CN112661739A - Terpene phenol compound and application of terpene phenol compound and cisplatin in antitumor medicine - Google Patents
Terpene phenol compound and application of terpene phenol compound and cisplatin in antitumor medicine Download PDFInfo
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Abstract
The invention discloses a terpene phenol compound and application of the terpene phenol compound and cisplatin in combined use in antitumor medicines. The compound obtained by the method has high purity, good stability and good biological activity. And when the composition is used together with cisplatin, the effect of inhibiting the proliferation of tumor cells is more obvious.
Description
Technical Field
The invention relates to a pharmaceutical compound, in particular to a terpene phenol compound and application thereof in antitumor medicines in combination with cisplatin.
Background
The hemp plant species have various compounds and rich pharmacological activity. The terpene phenolic compounds are used as the seedling-end compounds, and small molecules with better pharmacological activity can be obtained through a series of structural modifications. For example, HU-210, JWH-133, CP 47,497, etc., all of which have the functions of protecting the nervous system, easing pain, etc., to a certain extent, and some pharmacological actions are even stronger than tetrahydrocannabinol and cannabidiol.
Cancer (malignant tumor) refers to a disease caused by a malfunction in the mechanism of regulating cell proliferation, and is one of the most serious diseases in human today. The following treatments are typical: surgical methods, chemotherapy, radiotherapy, immunotherapy and monoclonal antibody treatment, but single therapeutic drugs often fail to achieve the desired therapeutic effect and are prone to multidrug resistance in tumors. Combination therapy is commonly used clinically to overcome the development of resistance and also to minimize side effects by dose adjustment to produce optimal combination doses.
The antitumor function of terpene phenol compounds has been reported in many cases: for example, cannabidiol or tetrahydrocannabinol can show obvious inhibition effect in tumors such as breast cancer, prostate cancer, glioma, leukemia, lung cancer, skin cancer, thyroid cancer, pancreatic cancer and the like. The compounds can be used as an antitumor agent alone or in combination with the existing antitumor agents, can enhance the drug effect, overcome drug resistance, relieve cancer pain and alleviate adverse reactions, and can become a clinical antitumor treatment scheme with a good application prospect.
Disclosure of Invention
The invention aims to provide a compound which is synthesized and has the effect of inhibiting the activity of tumor cells.
It is another object of the present invention to provide a process for preparing the compound.
The invention also aims to provide the application of the compound in preparing anti-tumor medicaments.
The invention also aims to provide the application of the compound and cis-platinum in the preparation of antitumor drugs.
In view of the above, it is an object of the present invention to obtain a compound which can be used for the preparation of an antitumor drug, the compound being obtained synthetically.
The technical scheme adopted by the invention for realizing the purpose is as follows:
a terpene phenolic compound having a structural formula as shown in formula I:
the molecular formula of the compound is C21H30O2, and the molecular weight is 314.22.
Correspondingly, the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:
adding a substrate THC, p-toluenesulfonic acid and toluene into a reaction bottle, and then placing the reaction bottle in an oil bath at 60 ℃ until the reaction is finished; cooling to room temperature, adding saturated sodium bicarbonate into a reaction bottle to quench reaction, extracting with diethyl ether, combining organic phases, washing with saturated salt water and drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (ordinary silica gel: 300-400 mesh, self-packing) to obtain a target compound; the reaction scheme is as follows:
in order to better realize the invention, a chromatography elution system of an upper column (common silica gel: 300-400 mesh, self-packing) is normal hexane: acetone 25: 1, and gradient elution.
The invention also provides application of the compound shown in the formula I in preparation of antitumor drugs.
In order to better implement the invention, the tumor is liver cancer.
The invention also provides an anti-tumor medicament which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises a compound shown in the formula I.
In order to better implement the present invention, the anti-tumor drugs include, but are not limited to, tumor cell proliferation inhibitors.
The invention also provides the application of the compound shown in the formula I and cisplatin in preparation of antitumor drugs.
In the antitumor drug, the mass concentration ratio of the cisplatin to the compound shown in the formula I is 0.16: 1 to 0.5: 1.
the invention also provides an anti-tumor pharmaceutical composition, which comprises a pharmaceutical active component and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutical active component comprises cisplatin and a compound shown in the formula I, and the mass concentration ratio of the cisplatin to the compound shown in the formula I is 0.16: 1 to 0.5: 1.
the invention has the beneficial effects that: the invention provides a terpene phenolic compound which is obtained by synthesis, and cell experiments show that the compound has better anti-tumor cell proliferation activity, and particularly has obvious effect of inhibiting tumor cell proliferation in liver cancer cells. The compound obtained by the method has high purity, good stability and good biological activity. And when the composition is used together with cisplatin, the effect of inhibiting the proliferation of tumor cells is more obvious.
Drawings
FIG. 1 is a chart showing the effect of CKK8 colorimetric method on tumor cell survival performance;
FIG. 2 is a CCK8 colorimetric method for detecting the effect of combination on tumor cell viability;
FIG. 3 is a graph showing the effect of drug combination on tumor cell migration performance in a cell scratch test;
FIG. 4 is a graph showing the effect of drug combinations on tumor cell proliferation in a cell clonogenic assay.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and alterations can be made without departing from the technical idea of the present invention as described above, according to the common technical knowledge and the conventional means in the field.
Example 1
A method of preparing a compound comprising the steps of:
a10 ml reaction bottle is taken, added with the substrate THC (330mg, 1.05mmol), the paratoluenesulfonic acid (400mg,2.10mmol) and the toluene (5ml), placed in an oil bath at 60 ℃ for reaction for 24h, and the HPLC detection shows that the reaction is finished. Cooling to room temperature, adding saturated sodium bicarbonate into the reaction system to quench the reaction, extracting with diethyl ether, combining organic phases, washing with saturated brine and drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by chromatography (normal silica gel: 300-400 mesh, self-packing) to obtain the target compound (210mg, 64% yield).
Structural analysis of the target compound: finally, the structure of the compound is comprehensively identified through data such as mass spectrum, nuclear magnetic resonance spectrum and the like, and is shown as the formula I:
the target compound data information is: (1H NMR (400MHz, CDCl3) δ: 6.27(d, J ═ 1.4Hz,1H),6.11(d, J ═ 1.5Hz,1H),5.43(d, J ═ 4.7Hz,1H),4.72(s,1H),3.19(dd, J ═ 15.8,4.3Hz,1H),2.69(td, J ═ 10.8,4.6Hz,1H),2.44(td, J ═ 7.4,2.3Hz,2H), 2.20-2.08 (m,1H), 1.91-1.75 (m,3H),1.70(s,3H), 1.59-1.51 (m,2H),1.37(s,3H), 1.35-1.26 (m,5H), 1.88 (s,3H), 0.9H, 9H), GC (t: (3H), 1.9H, 3H, GC, 3H).
The specific reaction route of the preparation method is as follows:
example 2
The method for measuring the anti-tumor cell proliferation activity of the combined medicine comprises the following steps:
(1) CKK8 colorimetric method for detecting influence of combined drug on tumor cell survival performance
Taking human liver cancer cells (HepG2) in a logarithmic growth phase, preparing a cell suspension with an appropriate concentration by using a DMEM culture solution, wherein the cell density is about 50000 cells/mL (namely, each 100 mu L of the culture solution contains about 5000 cells), inoculating the cells into a 96-well plate by using 100 mu L of the cell suspension per well, and culturing in an incubator at 37 ℃ until the cells are attached to the wall. DMSO is used as a solvent to prepare a compound solution shown in the formula I and a cisplatin compound solution with the concentration of 20mg/mL respectively, and the compound solution and the cisplatin compound solution are diluted to the required working concentration by using a culture solution during an experiment. After the culture solution is discarded from the 96-well plate, 100 mu L of cisplatin solution with the working concentration of 2.5 mu g/mL, 5 mu g/mL, 10 mu g/mL, 20 mu g/mL and 30 mu g/mL is respectively added into the single medicine group; adding 100 mu L of compound solution shown in the formula I with the same concentration gradient into another single medicine group, adding 100 mu L of the combined medicine group containing cisplatin and the compound solution shown in the formula I, wherein the working concentration of the combined medicine group is (2.5 mu g/mL +2.5 mu g/mL), (5 mu g/mL +5 mu g/mL) (10 mu g/mL +10 mu g/mL), (20 mu g/mL +20 mu g/mL), (30 mu g/mL +30 mu g/mL); after the 96-well plate is continuously placed in the incubator for 48 hours, the cell survival rate is detected by using a CCK8 reagent, and the experiment is repeated for 3 times to obtain an average value. The synergy index refers to a gold formula to calculate a Q value, the treatment effect of the two medicaments after combined use is judged through the Q value, if the Q is simply added (+) between 0.85 and 1.15, the Q is enhanced (+) between 1.15 and 20, the Q >20 is obviously enhanced (+ +), the Q is antagonistic between 0.85 and 0.55, and the Q <0.55 is obviously antagonistic (- -); the added Q value of the effect is expanded to 0.85-1.15 according to the error of about 15 percent in biological experiments; the Q is more than 1.15, namely the synergistic effect.
As shown in FIG. 1, the survival rate of human hepatoma cells (HepG2) was lower as the concentrations of the compound of formula I and cisplatin increased compared to the control group, and when the two drugs were used in combination, the survival rate was lower than that of the single drug group, indicating that the combined drug had a stronger inhibitory effect on the survival of human hepatoma cells (HepG 2). The Q value calculation shows that the combined action of low-concentration cisplatin and the compound shown in the formula I on HepG2 cells has a synergistic inhibition effect on HepG2 cells for 48 hours.
(2) CCK8 colorimetric method for detecting influence of combined medicine on tumor cell survival performance
The cell plating method was as above, and the concentrations of the combination drugs in this experiment were set according to the experimental results in (1), and a single concentration of the compound of formula I was used in combination with cisplatin having a concentration gradient. One single medicine group is added with 100 mu L of cisplatin solution with fixed concentration of 5 mu g/mL, and the other single medicine group is added with 100 mu L of compound solution shown in the formula I with working concentration of 2.5 mu g/mL, 5 mu g/mL, 10 mu g/mL, 20 mu g/mL and 30 mu g/mL; the combined drug contains 100 mu L of cisplatin solution of the compound shown in the formula I, and the working concentration of the combined drug is (2.5 mu g/mL +5 mu g/mL), (5 mu g/mL +5 mu g/mL) (10 mu g/mL +5 mu g/mL), (20 mu g/mL +5 mu g/mL), (30 mu g/mL +5 mu g/mL); and (3) continuously placing the 96-well plate in an incubator for 48 hours, detecting the cell survival rate by using a CCK8 reagent, repeating the experiment for 3 times, taking an average value, and calculating the synergy index as above.
As shown in FIG. 2, the survival rate of human liver cancer cells (HepG2) was lower as the concentration of the compound of formula I was increased, and the inhibition rate of HepG2 cells was higher when different concentrations of the compound of formula I were used in combination with 5. mu.g/mL of cisplatin, as compared to the control group. The Q value calculation shows that the compound of the formula I and cisplatin in low concentration have synergistic inhibition effect on HepG2 cells when acting on the HepG2 cells for 48 hours.
(3) Cell scratch experiment for detecting influence of drug combination on migration performance of tumor cells
Taking human liver cancer cells (HepG2) in logarithmic growth phase, preparing a cell suspension with proper concentration by using a DMEM culture solution, wherein the cell density is about 200000/mL, inoculating the cells into a 24-pore plate by using 1mL of cell suspension per pore, and culturing in an incubator at 37 ℃ until the cells are attached to the wall. DMSO is used as a solvent to prepare a compound solution with the concentration of 20mg/mL shown in the formula I, and the compound solution is diluted to the required working concentration by using a culture solution during an experiment. After discarding the culture solution from the 24-well plate, using a 200-microliter gun head to make a straight scratch along the center of the well, using PBS to gently wash off cell masses generated by the scratch, respectively adding 1mL of cisplatin solution with the working concentration of 5 mug/mL, 1mL of compound solution with the formula I with the working concentration of 5 mug/mL into the single medicine group, 1mL of compound solution with the formula I with the working concentration of 5 mug/mL into the combined medicine group, adding 1mL of cisplatin solution with the working concentration of 5 mug/mL and compound solution with the working concentration of 5 mug/mL into the combined medicine group, and adding 1 mL; and (3) photographing and recording scratch widths of each hole of 0h, 24h and 48h, calculating an average value of each hole, finally calculating an average scratch repair rate, repeating the experiment for 3 times, taking an average value, analyzing difference significance by using T-test among groups, wherein P is less than 0.05, and the statistical significance is achieved.
Scratch repair ratio (%) (0 hour scratch area-Nh scratch area)/0 hour scratch area 100
The results are shown in fig. 3, and the scratch test results show that compared with the control group, the low-concentration compound shown in formula I and the low-concentration cisplatin can inhibit the migration of HepG2 cells, and when the two medicines are combined, the scratch repair rate is lower than that of a single medicine group, which indicates that when the two medicines are combined, the migration of HepG2 cells can be significantly inhibited.
(4) Cell clone formation experiment for detecting influence of combined drug on tumor cell proliferation
Taking human liver cancer cells (HepG2) in a logarithmic growth phase, preparing a cell suspension with an appropriate concentration by using a DMEM culture solution, wherein the cell density is about 117 cells/mL (namely, about 117 cells are contained in 1mL of the culture solution), inoculating the cells into a 6-well plate by using 3mL of the cell suspension per well, and culturing in an incubator at 37 ℃ until the cells are attached to the wall. DMSO is used as a solvent to prepare a compound solution with the concentration of 20mg/mL shown in the formula I, and the compound solution is diluted to the required working concentration by using a culture solution during an experiment. After the culture solution is discarded by the 6-pore plate, 3mL of cisplatin solution with the working concentration of 5 mug/mL, 3mL of compound solution of formula I with the working concentration of 5 mug/mL are respectively added into the single medicine group, 3mL of compound solution of formula I with the working concentration of 5 mug/mL and 5 mug/mL are added into the combined medicine group, and 3mL of culture solution is added into the blank control group; continuously placing the 6-well plate in an incubator, replacing fresh culture solution or culture solution containing medicine every 2-3 days, continuously culturing for about two weeks, continuously observing cell morphology, and stopping culturing when macroscopic clone appears in a culture dish. Discard the culture medium, carefully wash with PBS 2 times, add 4% Paraformaldehyde (PFA)1mL fixed cells for 30 min. After PFA is abandoned, 1ml of 0.1% crystal violet is added into each hole for dyeing for 30min, the ultrapure water is used for washing away the dyeing solution, a 6-hole plate is dried in the air and then photographed (figure 5) and the clone formation rate is calculated, T-test is used among groups for analyzing the significance of the difference, and P is less than 0.05, thus having statistical significance.
The results are shown in fig. 4, compared with the control group, the low-concentration compound shown in formula I and the low-concentration cisplatin both can inhibit the clone formation of HepG2 cells, when the two drugs are combined, the clone formation rate is lower than that of the single drug group, and the two drugs have a remarkable synergistic inhibition effect on HepG2 proliferation when combined.
Although the embodiments have been described, once the basic inventive concept is obtained, other variations and modifications of these embodiments can be made by those skilled in the art, so that the above embodiments are only examples of the present invention, and not intended to limit the scope of the present invention, and all equivalent structures or equivalent processes using the contents of the present specification and drawings, or any other related technical fields, which are directly or indirectly applied thereto, are included in the scope of the present invention.
Claims (10)
1. A terpene phenolic compound, characterized by having the structure shown in formula I:
2. a process for the preparation of a compound of formula I according to claim 1, comprising the steps of:
adding a substrate THC, p-toluenesulfonic acid and toluene into a reaction bottle, and then placing the reaction bottle in an oil bath at 60 ℃ until the reaction is finished; cooling to room temperature, adding saturated sodium bicarbonate into a reaction bottle to quench reaction, extracting with diethyl ether, combining organic phases, washing with saturated salt water and drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying with silica gel column to obtain a target compound; the reaction scheme is as follows:
3. the preparation method according to claim 2, wherein the silica gel column chromatography elution system is n-hexane: acetone 25: 1, and gradient elution.
4. The application of the compound shown in the formula I in preparing antitumor drugs.
5. The use according to claim 4, wherein the tumor is liver cancer.
6. An antitumor drug is characterized by comprising an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises a compound shown as a formula I.
7. The antineoplastic drug as claimed in claim 6, wherein said antineoplastic drug includes but is not limited to tumor cell proliferation inhibitor.
8. The compound shown in the formula I and cisplatin are combined to be used for preparing antitumor drugs.
9. The use according to claim 8, wherein the mass concentration ratio of cisplatin to the compound represented by formula I in the antitumor medicament is 0.16: 1 to 0.5: 1.
10. an anti-tumor pharmaceutical composition is characterized by comprising a pharmaceutical active component and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutical active component comprises cisplatin and a compound shown in a formula I, and the mass concentration ratio of the cisplatin to the compound shown in the formula I is 0.16: 1 to 0.5: 1.
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| CN111574531A (en) * | 2020-05-15 | 2020-08-25 | 福建省中科生物股份有限公司 | Terpene phenolic compound NO85, and preparation method and application thereof |
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