays, the threat of cancer to human beings is increasing, and the means and drugs for treating cancer cannot fully meet the needs of people, so the development process of anti-cancer drugs is accelerated.
Genistein, also known as genistein, has a chemical structure very similar to that of endogenous estrogen estradiol, and the compound and its synthesized derivatives have a wide range of biological activities, including antioxidant, antitumor, antiviral, antiparasitic, anti-inflammatory and cardiovascular activities, which are attracting much attention.
Piperazine is a six-membered heterocyclic ring with two nitrogen atoms, is an important medical intermediate, and is mainly used for producing anthelmintic piperazine phosphate, piperazine citrate, and dyclonine and rifampicin.
The invention utilizes alkyl to bridge piperazine compound and genistein, and combinesA series of genistein bridged piperazine derivatives are formed, the compounds are subjected to antitumor activity research by adopting an MTT research method, experimental results show that different piperazine substituents show different antitumor activities, and cell experiments show that genistein piperazine pyridine substituent products have excellent broad-spectrum antitumor activity, particularly have obvious growth inhibition effects on human cervical cancer (Hela) and lung cancer (A549) cells, and have IC (integrated Circuit) of the genistein bridged piperazine derivatives50The value is below 10 mu mol/L, and the novel compounds have further development value according to the research experience of new drug development, and are expected to be developed into a new anti-tumor drug.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a genistein derivative with anti-tumor activity, and a preparation method and an application thereof.
The invention provides a genistein derivative, which is shown as a formula (I):
Figure GDA0002992613130000011
the chemical general formula is shown as above, wherein R is pyridyl, aldehyde group, hydroxyethyl, tert-butyloxycarbonyl, isopropyl, aminoethyl and ethyl formate.
Preferred are compounds represented by the formulae (I-1) to (I-4):
Figure GDA0002992613130000021
Figure GDA0002992613130000031
more preferred target compounds are represented by the formula (I-4).
The invention also provides a preparation method for preparing the genistein piperazine derivative under mild conditions, which comprises the following steps: the compounds represented by (I-1) to (I-4) can be prepared by reacting genistein and piperazine derivatives with methanol and 37% formaldehyde.
Particularly, the compound (I-4) has higher growth inhibition activity on five tumor cells, namely A549 cells, Hela cells, MCF-7 cells, SH-SY5Y cells and HepG2 cells, and is more remarkable in growth inhibition activity on A549 cells and Hela cells.
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In the drawings of the specification:
FIG. 1 is a general structural formula of a synthetic compound of the present invention;
FIG. 2 is a graph of the growth inhibition rate of the compound of the present invention, positive compounds 5-fluorouracil and genistein on HeLa cells at different concentrations;
FIG. 3 is a graph showing the growth inhibition rate of the compound of the present invention, positive compounds 5-fluorouracil and genistein against HepG2 cells at different concentrations;
FIG. 4 is a graph showing the evaluation of the growth inhibition rate of the A549 cells by the compound of the present invention and the positive compounds 5-fluorouracil and genistein at different concentrations;
FIG. 5 is a graph of the growth inhibition rate of SH-SY5Y cells evaluated by the related compounds of the invention and positive compounds 5-fluorouracil and genistein at different concentrations;
FIG. 6 is a graph showing the evaluation of the growth inhibition rate of MCF-7 cells by the compound of the present invention and the positive compounds 5-fluorouracil and genistein at different concentrations;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the 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.
Mixing genistein and piperazine derivative, formaldehyde according to a molar ratio of 1: (1-3): 1, more preferably 1: (1.1-2) 1, preferably 1: 1.2: 1; the reaction is carried out. In the present invention, the reaction is preferably carried out in an organic solvent; the organic solvent is a protonating agent well known to those skilled in the art, and is not particularly limited, and methanol is more preferable in the present invention; the ratio of the methanol to the genistein is preferably (20-100) ml: 1g, more preferably (50-80) ml: 1g, more preferably 67 ml: 1g of a compound; the reaction temperature is preferably 25-80 ℃, and more preferably 35 ℃; the reaction time is preferably 2-24 h, more preferably 8-20 h, and still more preferably 18 h.
After the reaction is completed, the product is separated from the reaction system by a method known to those skilled in the art without particular limitation, and the product is obtained after separation.
The invention also provides application of the genistein derivatives shown in the formulas (I-1) to (I-4) in preparation of antitumor drugs.
The antitumor activity of the target compound can be researched by adopting an MTT research method.
In order to further illustrate the present invention, the genistein piperazine derivatives provided by the present invention, the preparation method thereof and the application thereof in antitumor drug activity are described in detail below with reference to the examples.
The reagents used in the following examples are all commercially available.
Example 1
Preparation of Compound represented by the formula (I-1)
Figure GDA0002992613130000041
680.1mg (2.5mmol) of genistein, 45ml of methanol and 200. mu.L (2.5mmol) of 37% formaldehyde are added into a 100ml round-bottom flask, stirred and refluxed for 30min at 30 ℃, 405.51mg (3mmol) of 1-acetylpiperazine is added into the round-bottom flask, stirred and refluxed for 8h at 30 ℃ and reacted for 5h at normal temperature. Then the reaction is stopped, and the reaction is filtered under reduced pressure and separated into solid and liquid. Collecting solid containing a small amount of 1-acetylpiperazine, formaldehyde, a small amount of genistein and products; the liquid contains genistein and 1-acetylpiperazine dissolved in methanol. The solid was washed 5 times with 7ml methanol each time to give 660.6mg of a white solid with 64.43% yield.
Characterization of the product:
detecting the obtained white solid by nuclear magnetic resonance to obtain1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.35(d,J＝7.34Hz,2H),6.80(d,J＝6.78Hz,2H),6.24(s,1H),3.71(s,4H),3.40(q,J＝3.4Hz,5H),2.41(s,2H),1.39(s,3H).
Detecting the obtained white solid by a mass spectrometer to obtain ESI-MS M/z [ M + H ]]+＝411.1456。
Detecting the obtained white solid by using a melting point instrument to obtain a melting point of 268-272 ℃.
The compound shown in formula (I-1) of the invention synthesized above is tested by MTT research method to evaluate the inhibition rate and IC of the target compound for inhibiting the growth of different tumor cells50The value is obtained.
The cell culture adopted in the experiment is carried out at 37 ℃ and 5% CO2The culture is carried out in the environment of a sterile incubator, and the culture medium adopts DMEM culture medium containing 10% FBS.
Target compound concentration setting: the target compound of the present invention was formulated into test samples having a concentration gradient of 5. mu. mol/L, 10. mu. mol/L, 20. mu. mol/L, 30. mu. mol/L, 40. mu. mol/L, 50. mu. mol/L, 60. mu. mol/L, or 80. mu. mol/L. The medium served as a blank, i.e.the compound concentration was 0.
MTT method experimental process: taking an A549 cell line as an example, the cells recover from liquid ammonia, and after 3 passages, the cells are in a normal adherent growth state. 100 μ LPBS was added to the outermost round of wells of the 96-well plate, and cells were seeded at 6000 cells/well in the remaining wells of the 96-well plate, with the rightmost column as a blank set of no cells. After 24h after plating, adding samples with different concentration gradients after the cells are in an adherent state, wherein each concentration is set to be a row of 6 multiple holes. After 48h, the wells were aspirated, and 20. mu.L of 5mg/mL MTT solution diluted in PBS was added to each well, which had been sterilized by filtration, while 100. mu.L DMEM was added to each well. After 4h of action, the MTT containing solution was aspirated, DMSO was added and the purple crystals were dissolved in DMSO by gentle shaking for 5 min. Using enzyme-linked immunosorbent assayThe absorbance A of each well was measured at a wavelength of 490nm490And calculating the growth inhibition rate of the sample on the tumor cells. The inhibition rate was calculated using the following formula: growth inhibition rate of cells (control group a)490Sample set A490) /(control group A)490Blank group A490) X 100%, and IC of target compound on different tumor cells50Values were calculated using SPSS statistical software.
The results are shown in Table 1 and FIGS. 2-6.
TABLE 1 IC of Compounds of formula (I-1) on different tumor cells50Value of
Figure GDA0002992613130000051
Example 2
Preparation of Compound represented by the formula (I-2)
Figure GDA0002992613130000052
190.3(0.7mmol) of genistein, 15ml of methanol, 56. mu.L (0.7mmol) of 37% formaldehyde were added to a 50ml round bottom flask, stirred at 30 ℃ under reflux for 30min, 192mg (0.8mmol) of 1-boc piperazine was added to the round bottom flask, and stirred at 50 ℃ under reflux for 6 h. Then the reaction is stopped, and the reaction is filtered under reduced pressure and separated into solid and liquid. Collecting solid containing a small amount of 1-boc piperazine, formaldehyde, a small amount of genistein and products; the liquid contains genistein and 1-boc piperazine dissolved in methanol. The solid was washed 5 times with 7ml methanol each time to give 167.32mg of a white solid with 51.05% yield.
The product was characterized:
detecting the obtained white solid by nuclear magnetic resonance to obtain1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),8.35(s,1H),7.34(d,J＝7.33Hz,2H),6.78(d,J＝6.77Hz,2H),6.22(s,1H),3.69(s,2H),3.28(s,4H),2.41(t,J＝2.40Hz,4H),1.35(s,9H).
Detecting the obtained white solid by a mass spectrometer to obtain ESI-MS m/z[M+H]+＝469.1330。
Detecting the obtained white solid by using a melting point instrument to obtain the melting point of 320-322 ℃.
The compound shown in the formula (I-2) of the invention synthesized above is tested by MTT research method to evaluate the inhibition rate and IC of the target compound for inhibiting the growth of different tumor cells50The value is obtained.
The cell culture adopted in the experiment is carried out at 37 ℃ and 5% CO2The culture is carried out in the environment of a sterile incubator, and the culture medium adopts DMEM culture medium containing 10% FBS.
Target compound concentration setting: the target compound of the present invention was formulated into test samples having a concentration gradient of 5. mu. mol/L, 10. mu. mol/L, 20. mu. mol/L, 30. mu. mol/L, 40. mu. mol/L, 50. mu. mol/L, 60. mu. mol/L, or 80. mu. mol/L. The medium served as a blank, i.e.the compound concentration was 0.
MTT method experimental process: taking an A549 cell line as an example, the cells recover from liquid ammonia, and after 3 passages, the cells are in a normal adherent growth state. 100 μ LPBS was added to the outermost round of wells of the 96-well plate, and cells were seeded at 6000 cells/well in the remaining wells of the 96-well plate, with the rightmost column as a blank set of no cells. After 24h after plating, adding samples with different concentration gradients after the cells are in an adherent state, wherein each concentration is set to be a row of 6 multiple holes. After 48h, the wells were aspirated, and 20. mu.L of 5mg/mL MTT solution diluted in PBS was added to each well, which had been sterilized by filtration, while 100. mu.L DMEM was added to each well. After 4h of action, the MTT containing solution was aspirated, DMSO was added and the purple crystals were dissolved in DMSO by gentle shaking for 5 min. The absorbance A of each well was measured at a wavelength of 490nm using a microplate reader490And calculating the growth inhibition rate of the sample on the tumor cells. The inhibition rate was calculated using the following formula: growth inhibition rate of cells (control group a)490Sample set A490) /(control group A)490Blank group A490) X 100%, and IC of target compound on different tumor cells50Values were calculated using SPSS statistical software.
The results are shown in Table 2 and FIGS. 2 to 6
TABLE 2 IC of Compounds of formula (I-2) on different tumor cells50Value of
Figure GDA0002992613130000061
Example 3
Preparation of Compound represented by the formula (I-3)
Figure GDA0002992613130000062
809.9(3mmol) genistein, 60ml methanol and 240. mu.L (3mmol) of 37% formaldehyde are added into a 100ml round-bottom flask, stirred and refluxed for 30min at 30 ℃, then 500. mu.L (3.6mmol) of N- (2-hydroxyethyl) piperazine is added into the round-bottom flask, stirred and refluxed for 5h at 35 ℃ and reacted for 8h at normal temperature. Then the reaction is stopped, and the reaction is filtered under reduced pressure and separated into solid and liquid. Collecting solid containing a small amount of N- (2-hydroxyethyl) piperazine, formaldehyde and a small amount of genistein and products; the liquid contains genistein and N- (2-hydroxyethyl) piperazine dissolved in methanol. The solid was washed 10 times with 7ml methanol each time to give 829.7mg of a white solid in 67.13% yield.
The intermediate products were tested:
detecting the obtained white solid by nuclear magnetic resonance to obtain1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.37(d,J＝7.37Hz,2H),6.82(d,J＝6.81Hz,2H),6.19(s,1H),3.82(s,2H),6.42(t,J＝6.16Hz,2H),2.56(s,4H),2.49(s,2H),2.40(t,J＝2.36Hz,4H).
Detecting the obtained white solid by a mass spectrometer to obtain ESI-MS M/z [ M + H ]]+＝413.1751。
Detecting the obtained white solid by using a melting point instrument to obtain a melting point of 94-96 ℃.
The compound shown in formula (I-3) of the invention synthesized above is tested by MTT research method to evaluate the inhibition rate and IC of the target compound for inhibiting the growth of different tumor cells50The value is obtained.
The cell culture adopted in the experiment is carried out at 37 ℃ and 5% CO2The culture is carried out in the environment of a sterile incubator, and the culture medium adopts DMEM culture medium containing 10% FBS.
Target compound concentration setting: the target compound of the present invention was formulated into test samples having a concentration gradient of 5. mu. mol/L, 10. mu. mol/L, 20. mu. mol/L, 30. mu. mol/L, 40. mu. mol/L, 50. mu. mol/L, 60. mu. mol/L, or 80. mu. mol/L. The medium served as a blank, i.e.the compound concentration was 0.
MTT method experimental process: taking an A549 cell line as an example, the cells recover from liquid ammonia, and after 3 passages, the cells are in a normal adherent growth state. 100 μ LPBS was added to the outermost round of wells of the 96-well plate, and cells were seeded at 6000 cells/well in the remaining wells of the 96-well plate, with the rightmost column as a blank set of no cells. After 24h after plating, adding samples with different concentration gradients after the cells are in an adherent state, wherein each concentration is set to be a row of 6 multiple holes. After 48h, the wells were aspirated, and 20. mu.L of 5mg/mL MTT solution diluted in PBS was added to each well, which had been sterilized by filtration, while 100. mu.L DMEM was added to each well. After 4h of action, the MTT containing solution was aspirated, DMSO was added and the purple crystals were dissolved in DMSO by gentle shaking for 5 min. The absorbance A of each well was measured at a wavelength of 490nm using a microplate reader490And calculating the growth inhibition rate of the sample on the tumor cells. The inhibition rate was calculated using the following formula: growth inhibition rate of cells (control group a)490Sample set A490) /(control group A)490Blank group A490) X 100%, and IC of target compound on different tumor cells50Values were calculated using SPSS statistical software.
The results are shown in Table 3 and FIGS. 2 to 6
TABLE 3 IC of Compounds of formula (I-3) on different cells50Value of
Figure GDA0002992613130000071
Example 4
Preparation of Compound represented by the formula (I-4)
Figure GDA0002992613130000072
809.9g (3mmol) of genistein, 60ml of methanol and 240. mu.L (3mmol) of 37% formaldehyde are added into a 100ml round-bottom flask, stirred and refluxed for 30min at 30 ℃, 583.4mg (3.6mmol) of 1- (4-pyridyl) piperazine is added into the round-bottom flask, stirred and refluxed for 8h at 35 ℃, and reacted for 8h at normal temperature. Then the reaction is stopped, and the reaction is filtered under reduced pressure and separated into solid and liquid. Collecting solid containing a small amount of 1- (4-pyridyl) piperazine, formaldehyde and a small amount of genistein and products; the liquid contains genistein and 1- (4-pyridyl) piperazine dissolved in methanol. The solid was washed 6 times with 10ml methanol each time to give 1022.8mg of a white solid with a yield of 76.61%.
The product was characterized:
detecting the obtained white solid by nuclear magnetic resonance to obtain1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.16(d,J＝8.15Hz,2H),7.39(d,J＝7.38Hz,2H),6.83(m,4H),6.28(s,1H),3.79(s,2H),3.30(s,4H),2.61(s,4H).
Detecting the obtained white solid by a mass spectrometer to obtain ESI-MS M/z [ M + H ]]+＝446.1751。
Detecting the obtained white solid by using a melting point instrument to obtain a melting point of 362-365 ℃.
The compound shown in the formula (I-4) of the invention synthesized above is tested by MTT research method to evaluate the inhibition rate and IC of the target compound for inhibiting the growth of different tumor cells50The value is obtained.
The cell culture adopted in the experiment is carried out at 37 ℃ and 5% CO2The culture is carried out in the environment of a sterile incubator, and the culture medium adopts DMEM culture medium containing 10% FBS.
Target compound concentration setting: the target compound of the present invention was formulated into test samples having a concentration gradient of 5. mu. mol/L, 10. mu. mol/L, 20. mu. mol/L, 30. mu. mol/L, 40. mu. mol/L, 50. mu. mol/L, 60. mu. mol/L, or 80. mu. mol/L. The medium served as a blank, i.e.the compound concentration was 0.
MTT method experimental process: taking an A549 cell line as an example, the cells recover from liquid ammonia, and after 3 passages, the cells are in a normal adherent growth state. 100 μ LPBS was added to the outermost round of wells of the 96-well plate, and cells were seeded at 6000 cells/well in the remaining wells of the 96-well plate, with the rightmost column as a blank set of no cells. After 24h after plating, adding samples with different concentration gradients after the cells are in an adherent state, wherein each concentration is set to be a row of 6 multiple holes. After 48h, the wells were aspirated, and 20. mu.L of 5mg/mL MTT solution diluted in PBS was added to each well, which had been sterilized by filtration, while 100. mu.L DMEM was added to each well. After 4h of action, the MTT containing solution was aspirated, DMSO was added and the purple crystals were dissolved in DMSO by gentle shaking for 5 min. The absorbance A of each well was measured at a wavelength of 490nm using a microplate reader490And calculating the growth inhibition rate of the sample on the tumor cells. The inhibition rate was calculated using the following formula: growth inhibition rate of cells (control group a)490Sample set A490) /(control group A)490Blank group A490) X 100%, and IC of target compound on different tumor cells50Values were calculated using SPSS statistical software.
The results are shown in Table 4 and FIGS. 2-6.
TABLE 4 IC of Compounds of formula (I-4) on different tumor cells50Value of
Figure GDA0002992613130000081
Table 5: IC of target compound and raw material on 5 kinds of tumor cells50The value:
Figure GDA0002992613130000082

Claims (3)

1. a piperazine-modified genistein derivative, which is characterized by being a compound represented by the general formula (I):
Figure FDA0002994229250000011
wherein R is pyridyl, acetyl and hydroxyethyl.
2. The piperazine-modified genistein derivative according to claim 1, wherein the structure is represented by formula (I-1) to formula (I-3)
Figure FDA0002994229250000012
Figure FDA0002994229250000021
3. Use of a piperazine-modified genistein derivative according to claim 1 or 2 for the preparation of a medicament for inhibiting the growth of cancer cells, characterized in that: the cancer cells are A549, Hela, and HepG2 cells.
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