[go: up one dir, main page]

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

Info

Publication number
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
Authority
CN
China
Prior art keywords
genistein
cells
mol
piperazine derivatives
piperazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910793375.0A
Other languages
Chinese (zh)
Other versions
CN110483465A (en
Inventor
延玺
于渼璇
宋静磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Normal University
Original Assignee
Beijing Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Normal University filed Critical Beijing Normal University
Priority to CN201910793375.0A priority Critical patent/CN110483465B/en
Publication of CN110483465A publication Critical patent/CN110483465A/en
Application granted granted Critical
Publication of CN110483465B publication Critical patent/CN110483465B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了一种染料木素衍生物，如式(I)所示，其中，R为吡啶基，醛基，羟乙基，叔丁氧羰基。与现有技术相比，本发明提供的染料木素衍生物对多种肿瘤细胞具有良好的生长抑制作用，尤其R为吡啶取代基时，对于A549细胞、Hela细胞、MCF‑7细胞、SH‑SY5Y细胞与HepG2细胞五类肿瘤细胞具有较高的抑制生长活性。

Figure 201910793375

The present invention provides a genistein derivative, as shown in formula (I), wherein, R is a pyridyl group, an aldehyde group, a hydroxyethyl group, and a tert-butoxycarbonyl group. Compared with the prior art, the genistein derivatives provided by the present invention have a good growth inhibitory effect on various tumor cells, especially when R is a pyridine substituent, for A549 cells, Hela cells, MCF-7 cells, SH- SY5Y cells and HepG2 cells have high growth inhibitory activity.

Figure 201910793375

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.
Drawings
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.
CN201910793375.0A 2019-08-27 2019-08-27 Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction Active CN110483465B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910793375.0A CN110483465B (en) 2019-08-27 2019-08-27 Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910793375.0A CN110483465B (en) 2019-08-27 2019-08-27 Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction

Publications (2)

Publication Number Publication Date
CN110483465A CN110483465A (en) 2019-11-22
CN110483465B true CN110483465B (en) 2021-05-07

Family

ID=68554348

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910793375.0A Active CN110483465B (en) 2019-08-27 2019-08-27 Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction

Country Status (1)

Country Link
CN (1) CN110483465B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113549044B (en) * 2021-07-23 2024-01-23 中国药科大学 8-azacyclo-substituted chromone derivative and preparation method and pharmaceutical application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102161647A (en) * 2011-03-07 2011-08-24 中国药科大学 Preparation method and applications of isoflavone type multidrug resistance reversal agent of cancer cell
CN107550911A (en) * 2017-08-17 2018-01-09 山东理工大学 A kind of method of the genistein derivative treatment canker sore containing phenylpiperazine
CN107602520A (en) * 2017-10-16 2018-01-19 厦门大学 A kind of quasi-isoflavone compound containing piperazine ring and its preparation method and application

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101066961A (en) * 2007-06-08 2007-11-07 浙江大学 Flavonoid derivatives and their preparation and use
CN104860993B (en) * 2015-05-22 2017-08-22 北京盛诺基医药科技有限公司 A kind of chromocor compound prodrug and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102161647A (en) * 2011-03-07 2011-08-24 中国药科大学 Preparation method and applications of isoflavone type multidrug resistance reversal agent of cancer cell
CN107550911A (en) * 2017-08-17 2018-01-09 山东理工大学 A kind of method of the genistein derivative treatment canker sore containing phenylpiperazine
CN107602520A (en) * 2017-10-16 2018-01-19 厦门大学 A kind of quasi-isoflavone compound containing piperazine ring and its preparation method and application

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Jian Xin 等.Design, synthesis, and biological evaluation of novel iso-flavones derivatives as H3R antagonists.《Journal of Enzyme Inhibition and Medicinal Chemistry》.2018,第33卷(第1期),第1545-1553页. *
刘娜 等.染料木素衍生物的合成及其生物活性研究.《食品与药品》.2016,第18卷(第4期),第235-238页. *
芦金荣等.具有选择性雌激素受体调节活性的大豆苷元衍生物的合成及生物活性研究.《有机化学》.2011,第31卷(第11期),第1852-1863页. *
芦金荣等.金雀异黄素衍生物的合成及潜在的雌激素受体调节活性.《中国药科大学学报》.2011,第42卷(第6期),第495-502页. *

Also Published As

Publication number Publication date
CN110483465A (en) 2019-11-22

Similar Documents

Publication Publication Date Title
CN108530343B (en) A kind of organic compound modified by rhein specific group, its aryl metal complex, its preparation method and application
CN105712932B (en) Preparation and application of a pyrazole oxime ether compound containing 1-methyl-3-aryl-4-chloropyrazole structure
CN110483465B (en) Synthesis method of genistein bridged piperazine derivatives and application of genistein bridged piperazine derivatives in anti-tumor direction
CN105130895B (en) A class of naphthalimide derivatives, their preparation method and application
CN108299398B (en) Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof
CN110606843B (en) Structure, preparation and application of bipyridyl ketone hydrazone-2-acetylpyrazine
CN107043345A (en) Preparation, structure and the purposes of the diketone Schiff base of 4-acetylbiphenyl hydrazone indoline 2,3
CN114057736B (en) Synthetic method of chrysin bridged indole derivatives and application of chrysin bridged indole derivatives in anti-tumor direction
CN108530436B (en) Pyrazole compound and preparation method and application thereof
CN109020883B (en) A kind of 3-cyano-2-aminopyridine derivative and its preparation method and application
CN110078706B (en) Imatinib derivative and preparation method and application thereof
CN110194741B (en) 4-benzoyl piperazine-3-nitro-1, 8-naphthalimide derivative and preparation method and application thereof
CN108276394B (en) Daidzein derivative, its preparation method and application
CN107382944B (en) Coumarin gossypol derivatives with anti-tumor activity and synthesis method thereof
US20170266648A1 (en) Iron and cobalt catalyzed hydrogen isotope labeling of organic compounds
CN107903244B (en) 2- amido with anti-tumor activity replaces Benzodiazepine compound and preparation method thereof
CN105130896B (en) A class of naphthalimide derivatives containing a thiourea substituent, its preparation method and application
CN113735840B (en) Hesperetin quinoline hydrazone derivative with anti-tumor activity and preparation method and application thereof
CN111518078B (en) A kind of pyrimidine compound containing aminopyridine and application thereof
CN110317171B (en) 4-Dithiocarboxylate piperazine-1,8-naphthalimide derivative and its preparation method and application
CN109160902B (en) Asymmetric bisquinazoline Schiff base derivative for treating tumors and preparation and medical application thereof
CN105218566A (en) A kind of Zn complex containing 5-bromosalicylaldehyde contracting 4-nitro o-aminophenol Schiff and pyridine and its preparation method and application
CN110194740A (en) 4-tert-butoxycarbonylpiperazine-1,8-naphthalimide derivative and its synthesis method and application
CN117185992A (en) Preparation method and application of benzamide derivative containing aryloxy bipyridine methyl thiourea unit
CN104370799B (en) A kind of 3 oxo diazanyl substituted indole ketones derivants and preparation method and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant