CN114014905A - PPAR gamma targeted glycyrrhetinic acid derivative and preparation method and application thereof - Google Patents
PPAR gamma targeted glycyrrhetinic acid derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a PPARgamma-targeted glycyrrhetinic acid derivative, a preparation method and application thereof, and relates to a PPARgamma agonist containing a PPARgamma skeleton. The structural formula of the PPARgamma-targeted glycyrrhetinic acid derivative is shown as a formula I. The glycyrrhetinic acid derivative containing the cinnamic acid structure has an obvious inhibiting effect on cancer cells, and the raw materials are cheap, simple and easily available, have few reaction steps, are suitable for industrial production, and are a medicine with great potential.
Description
Technical Field
The invention relates to a PPAR gamma agonist containing a glycyrrhetinic acid skeleton, in particular to a PPAR gamma targeted glycyrrhetinic acid derivative and a preparation method and application thereof.
Background
Glycyrrhetinic Acid (GA) is a pentacyclic triterpenoid compound extracted from the rhizome of traditional Chinese herbal medicine liquorice, and mainly takes 18-beta-Glycyrrhetinic Acid as the main component. Through continuous research, the glycyrrhetinic acid and the derivatives thereof have the effects of resisting inflammation, ulcer, virus, tumor, allergy, blood fat and insulin absorption. But the inhibition effect of glycyrrhetinic acid on tumors is very weak.
The application patent with the publication number of CN108558986B discloses a glycyrrhetinic acid derivative containing a piperazine structure, and a preparation method and application thereof, wherein the piperazine ring is introduced into the C3 position of glycyrrhetinic acid, so that various biological activities of glycyrrhetinic acid can be enhanced. Meanwhile, the phenyl piperazine substituent of the glycyrrhetinic acid derivative can be effectively combined with an active pocket restraining cavity formed by an H12 spiral of PPAR gamma, so that the function similar to that of a ship anchor is realized, and molecules are anchored on the PPAR gamma; the main body skeleton of the glycyrrhetinic acid is positioned near the opening of the constrained cavity, and a strong hydrogen bond can be formed to enhance the stability of the combination of the small molecules and the PPAR gamma; the carboxyl at the 30-position of glycyrrhetinic acid is replaced by methyl ester and can extend to the rear side of an H12 spiral restraint cavity of PPAR gamma, so that the affinity with PPAR gamma is further enhanced, and a good anti-tumor effect is achieved.
Application patent with publication number CN110551169A discloses glycyrrhetinic acid derivatives, and a preparation method and application thereof, wherein C3 position of glycyrrhetinic acid is connected with 5 '-hydroxyl of 5' -hydroxyflavone structure through an ethyl ester structure, so that various biological activities of glycyrrhetinic acid can be enhanced. The glycyrrhetinic acid derivative containing the flavone structure has obvious inhibition effect on cancer cells and is suitable for industrial production.
In recent years, the search for bioactive substances with antitumor effect from natural plants to prevent and treat cancers has become a hot spot of research at home and abroad. The finding that glycyrrhetinic acid and its derivatives can target peroxisome proliferator-activated receptor gamma (PPAR γ) opens a new way to combat cancer associated with poor prognosis, i.e. cancers that show various levels of resistance to pro-apoptotic stimuli. However, structural modification of glycyrrhetinic acid and derivatives thereof aiming at PPAR γ targets shows certain activity, but has disadvantages. The mechanism of action is not clear, and the toxicity of the derivative is not further improved. Particularly important is the lack of systematic structure-activity relationship research due to the limited number and structure. The main reason for this is that PPAR γ has a complex structure, and the site specificity of a tumor marker is not determined from the PPAR γ structure, so that it is impossible to design a molecule precisely. Therefore, the method takes the structure-defined part of the PPAR gamma as a target, clarifies the binding mode of the PPAR gamma and a small molecule inhibitor, improves the mutual recognition of specificity, and designs and synthesizes efficient glycyrrhetinic acid derivatives, which is a key research direction of the research.
Disclosure of Invention
The invention aims to combine the molecular structure of the glycyrrhetinic acid compound with calculation simulation and activity result data, and designs a novel PPAR gamma-targeted agonist by means of calculation software, so that the novel PPAR gamma-targeted agonist has an obvious inhibiting effect on cancer cells; the invention also provides a preparation method of the glycyrrhetinic acid derivative containing the cinnamic acid structure, and the provided method is scientific, reasonable, simple and feasible, has few reaction steps and high yield, and is suitable for industrial production.
The PPAR gamma agonist not only has obvious curative effect on the traditional metabolic diseases such as type II diabetes mellitus, but also has important effect on the inhibition of tumor cells and the treatment of cancer diseases. When the ligand activates PPAR gamma protein, it can inhibit the growth of tumor cells in liver, pancreas, biliary tract, oral cavity, lung, cervix, breast, ovary, esophagus, stomach, colon, rectum, etc.
The technical scheme of the invention is as follows:
the glycyrrhetinic acid derivative containing the cinnamic acid structure is designed according to the following concept: the PPAR gamma crystal structure is obtained from a Protein Data Bank (RSCB PDB) website, a representative PPAR gamma agonist is selected, classification and correction are carried out by using Discovery studio 4.5 software, and a training set database is established. And decomposing the small molecular agonists into fragments by using Schrodinger' Canvas, analyzing and calculating various parameters such as 3D pharmacophore fingerprints, surface polarization area ratio, torsional energy, electronic potential energy and the like, and screening out an active framework. And then carrying out simulated docking on the active skeleton and an active site in a PPAR gamma protein crystal compound, finally constructing a 3D-QSAR model for molecular simulation calculation and scoring, and finally screening out a potential PPAR gamma-based agonist, namely a PPAR gamma-targeted glycyrrhetinic acid derivative, by combining a bioelectronic isosteric theory, a similar synthesis method, a natural biological glycyrrhetinic acid and other pilot design methods, wherein the structural formula of the PPAR gamma-targeted glycyrrhetinic acid derivative is shown as a formula I:
wherein R is H atom or R is H atom mono-, di-, tri-, tetra-or penta-substituted, and R is selected from halogen, methyl, methoxy, nitro, halogen-substituted methyl and halogen-substituted methoxy. Wherein the halogen-substituted methyl and halogen-substituted methoxy groups comprise 1, 2,3 halogen substitutions, wherein halogen is chlorine, bromine, fluorine or iodine.
Preferably, R is mono-, di-or tri-substituted.
In the structural formula, R is 2-methyl, 3-methyl, 4-methyl, 2-nitro, 3-nitro, 4-nitro, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 3-bromo, 4-bromo, 2, 3-dimethoxy, 2, 4-dimethoxy, 2, 5-dimethoxy, 2, 6-dimethoxy, 3, 4-dimethoxy, 3, 5-dimethoxy, 3, 6-dimethoxy, 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 3, 4-dichloro, 3, 5-dichloro, 3, 6-dichloro, 2, 3-dibromo, 2-nitro, 3-nitro, 4-nitro, 2-bromo, 2, 3-dimethoxy, 3, 4-dimethoxy, 3, 5-dimethoxy, 3, 6-dimethoxy, 2, 6-dimethoxy, 3, 4-dichloro, 3, 5-dichloro, 3, 6-dichloro, 2, 3-dibromo, 2, 3-dichloro, or 2, 3-dichloro, 2, 4-dibromo, 2, 5-dibromo, 2, 6-dibromo, 3, 4-dibromo, 3, 5-dibromo, 3, 6-dibromo, 2, 3-difluoro, 2, 4-difluoro, 2, 5-difluoro, 2, 6-difluoro, 3, 4-difluoro, 3, 5-difluoro, 3, 6-difluoro, 2, 3-dimethyl, 2, 4-dimethyl, 2, 5-dimethyl, 2, 6-dimethyl, 3, 4-dimethyl, 3, 5-dimethyl, 3, 6-dimethyl, 2, 3-dinitro, 2, 4-dinitro, 2, 5-dinitro, 2, 6-dinitro, 3, 4-dinitro, 3, 5-dinitro, 3, 6-dinitro, 2,3, 4-trichloro, 2,3, 4-trifluoro, 2,3, 4-tribromo, 2,3, 4-trimethyl, 2,3, 4-trinitro, 2,3, 4-trimethoxy, 2-trifluoromethyl, 4-trifluoromethyl or 3-trifluoromethyl.
Preferably, in the structural formula, R is 2-methyl, 3-methyl, 4-methyl, 2-nitro, 3-nitro, 4-nitro, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 3-bromo, 4-bromo, 2,3, 4-trimethoxy, 2, 6-dichloro, 4-trifluoromethyl or 3-trifluoromethyl.
The glycyrrhetinic acid derivative is an agonist of PPAR gamma, and as shown in figure 1, O at the 11-position of glycyrrhetinic acid (circled by a dotted line in figure 1) forms a hydrogen bond with an important amino acid Tyr473 on PPAR gamma protein, and carbonyl O newly introduced at the 3-position (carbonyl O at the right side of the circled part of the dotted line in figure 1) forms a key hydrogen bond with His449 (figure 1 is a plan view, and His449 is close to the position of the newly introduced carbonyl O at the 3-position in an actual perspective view). More importantly, the cinnamic acid skeleton containing different substituents at the end of a 3-bit long chain forms a covalent bond with a key amino acid residue Lys457 involved in PPAR gamma agonistic activity, so that the enzyme activity is irreversibly inhibited, and the problem of drug resistance can be overcome.
The invention also provides a medicament containing the glycyrrhetinic acid derivative.
The glycyrrhetinic acid derivative containing the cinnamic acid structure has an obvious inhibiting effect on cancer cells, so that the glycyrrhetinic acid derivative containing the cinnamic acid structure can be used for preparing anti-cancer (such as liver cancer, breast cancer, cervical cancer and lung cancer) medicaments. The medicine also contains auxiliary materials which can be added in pharmacy, and is prepared into proper dosage forms.
The invention also provides application of the glycyrrhetinic acid derivative in preparing a medicament for treating diseases caused by the inhibition or activity reduction of PPAR gamma protein expression.
In particular, the disease is type II diabetes, or a tumor of a liver, pancreas, biliary tract, oral cavity, lung, cervix, breast, ovary, esophagus, stomach, colon or rectum.
The invention also provides a preparation method of the glycyrrhetinic acid derivative, which comprises the following steps:
(1) dissolving glycyrrhetinic acid in a solvent, and adding concentrated sulfuric acid or concentrated hydrochloric acid for reaction to obtain a product a;
(2) dissolving the product a in a solvent, and adding bromoacetyl bromide for reaction to obtain a product b;
(3) dissolving the product b and cinnamic acid with different substituents in an organic solvent, and adding a catalyst for reaction to prepare the glycyrrhetinic acid derivative;
wherein, in the step (1), the solvent is an alcohol solvent; in the step (2), the solvent is dichloromethane; in the step (3), the organic solvent is acetonitrile or ethanol, and in the cinnamic acid with different substituents, the substituent is the R group.
Preferably, the molar ratio of the product a to bromoacetyl bromide is 1: 1-2.
Preferably, in the step (3), the catalyst is potassium carbonate or triethylamine.
Preferably, the molar ratio of the product b to the cinnamic acid with different substituents is 1: 1-1.5.
Has the advantages that:
the glycyrrhetinic acid derivative containing the cinnamic acid structure has an obvious inhibiting effect on cancer cells, and the raw materials are cheap, simple and easily available, and few in reaction steps, so that the glycyrrhetinic acid derivative is suitable for industrial production and is a medicine with great potential.
Drawings
FIG. 1 is a site diagram of glycyrrhetinic acid derivatives.
FIG. 2 is the structural formula of Compound 1; wherein a represents the structural formula of a product a; b represents the structural formula of a product b; c represents the structural formula of the compound 1.
FIG. 3 is the structural formula of Compound 2.
FIG. 4 is the structural formula of Compound 3.
FIG. 5 is the structural formula of Compound 4.
FIG. 6 is the structural formula of Compound 5.
FIG. 7 is the structural formula of Compound 6.
FIG. 8 is the structural formula of Compound 7.
FIG. 9 is the structural formula of Compound 8.
FIG. 10 is the structural formula of Compound 9.
Fig. 11 is the structural formula of compound 10.
FIG. 12 is the structural formula of Compound 11.
FIG. 13 is the structural formula of Compound 12.
FIG. 14 is the structural formula of Compound 13.
FIG. 15 is the structural formula of Compound 14.
FIG. 16 is the structural formula of Compound 15.
FIG. 17 is the structural formula of Compound 16.
FIG. 18 is the structural formula of Compound 17.
FIG. 19 is the structural formula of Compound 18.
FIG. 20 is the structural formula of Compound 19.
Fig. 21 is the structural formula of compound 20.
Detailed Description
The glycyrrhetinic acid derivative containing the cinnamic acid structure is designed according to the following concept: the PPAR gamma crystal structure is obtained from a Protein Data Bank (RSCB PDB) website, a representative PPAR gamma agonist is selected, classification and correction are carried out by using Discovery studio 4.5 software, and a training set database is established. And decomposing the small molecular agonists into fragments by using Schrodinger' Canvas, analyzing and calculating various parameters such as 3D pharmacophore fingerprints, surface polarization area ratio, torsional energy, electronic potential energy and the like, and screening out an active framework. And then performing simulated docking on the active skeleton and the active site in the PPAR gamma protein crystal compound, finally constructing a 3D-QSAR model for molecular simulation calculation and scoring, and finally screening out the potential PPAR gamma-based agonist by combining a biological electron isostere theory, an analogous synthesis method, a natural biological glycyrrhetinic acid and other pilot design methods, wherein the action site of the PPAR gamma-based agonist is shown in figure 1.
Example 1
Preparation of compound 1.
(1) Dissolving 3g glycyrrhetinic acid in 100mL methanol, adding 1mL concentrated sulfuric acid, refluxing for 8 hr (reaction temperature is 75 deg.C), evaporating the reaction solution under reduced pressure, extracting with ethyl acetate and water (volume ratio of the two is 2:1), collecting organic layer, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressureDrying to obtain a crude product, and recrystallizing the crude product by using ethanol to obtain a pure product a. The product a is white powder, and the structural formula is shown in figure 2-a;1H NMR(400MHz,CDCl3)：δ5.67(s,1H)，3.70(s,3H)，3.23(m,1H)，2.80(dt,J＝13.6,4.5Hz,1H)，2.37(s,1H)，1.37(s,3H)，1.15(s,3H)，1.14(s,3H)，1.13(s,3H)，1.01(s,3H)，0.81(s,6H)。
(2) dissolving the product a (1 mmol) in dichloromethane (20 mL), adding bromoacetyl bromide (1.2 mmol), reacting in ice bath for 1.5 hr, evaporating the reaction solution under reduced pressure, and adding ethyl acetate and NaHCO3Extracting with saturated water solution (the volume ratio of the two is 2:1), collecting the organic layer, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure to dryness to obtain a crude product, and recrystallizing with acetone to obtain a pure product b. The product b is white powder, the melting point is 227.9-229.9 ℃, and the structural formula is shown in figure 2-b;1H NMR(400MHz,CDCl3)：δ5.70(s,1H)，5.60(s,1H)，4.61-4.58(m,2H)，3.71(s,6H)，2.86(d,j＝32.68Hz,1H)，2.38(s,1H)，2.30(S,1H)，2.03-2.00(m,3H)，1.95(d,j＝4.2HZ,4H)，1.68(s,1H)，1.63-1.59(m,4H)，1.39(s,4H)，1.36(s,2H)，1.25(d,j＝1.56Hz,4H)，0.94(s,10H)，0.83(d,j＝6.44Hz,4H)，0.73(s,2H)。
(3) dissolving 1mmol of the product b and 1mmol of p-methyl cinnamic acid in acetonitrile, adding 1.5mmol of potassium carbonate, refluxing for 6 hours (reaction temperature is 82 ℃), filtering to remove the potassium carbonate after the reaction is finished, then evaporating the reaction liquid under reduced pressure to dryness, and recrystallizing the obtained crude product with acetone to obtain a compound 1, wherein the chemical structural formula of the compound is shown in figure 2-c, and the melting point of the product is 157.4-160.1 ℃.1H NMR(400MHz,CDCl3)：δ7.79(s,1H)，7.75(s,1H)，7.47(s,1H)，7.45(s,2H)，7.23(s,2H)，7.21(s,1H)，6.51(s,1H)，6.47(s,1H)，5.68(s,1H)，4.76(d,J＝1.84Hz,2H)，3.71(d,J＝3.12Hz,6H)，2.40(s,4H)，1.63(s,1H)，1.38(s,3H)，1.16(d,J＝1.24Hz,8H)，1.13(s,4H)，0.92(s,6H)，0.87(d,J＝6.8Hz,6H)，0.81(s,6H)，0.72(s,1H)。
Example 2
Preparation of compound 2.
The preparation method is the same as that of the example 1,in the step (3), m-methyl cinnamic acid is used to replace p-methyl cinnamic acid to obtain a compound 2, and the structural formula of the compound is shown in figure 3. The melting point of the material is 208.5-213.1 ℃,1H NMR(400MHz,CDCl3)：δ7.78(s,1H)，7.74(s,1H)，7.35(d,J＝6.04Hz,3H)，7.23(s,1H)，6.55(s,1H)，6.50(s,1H)，5.67(s,1H)，4.74(d,J＝2.52Hz,3H)，4.65(t,J＝6.88Hz,1H)，3.69(d,J＝3.2Hz,4H)，2.85(d,J＝3.68Hz,1H)，2.82(t,J＝6.76Hz,1H)，2.38(s,1H)，1.37(s,1H)，1.16(d,J＝1.68Hz,8H)，1.13(s,1H)，0.91(s,1H)，0.87(s,1H)，0.80(d,J＝4.88Hz,6H)，0.71(s,1H)。
example 3
Preparation of compound 3.
The preparation method is the same as example 1, and in the step (3), p-chlorocinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 3, and the structural formula of the compound is shown in figure 4. The melting point is 155.3-157.9 ℃,1H NMR(400MHz,CDCl3)：δ7.75(s,1H)，7.72(s,1H)，7.49(s,1H)，7.47(s,1H)，7.39(s,1H)，7.37(s,1H)，6.53(s,1H)，6.49(s,1H)，5.68(s,1H)，4.75(d,J＝0.88Hz,3H)，3.70(d,J＝3.32Hz,4H)，2.37(s,1H)，1.38(s,1H)，1.23(d,J＝3.28Hz,3H)，1.16(d,J＝2.08Hz,8H)，1.13(s,4H)，0.92(s,6H)，0.87(t,J＝9.68Hz,6H)，0.81(t，J＝11.56Hz,6H)，0.72(s,1H)。
example 4
Preparation of compound 4.
The preparation method is the same as example 1, and in the step (3), p-fluoro cinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 4, and the structural formula of the compound is shown in figure 5. The melting point of the material is 159.3-163.9 ℃,1H NMR(400MHz,CDCl3)：δ7.75(d,J＝16.04Hz,1H)，7.56-7.53(m,2H)，7.12-7.08(m,2H)，6.46(d,J＝16.04Hz,1H)，5.68(s,1H)，4.75(d,J＝0.96Hz,2H)，4.67(d,J＝2.72Hz,1H)，3.70(d,J＝3.24Hz,4H)，2.37(s,1H)，1.72-1.59(m,7H)，1.44(s,1H)，1.37(s,4H)，1.31(s,1H)，1.23(d,J＝3.2Hz,2H)，1.15(dd,J＝2.08,3.16Hz,10H)，0.92-0.80(m,14H)，0.72(s,1H)。
example 5
Preparation of compound 5.
The preparation method is the same as that of the traditional Chinese medicineExample 1, in step (3), o-chlorocinnamic acid was used instead of p-methyl cinnamic acid to give compound 5, whose chemical formula is shown in fig. 6. The melting point of the material is 167.5-169.5 ℃,1H NMR(400MHz,CDCl3)：δ7.65(dd,J＝1.76,1.76Hz,1H)，7.30(dd,J＝1.92,7.32Hz,2H)，6.53(d,J＝16Hz,1H)，5.67(s,1H)，4.77(s,2H)，3.70(s,4H)，2.84(d,J＝13.68Hz,1H)，2.37(s,1H)，2.11-1.91(m,5H)，1.73-1.58(m,6H)，1.35(dd,J＝8.84,1.92Hz,4H)，1.15(t,J＝14.52Hz,11H)，0.92-0.81(m,13H)，0.72(s,1H)。
example 6
Preparation of compound 6.
The preparation method is the same as example 1, and in the step (3), o-methyl cinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 6, and the structural formula of the compound is shown in figure 7. Melting point: 184.2-188.3 ℃ of the total weight,1H NMR(400MHz,CDCl3)：δ7.58(d,J＝7.76Hz,1H)，7.22(d,J＝7.6Hz,2H)，6.46(d,J＝15.88Hz,1H)，5.68(s,1H)，4.75(d,J＝2.32Hz,2H)，3.70(d,J＝3.28Hz,4H)，2.84(d,J＝13.68Hz,1H)，2.45(s,4H)，2.37(s,1H)，2.07-1.95(m,4H)，1.71-1.59(m,6H)，1.37(d,J＝8.88Hz,5H)，1.18-1.13(m,11H)，0.92-0.81(m,14H)，0.72(s,1H)。
example 7
Preparation of compound 7.
The preparation method is the same as example 1, in step (3), 3,4, 5-trimethoxy cinnamic acid is used to replace p-methyl cinnamic acid, and compound 8 is obtained, and the chemical formula is shown in figure 7. The melting point of the material is 190.2-192.1 ℃,1H NMR(400MHz,CDCl3)：δ7.70(d,J＝15.88Hz,1H)，6.78(s,2H)，645(d,J＝15.92Hz,1H)，5.67(s,1H)，4.75(d,J＝2.04Hz,2H)，3.89(t,J＝4.76Hz,12H)，3.69(s,4H)，2.36(s,1H)，2.18(s,2H)，2.04-1.99(m,2H)，1.71-1.68(m,6H)，1.37(s,4H)，1.15(dd,J＝2.8,3.0Hz,10H)，0.91-0.81(m,13H)，0.72(s,1H)。
example 8
Preparation of compound 8.
The preparation method is the same as example 1, and in the step (3), p-bromocinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 8, and the structural formula of the compound is shown in figure 9. Its melting point is 193.0-196.3℃，1H NMR(400MHz,CDCl3)：δ7.72(d,J＝16.04Hz,1H)，7.54(d,J＝8.44Hz,2H)，7.41(d,J＝8.52Hz,2H)，6.53(d,J＝16Hz,1H)，5.68(s,1H)，4.75(s,2H)，3.70(d,J＝3.16Hz,4H)，2.84(d,J＝13.72Hz,1H)，2.37(s,1H)，2.19(s,1H)，2.04-1.99(m,2H)，1.71-1.58(m,6H)，1.37(d,J＝8.84Hz,4H)，1.15(dd,J＝1.56,3.04Hz,10H)，0.91-0.81(m,13H)，0.73(s,1H)，0.08(d,J＝3.48Hz,2H)。
Example 9
Preparation of compound 9.
The preparation method is the same as example 1, and in the step (3), o-fluoro cinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 9, and the structural formula of the compound is shown in figure 10. The melting point is 185.1-187.0 ℃,1H NMR(400MHz,CDCl3)：δ7.95(s,1H)，7.91(s,1H)，7.58(t,j＝8.00HZ,1H)，7.41-7.39(m,1H)，7.71(d,J＝8.36HZ,2H)，6.67(s,1H)，6.64(s,1H)，6.64(s,1H)，5.69(s,1H)，4.77(s,3H)，4.67-4.64(m,2H)，3.70(s,6H)，2.85(d,J＝13.72HZ,1H)，2.38(s,2H)，1.61(s,2H)，1.41-1.36(m,4H)，1.14(s,4H)，0.93(s,4H)，0.89(s,4H)，0.82(s,4H)，0.82(d,J＝7.64HZ,4H)。
example 10
Preparation of compound 10.
The preparation method is the same as example 1, and m-fluoro cinnamic acid is used for replacing p-methyl cinnamic acid in the step (3) to obtain a compound 10, and the structural formula of the compound is shown in figure 11. The melting point is 186.6-191.2 ℃,1H NMR(400MHz,CDCl3)：δ7.77(s,1H)，7.73(s,1H)，7.39-7.37(m,1H)，7.33(d,J＝5.4Hz,2H)，7.12(d,J＝1.6Hz,1H)，6.56(s,1H)，6.52(s,1H)，5.69(s,1H)，4.76(s,3H)，4.67-4.62(m,2H)，3.71(s,6H)，2.85(d,J＝13.72Hz,1H)，2.38(s,1H)，1.63(s,3H)，1.38-1.33(m,4H)，1.17(d,J＝2.8Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.89(s,4H)，0.82(d,J＝7.28Hz,4H)。
example 11
Preparation of compound 11.
The preparation method is the same as example 1, in the step (3), 2, 6-dichlorocinnamic acid is used to replace p-methyl cinnamic acid to obtain compound 11, the structural formula of which is shown in figure 12Shown in the figure. The melting point is 218.3-221.3 ℃,1H NMR(400MHz,CDCl3)：δ7.93(s,1H)，7.88(s,1H)，7.40(s,1H)，7.38(s,1H)，7.22(t,d＝16.12Hz,2H)，6.74(s,1H)，6.69(s,1H)，5.69(s,1H)，4.83-4.74(m,3H)，4.66-4.64(m,2H)，3.72(s,6H)，2.85(d,J＝13.72Hz,1H)，2.39(s,1H)，1.63-1.61(m,2H)，1.39(s,4H)，1.18(d,J＝3.6Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.89(s,4H)，0.82(d,J＝6.76Hz,2H)。
example 12
Preparation of compound 12.
The preparation method is the same as example 1, and in the step (3), p-nitrocinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 12, and the structural formula of the compound is shown in figure 13. The melting point of the material is 218.4-222.8 ℃,1H NMR(400MHz,CDCl3)：δ8.29(d,J＝8.76Hz,2H)，7.84(s,1H)，7.81(s,1H)，7.71(d,J＝8.76Hz,2H)，6.69(s,1H)，6.65(s,1H)，5.70(s,2H)，4,79(s,3H)，4.69-4.65(m,2H)，3.71(s,6H)，2.85(d,J＝13.76Hz,1H)，2.38(s,1H)，1.63-1,56(m,2H)，1.38(s,4H)，1.17(d,J＝3.64Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.89(s,4H)，0.82(d＝8.32Hz,4H)。
example 13
Preparation of compound 13.
The preparation method is the same as example 1, in the step (3), o-nitrocinnamic acid is used for replacing p-methyl cinnamic acid, and a compound 13 is obtained, and the structural formula of the compound is shown in figure 14.1H NMR(400MHz,CDCl3)：δ8.29(s,1H)，8.23(s,1H)，8.09(d,J＝7.88Hz,2H)，7.69-7.67(m,2H)，6.49(s,1H)，6.45(s,1H)，5.69(s,1H)，4.79(s,3H)，4.68-4.64(m,2H)，3.71(s,6H)，2.85(d,J＝13.72Hz,1H)，2.38(s,2H)，1.63(s,2H)，1.39(s,4H)，1.17(d,J＝4.48Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.89(s,4H)，0.83(d,J＝7.76Hz,4H)。
Example 14
Preparation of compound 14.
The preparation method is the same as example 1, and in the step (3), 4-trifluoromethyl cinnamic acid is used for replacing p-methyl cinnamic acid, so that a compound 14 is obtained, and the structural formula of the compound is shown in figure 15. The melting point of the material is 192.4-194.6 ℃,1H NMR(400MHz,CDCl3)：δ7.83(s,1H)，7.79(s,1H)，7.68(d,J＝9.20Hz,5H)，6.65(s,1H)，6.60(s,1H)，5.69(s,1H)，4.78(s,3H)，4.69-4.65(m,2H)，3.72(s,4H)，2.38(d,J＝13.76Hz,1H)，1.59(s,1H)，1.38(s,3H)，1.18(d,J＝3.2Hz,10H)，1.14(s,4H)，0.94(s,4H)，0.89(s,4H)，0.82(d,J＝7.96Hz,4H)。
example 15
Preparation of compound 15.
The preparation method is the same as example 1, and in the step (3), m-bromocinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 15, and the structural formula of the compound is shown in figure 16. The melting point is 186.1-188.5 ℃,1H NMR(400MHz,CDCl3)：δ7.73(s,1H)，7.70(d,J＝1.68Hz,1H)，7.54(d,J＝0.88Hz,1H)，7.48(d,J＝7.80Hz,1H)，6.55(s,1H)，6.52(s,1H)，5.68(s,1H)，4.76(s,3H)，4.68-4.64(m,2H)，3.70(s,6H)，2.85(d,J＝13.68Hz,1H)，2.38(s,2H)，2.06(s,1H)，1.64(s,2H)，1.38(s,4H)，1.17(d,J＝2.56Hz,10H)，1.14(s,4H)，0.92(s,4H)，0.88(s,4H)，0.82(d,J＝7.08Hz,4H)。
example 16
Preparation of compound 16.
The preparation method is the same as example 1, and in the step (3), p-methoxycinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 16, and the structural formula of the compound is shown in figure 17. The melting point of the material is 132.0-134.4 ℃,1H NMR(400MHz,CDCl3)：δ7.78(s,1H)，7.74(s,1H)，7.52(d,J＝8.76Hz,2H)，6.93(d,J＝5.36Hz,2H)，6.43(s,1H)，6.40(s,1H)，5.69(s,1H)，5.59(s,1H)，4.75(s,3H)，4.67-4.63(m,2H)，3.87(s,4H)，3.71(s,6H)，2.74(d,J＝13.56Hz,1H)，2.38(s,1H)，2.29(s,1H)，1.68(s,2H)，1.37(s,4H)，1.24(d,J＝3.60Hz,10H)，1.16(s,4H)，0.93(s,4H)，0.88(s,4H)，0.83(d,J＝4.64Hz,4H)，0.73(s,1H)。
example 17
Preparation of compound 17.
The preparation method is the same as example 1, and in the step (3), m-chlorocinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 17, and the chemical formula of the compound is shown in figure 18. The melting point of the material is 197.5-201.7 ℃,1H NMR(400MHz,CDCl3)：δ7.75(s,1H)，7.70(s,1H)，7.54(s,2H)，7.42(s,1H)，7.38(s,1H)，6.58(s,1H)，6.52(s,1H)，5.69(s,1H)，4.76(s,3H)，4.68-4.64(m,2H)，4.15(s,1H)，3.72(s,6H)，3.51(s,1H)，2.85(d,J＝13.68Hz,1H)，2.38(s,2H)，2.06(s,2H)，1.62-1.59(m,2H)，1.38(s,4H)，1.17(d,J＝2.72Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.88(s,4H)，0.82(d,J＝7.36Hz,4H)。
example 18
Preparation of compound 18.
The preparation method is the same as example 1, and in the step (3), cinnamic acid is used for replacing p-methyl cinnamic acid to obtain a compound 18, and the chemical structural formula of the compound is shown in figure 19. The melting point of the material is 195.1-196.8 ℃,1H NMR(400MHz,CDCl3)：δ7.82(s,1H)，7.78(s,1H)，7357-7.55(m,2H)，7.42(t,J＝6.40Hz,3H)，6.57(s,1H)，6.53(s,1H)，5.68(s,2H)，4.76(s,3H)，4.68-4.64(m,2H)，3.70(s,6H)，2.84(d,J＝13.72Hz,1H)，2.38(s,1H)，2.06(s,2H)，1.62(s,2H)，1.38(s,4H)，1.17(d,J＝2.40Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.88(s,4H)，0.82(d,J＝7.76Hz,4H)，0.72(s,1H)。
example 19
Preparation of compound 19.
The preparation method is the same as example 1, in the step (3), m-nitrocinnamic acid is used for replacing p-methyl cinnamic acid, and a compound 19 is obtained, and the structural formula of the compound is shown in figure 20. The melting point of the material is 262.6-266.5 ℃,1H NMR(400MHz,CDCl3)：δ8.41(d,J＝18.68Hz,2H)，8.27(s,1H)，7.87(d,J＝7.96Hz,2H)，6.69(s,1H)，6.65(s,1H)，5.69(s,1H)，4.78(s,3H)，4.68-4.65(m,2H)，4.14(s,1H)，3.70(s,6H)，2.85(d,J＝13.74Hz,1H)，2.38(s,1H)，2.06(s,1H)，1.63(s,2H)，1.37(s,4H)，1.17(d,J＝3.32Hz,10H)，1.14(s,4H)，0.92(s,4H)，0.88(s,4H)，0.81(d,J＝3.92Hz,4H)。
example 20
Preparation of compound 20.
The preparation method is the same as example 1, in the step (3), the p-methyl cinnamic acid is replaced by the 3-trifluoromethyl cinnamic acid, and the compound 20 is obtained, and the structural formula of the compound is shown in figure 21. The melting point is 197.8-199.6 ℃,1H NMR(400MHz,CDCl3)：δ7.83(s,1H)，7.80(d,J＝3.60Hz,2H)，7.74(d,J＝7.84Hz,2H)，7.67(d,J＝7.80Hz,2H)，7.56(t,J＝15.52Hz,2H)，6.64(s,1H)，6.60(s,1H)，5.69(s,1H)，4.78(s,3H)，4.67-4.65(m,2H)，3.71(s,6H)，3.50(s,1H)，2.85(d,J＝13.72Hz,1H)，2.38(s,1H)，2.06(s,1H)，1.67(s,2H)，1.38(s,4H)，1.17(d,J＝3.20Hz,10H)，1.14(s,4H)，0.93(s,4H)，0.88(s,4H)，0.82(d,J＝4.08Hz,4H)，0.73(s,1H)。
example 21
Examples 1 to 20 examination of anticancer activity of glycyrrhetinic acid derivatives containing cinnamic acid structures.
(1) Experimental Material
Cell line
Human hepatoma cell line HepG 2; human breast cancer cell line MCF-7; human cervical cancer cell line Hela; human lung cancer cell strain A549.
(2) Reagent
DMEM medium (GIBCO), newborn bovine serum (hangzhou ilex bioengineering material), trypsin (Sigma), 10000 units of diabody (GIBCO USA), PBS buffer (shanghai yuan culture biotechnology limited). Other common chemical reagents are all domestic analytical purifiers.
(3) Experimental methods
1) Preparation of culture Medium
90mL of DMEM medium (Gibcio USA) is added with 10mL of inactivated newborn bovine serum (Hangzhou Chinese holly bioengineering material) and 1mL of 10000 units of double antibody (Gibco USA) to obtain a complete culture solution, and the complete culture solution is marked and stored at 4 ℃ for later use. Trypsin is prepared into 0.25% solution by PBS buffer solution, and the solution is stored at 4 ℃ for standby after filtration and sterilization.
2) Preparation of medicinal liquid
Accurately weighing 1.0mg of the sample to be detected. The mixture was put into a sterilized 1.5mL centrifuge tube, and 1mL of DMSO was added to prepare a stock solution of 1mg/mL, which was then stored at-40 ℃ under refrigeration. The composition is thawed before use and diluted into corresponding concentration by using a proper amount of PBS flushing liquid for application.
3) Cell culture and passage
Culturing the cell strain in a cell culture bottle containing 10mL of complete culture solution in an adherent manner at 37 ℃ and 5% CO2And culturing under saturated humidity. After the cells overgrow the bottom of the bottle, washing twice with sterilized PBS buffer, adding 0.25% trypsin to digest the cells for 1min, pouring off the trypsin, after the cells can completely shed by shaking lightly, adding 30mL of complete culture solution, blowing off the cells with a pipette, subpackaging in 3 new cell culture bottles, and continuing to culture.
4) Test for anticancer Activity
Collecting the cells which just grow into a complete monolayer in one bottle, collecting the cells after trypsinization, uniformly blowing and beating the cells by using a pipette, taking two drops of cell suspension Trypan Blue (Trypan Blue) for dyeing, and counting the number of living cells to 1 multiplied by 10 under a microscope4Individual cells/mL. Add 90. mu.L of cell suspension to each well of a 96-well plate, and place the plate in CO2Culturing in incubator for 24h, taking out culture plate, adding 10 μ L solution containing samples to be tested with different concentrations into each well to make final concentration of drug be 50, 25, 12.5, 6.25, 3.125 μ M, setting 3 parallel wells for each concentration, and setting 6 wells as normal control well and positive control well. Adding the medicine, vibrating the culture plate on a microplate oscillator, mixing, and placing in CO2The incubator continues to culture for 24 h. The plate was removed, 10. mu.L of 5mg/mL MTT solution was added to each well, shaken and mixed, and the culture was continued for 4 hours. Add 150. mu.L DMSO per well and shake for 15 min. The microplate reader measures the light absorption (OD value) of each well, and the measurement wavelength is 490 nm. Calculating the inhibition rate of the drug on the proliferation of four tumor cells, namely IC according to the OD value of each well50The values, experimental results are shown in table 1.
TABLE 1
Table 1 shows that the glycyrrhetinic acid derivatives prepared in examples 1-20 all have significant effects on inhibition of four cell proliferation strains, and have broad anticancer application prospects.
Claims (10)
1. A PPAR gamma-targeting glycyrrhetinic acid derivative has a structural formula shown in formula I:
wherein R is H atom or R is H atom mono-, di-, tri-, tetra-or penta-substituted, and R is selected from halogen, methyl, methoxy, nitro, halogen-substituted methyl and halogen-substituted methoxy.
2. The glycyrrhetinic acid derivative according to claim 1, wherein R is mono-, di-or tri-substituted.
3. The glycyrrhetinic acid derivative of claim 2 wherein R is 2-methyl, 3-methyl, 4-methyl, 2-nitro, 3-nitro, 4-nitro, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 3-bromo, 4-bromo, 2, 3-dimethoxy, 2, 4-dimethoxy, 2, 5-dimethoxy, 2, 6-dimethoxy, 3, 4-dimethoxy, 3, 5-dimethoxy, 3, 6-dimethoxy, 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 3, 4-dichloro, 3, 5-dichloro, 3, 6-dichloro, 3-dichloro, 4-dichloro, 2, 5-dichloro, 2-dichloro, 3, 4-dichloro, 3, 5-dichloro, or, 3, 6-dichloro, 2, 3-dibromo, 2, 4-dibromo, 2, 5-dibromo, 2, 6-dibromo, 3, 4-dibromo, 3, 5-dibromo, 3, 6-dibromo, 2, 3-difluoro, 2, 4-difluoro, 2, 5-difluoro, 2, 6-difluoro, 3, 4-difluoro, 3, 5-difluoro, 3, 6-difluoro, 2, 3-dimethyl, 2, 4-dimethyl, 2, 5-dimethyl, 2, 6-dimethyl, 3, 4-dimethyl, 3, 5-dimethyl, 3, 6-dimethyl, 2, 3-dinitro, 2, 4-dinitro, 2, 5-dinitro, 2, 6-dinitro, 3, 4-dinitro, 3, 5-dinitro, 3, 6-dinitro, 2,3, 4-trichloro, 2,3, 4-trifluoro, 2,3, 4-tribromo, 2,3, 4-trimethyl, 2,3, 4-trinitro, 2,3, 4-trimethoxy, 2-trifluoromethyl, 4-trifluoromethyl or 3-trifluoromethyl.
4. The glycyrrhetinic acid derivative according to claim 3, wherein R is 2-methyl, 3-methyl, 4-methyl, 2-nitro, 3-nitro, 4-nitro, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 3-bromo, 4-bromo, 2,3, 4-trimethoxy, 2, 6-dichloro, 4-trifluoromethyl, or 3-trifluoromethyl.
5. A medicament comprising the glycyrrhetinic acid derivative according to any one of claims 1 to 4.
6. Use of a glycyrrhetinic acid derivative according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of a disease caused by the inhibition or reduction of the activity of PPAR γ protein expression.
7. The use according to claim 6, wherein the disease is type II diabetes, or a tumor of the liver, pancreas, biliary tract, oral cavity, lung, cervix, breast, ovary, esophagus, stomach, colon or rectum.
8. A method for preparing a glycyrrhetinic acid derivative according to any one of claims 1 to 4, comprising the steps of:
(1) dissolving glycyrrhetinic acid in a solvent, and adding concentrated sulfuric acid or concentrated hydrochloric acid to perform esterification reaction to obtain a product a;
(2) dissolving the product a in a solvent, and adding bromoacetyl bromide for reaction to obtain a product b;
(3) dissolving the product b and cinnamic acid with different substituents in an organic solvent, and adding a catalyst for reaction to prepare the glycyrrhetinic acid derivative;
wherein, in the step (1), the solvent is an alcohol solvent; in the step (2), the solvent is dichloromethane; in the step (3), the organic solvent is acetonitrile or ethanol, and in the cinnamic acid with different substituents, the substituent is the R group.
9. The method of claim 8, wherein the molar ratio of product a to bromoacetyl bromide is 1: 1-2; the molar ratio of the product b to the cinnamic acid with different substituents is 1: 1-1.5.
10. The method according to claim 8, wherein in the step (3), the catalyst is potassium carbonate or triethylamine.
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