CN110680820A - Application of ursolic alkane type pentacyclic triterpenoid in preparing tumor radiotherapy sensitizing drugs - Google Patents
Application of ursolic alkane type pentacyclic triterpenoid in preparing tumor radiotherapy sensitizing drugs Download PDFInfo
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Abstract
The invention discloses an application of a ursolic alkane type pentacyclic triterpenoid compound in preparing a tumor radiotherapy sensitizing medicament, wherein the structural general formula of the ursolic alkane type pentacyclic triterpenoid compound is shown as a formula I. The application discovers that the ursolic alkane type pentacyclic triterpenoid can improve the sensitivity of tumor cells to irradiation by inhibiting the activity of specific desSUMO protease 1(SENP1) for the first time, and is expected to become a new tumor radiotherapy sensitizing medicament.
Description
Technical Field
The invention relates to a new application of a ursolic alkane type pentacyclic triterpenoid compound, in particular to an application of the ursolic alkane type pentacyclic triterpenoid compound serving as a specific SUMO-removed protease 1 inhibitor in preparing a tumor radiotherapy sensitizing medicament.
Background
The following discussion is presented in the context of a description of the invention to aid in understanding the invention, but is not to be construed as prior art to the invention. All cited publications are incorporated herein by reference in their entirety.
The natural products are always an important source for the development of antitumor drugs due to the diversity of self chemical structures, the wide source and higher safety. Ursolic acid, a natural product of pentacyclic triterpenes from a wide variety of sources, has been reported to have radiosensitizing and chemosensitizing activities. Chironxin et al believe that the reason why ursolic acid exhibits radiosensitization activity is that it can inhibit the expression of HIF-1 α, thereby affecting the NADPH level in tumor cells, causing a decrease in Glutathione (GSH) content, and increasing the sensitivity of cells to irradiation (chirong. experimental study of ursolic acid to improve the radiosensitivity of NSCLC cells. [ D ]. symposium: university of medical, anhui, 2014.); koh et al believe that ursolic acid can increase the content of ROS in tumor cells, thereby enhancing radiation-induced apoptosis and achieving radiosensitization (2012, Free Radials research,46: 339-. Although the research analyzes the reason of the generation of the ursolic acid radiosensitization activity from different angles, the direct action target and the specific action mechanism of the ursolic acid are not given.
The small ubiquitin-related modifier (SUMO) modification of protein is an important dynamic and reversible posttranslational modification type, and the modified substrate protein participates in the processes of regulating the activity of transcription factors, regulating the cell cycle, responding to DNA damage, transporting nucleoplasm and the like. Specific dessumoylation proteases (SENPs) are key proteases for catalyzing dessumoylation modification of corresponding substrates in cells, and because SUMO and dessumoylation modification are widely existed in various tumor-related signal channels, abnormal expression of SENPs can obviously influence the occurrence and development of tumors at different levels. Radiotherapy is an important clinical way of treating tumors, and the DNA damage response mechanism existing in tumor cells can repair the damage caused by radiotherapy to different degrees and form radioresistance. A plurality of SUMO modified substrate proteins exist in the pathway, and SUMO modification and SUMO de-modification of the proteins regulate recognition of cellular DNA damage signals and recruitment of repair proteins in different ways (2017, CellRep.,21: 546-. SENP1 is a main enzyme catalyzing SUMO reaction, and the expression level can have significant influence on DNA damage response and radiation resistance. Studies have shown that silencing the expression of SENP1 by Small Interfering RNA (SiRNA) significantly improves the resistance of lung cancer cells A549 and H460 to ionizing radiation, and induces cell cycle arrest, increased expression of gamma-H2 AX, and apoptosis (exp. ther. Med.,2013,6: 1054-one 1058).
Our previous study results show that the expression of SENP1 protein of SKOV3 cells shows a rising trend after being irradiated, and the trend has irradiation dose dependence and time dependence. Ursolic acid, a natural product of pentacyclic triterpenes of the ursolic acid type, can effectively inhibit the activity of specific dessumoylprotease 1(SENP1), and IC (integrated circuit) for inhibiting SENP1 activity at the level of cells and proteins50The values were 0.17. mu.M and 0.0064. mu.M, respectively. Although the role of SENP1 in the DNA damage response pathway is not clearly explained, the evidence indicates that SENP1 plays an important role in the DNA damage response pathway and the formation of tumor radiotherapy resistance caused by hypoxia, and suggests that inhibition of SENP1 activity may affect the DNA damage repair pathway of irradiated cells and achieve a radiosensitization effect. Modifying and transforming the structure of ursolic acid to obtain a series of pentacyclic triterpenoids, and hopefully finding out the selected compounds with higher activity and stronger radiosensitization effect.
Disclosure of Invention
The invention aims to provide a preparation method and application of a novel ursolic alkane type pentacyclic triterpenoid specific SUMO-free protease 1 inhibitor compound aiming at the defect that tumor cells are easy to generate radiotherapy resistance, so as to solve the technical problem that the tumor radiotherapy resistance in the prior art is difficult to overcome, wherein the ursolic alkane type pentacyclic triterpenoid compound has the following structural general formula:
wherein:
a) x is independently selected from: an O atom, -NH;
b) y is independently selected from: an H atom or an O atom;
c)R1independently selected from: h atom, chemical structure:
d)R2independently selecting hydrogen atom, formyl and acetyl;
preferably, the compound or a pharmaceutically acceptable salt thereof is selected from:
the ursolic alkane type pentacyclic triterpenoid or the pharmaceutically available salt thereof can be used for preparing the application of the active medicine for inhibiting the specific SUMO-removed protease 1.
Further, the use of the compound or a pharmaceutically acceptable salt thereof for increasing the sensitivity of tumor cells to irradiation.
Drawings
FIG. 1: results of immunoprecipitation experiments with compounds inhibiting SENP1 activity;
FIG. 2: cloning the compound under 0Gy to form an experimental result graph;
FIG. 3: cloning the compound under 2Gy to form an experimental result graph;
FIG. 4: cloning the compound under 4Gy to form an experimental result graph;
FIG. 5: cloning the compound under 6Gy to form an experimental result graph;
FIG. 6: the compound clone under 8Gy forms an experimental result graph.
FIG. 7: fraction of survival-to-exposure dose curve for test compound;
Detailed Description
The compounds and preparations of the present invention are better illustrated by the following examples. These examples should not be construed as limitations of the present invention, and variations of these compounds, now known or later developed, should also be considered within the scope of the present invention and claimed.
Hereinafter, specific embodiments of the present invention will be described in detail. Well-known structures or functions may not be shown in detail in a following embodiment in order not to obscure the unnecessary detail.
Approximating language, as used herein in the following examples, may be applied to identify quantitative representations that could permissibly vary in number without resulting in a change in the basic function. Accordingly, a numerical value modified by a language such as "about", "left or right" is not limited to the precise numerical value itself. In some embodiments, "about" indicates that the value allowed for correction varies within plus or minus ten percent (+ -10%), for example, "about 100" indicates that any value between 90 and 110 is possible. Further, in the expression "about a first value to a second value", both the first and second values are corrected at about the same time. In some cases, the approximating language may be related to the precision of a measuring instrument.
Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
EXAMPLE 1 immunoprecipitation assay of inhibitory Activity of Compounds on specific Dessumoylated protease 1
Taking Hela cells in logarithmic growth phase and inoculating the Hela cells in 25cm2Culturing in a cell culture bottle overnight; after the cells are completely attached to the wall and the shape is recovered, replacing the cells with a culture medium containing 5 mu M ursolic acid or a tested compound, and continuing to culture for 24 hours; removing the culture medium, washing twice with PBS, digesting with 0.25% pancreatin, centrifuging at 1500rpm for 5min, and collecting cells; 200. mu.l of RIPA lysate (already in each case) were added to each sampleAdding protease inhibitors PMSF and aprotinin), and performing ice lysis for 1h, and suspending once every 15 min; centrifugation was carried out at 4 ℃ and a low temperature of 14000 Xg for 15min, and the supernatant was carefully aspirated (to avoid aspiration of the pellet). Protein quantification was performed on the recovered supernatant.
Protein quantification was performed using BCA method. Preparing a protein standard solution, and diluting to a final concentration of 0.5 mg/mL; the diluted standards were added to wells of a 96-well plate in 0, 1, 2, 4, 8, 12, 16 and 20. mu.l each, and PBS was added to make up to 20. mu.l, corresponding to standard concentrations of 0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5mg/ml, respectively. And (3) taking 4 mu L of sample, supplementing PBS to 80 mu L, uniformly mixing, taking 20 mu L, adding into a sample well of a 96-well plate, and making 3 multiple wells. Preparing a BCA working solution according to the quantity of the standard substance and the sample, preparing a proper amount of BCA working solution from the BCA reagent A and the BCA reagent B according to the proportion of 50:1, fully and uniformly mixing, and preparing the BCA working solution at present when the BCA reagent A and the BCA reagent B are used. Adding 200 mu L of BCA working solution into each well, and incubating for 30min at 37 ℃; measuring absorbance of 562nm wavelength with enzyme-labeling instrument; and calculating the protein concentration of the sample according to the standard curve and the sample volume.
Mu.g of lysate (added with 1. mu.g of IgG and 20. mu.L of protein A/G-beads, incubated at 4 ℃ for 30min with slow shaking, centrifuged at 4 ℃ at 3000rpm for 5min, the supernatant was collected), 2. mu.g of the corresponding antibody was added to the cell lysate, and incubated overnight at 4 ℃ with slow shaking. 20 μ L of protein A/G-beads were washed 3 times with the appropriate amount of lysis buffer and centrifuged 5min at 3000rpm each time. mu.L of the pretreated protein A/G-beads were added to the cell lysate overnight incubated with the antibody, and the antibody was coupled to the protein A/G-beads by slow shaking for 2-4h at 4 ℃. After immunoprecipitation, the mixture was centrifuged at 3000rpm for 5min at 4 ℃ to centrifuge the protein A/G-beads to the bottom of the tube, and the supernatant was carefully aspirated. The protein A/G-beads were washed 5 times with 1mL lysis buffer, and finally 20. mu.l of 2 XSDS loading buffer was added and the metal bath was allowed to run at 98 ℃ for 5 min. SDS-PAGE analysis was performed.
Protein electrophoresis and transfer printing: the concentration of the separation gel was selected according to the molecular weight of the detection index, and the concentration was 5%, and the preparation method is shown in Table 1, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed. The loading amount of protein was controlled at 40. mu.g. And (4) performing protein electrophoresis at 70V for 25min, increasing the voltage to 110V when the sample runs to a boundary between the concentrated gel and the separation gel, continuing electrophoresis for 80min until a blue band of the sample buffer runs to the end, and stopping electrophoresis. The protein transfer printing adopts a wet transfer method, the protein is transferred for 120min under a constant current of 100mA (the transfer printing time is determined according to the molecular weight of the protein, the smaller the molecular weight of the protein is, the corresponding reduction of the film transfer time), and the protein is transferred to the PVDF film.
TABLE 1 preparation methods and compositions of separation gums and concentrated gums
Antibody incubation and development: putting the PVDF membrane into a 5% skimmed milk powder solution prepared from a TBST solution, and sealing for more than 1 h; the bands were cut according to the molecular weight of the detected protein index, added with the corresponding primary antibody, and incubated overnight in a 4 ℃ freezer. The strips were then washed 3 times with TBST solution, 10min each time; the membrane was incubated with the corresponding horseradish peroxidase (HRP) -labeled secondary antibody for 2h at room temperature, and the band was washed 2 times for 5min with TBST solution, followed by 1 time for 5min with PBS solution. Protein expression images were obtained using ECL methods in a dark room using X-ray film exposure. Scanning the protein band into an electronic version, analyzing the gray value of the target protein band by using Scion Corporation software, and calculating the relative expression quantity (the gray value of the target protein/the gray value of the beta-actin) of each target protein by using the beta-actin as an internal reference. In the experiment, the compound 11 is used as a control drug, the inhibitory activity of the compound on immunoprecipitation is 1, and the relative activity value of the tested compound is obtained according to the relative expression quantity of the protein.
The results of the compounds inhibiting SENP1 activity are shown in Table 2 and FIG. 1
Table 2 test results of the activity of the compounds on the inhibition rate of SENP1
As can be seen from Table 1, most of the compounds of the present invention exhibited significant specific desSUMO protease inhibitory activity.
EXAMPLE 2 cytotoxicity test
Hela cells in logarithmic growth phase were grown at 3X 104The cells were plated at a density of 100. mu.L/well in 96-well plates and incubated overnight. Observing cell adherence by using a microscope and recovering the morphology, removing an original culture medium by suction, washing by using a D-hanks buffer solution, adding a compound drug solution to be tested prepared by using a culture medium without fetal calf serum, wherein the final concentration is 0.7, 2.2, 6.6 and 20 mu M in sequence, each group is provided with three compound holes and a corresponding blank group, 0.1% DMSO is added into a control group, each group is provided with 3 compound holes and the corresponding blank group is arranged; at 37 deg.C, 5% CO2The culture was continued for 72h, 10. mu.L of CCK-8 assay was added to each well, and the incubation was continued for 1h in an incubator at 37 ℃. Reading the absorbance value (A) of each hole at 490nm wavelength by using a microplate reader, and calculating the inhibition rate and IC50Values, calculation formulas and methods are as follows:
inhibition rate ═ 1- (A)Medicine－ABlank space)/(AControl－ABlank space)]×100％
Using the inhibition ratio as ordinate, lg [ M ]]For the abscissa (M is the dosing concentration), the IC of the corresponding test compound was calculated using Graphpad Prism 6.0 software to fit the curve50The value is obtained.
The results of the compound cytotoxicity activity test are shown in table 3:
TABLE 3 test results of Hela cell proliferation inhibitory Activity of Compounds
As can be seen from table 2, most of the compounds of the present invention, except 13, showed low cytotoxicity and were suitable for further studies as radiosensitizers.
EXAMPLE 53 clone formation experiment
Hela cells in logarithmic growth phase were taken, digested with 0.25% trypsin and blown into single cells, and the cell suspension was diluted to the appropriate concentration. Experiments were performed with 1, 18 and 22 as experimental groups, 5 different irradiation doses (0Gy, 2Gy, 4Gy, 6Gy, 8Gy) were set per group, different irradiation dose groups were seeded with different numbers of cells, three parallel experimental wells were set per dose for each group of drugs, where 0Gy and 2Gy groups were seeded with 200 cells per well, 4Gy group was seeded with 500 cells per well, 6Gy group was seeded with 2000 cells per well, and 8Gy group was seeded with 5000 cells per well. After inoculating the cells into a 24-well plate containing 500 mu L of culture medium, pre-warming at 37 ℃, shaking in a shape like a Chinese character 'mi' to uniformly disperse the cells, and incubating overnight to ensure that the cells grow adherent to the wall.
The control group is not treated, and is continuously cultured for 24h and then irradiated; after discarding the medium in the drug group, 500. mu.L of the medium containing the test compound at a final concentration of 5. mu.M was added and the culture was continued for 24 hours. The control and drug groups were then irradiated at different doses (0Gy, 2Gy, 4Gy, 6Gy, 8Gy) at a dose rate of 1 Gy/min. After completion of irradiation at 5% CO2After 2 weeks in an incubator at 37 ℃ the culture was terminated, during which the medium was changed every 3 days.
After the culture was completed, the supernatant was discarded, washed 2 times with PBS, and the cells were fixed with 4% paraformaldehyde for 15 min. Discarding the fixing solution, washing with PBS for 2 times, adding appropriate amount of 0.1% crystal violet dye solution, dyeing for 10min, washing with PBS for 3 times, and air drying. The number of clones was counted visually, colonies larger than 50 cells counted as 1 clone, and the colony formation rate and the cell survival score were calculated for each irradiation dose. The results of the colony formation experiments are shown in FIGS. 2-6.
The clone formation rate calculation formula is as follows:
the clone formation rate is the number of control group clones/number of control group seeding cells × 100%;
the cell survival fraction calculation formula is as follows:
cell survival Score (SF) ═ experimental colony number/(experimental colony seeding cell number × colony formation rate) × 100%
The samples of experimental data were analyzed and compared using GraphPad Prism 6.0 software, and the experimental data were averaged. + -. standard deviation
Expressed by a one-way analysis of variance, P<0.05, a statistical difference was considered. Further calculating D from the multi-target one-click model0Values and Dq values, and fitting the dose-effect curves of the control group and the experimental group, calculating the radiosensitization ratio (SER).
The results of the cell survival fractions of Hela cells after compound treatment in combination with irradiation are shown in Table 4.
TABLE 4 cell survival fraction of Hela cells after test Compound treatment in combination with irradiation
The fraction of survival-the-irradiation dose curves of the test compounds fitted according to the multi-target one-click model are shown in FIG. 7, and D of the control group and the drug group is obtained0、DqAnd drug group SER values are shown in table 5.
TABLE 5 parameters associated with radiosensitization of Hela cells after treatment with test Compounds
As can be seen from FIG. 1 and Table 4, the compound of the present invention shows good radiosensitization activity and is expected to be used as a new tumor radiosensitizer.
Claims (5)
1. The application of the compound of the formula I in preparing tumor radiotherapy sensitizing drugs:
2. the use of claim 1, wherein the compound of formula I:
a) x is independently selected from: an O atom, -NH;
b) y is independently selected from: h atom, O atom;
c)R1independently selected from: h atom or the chemical structure:
d)R2independently selected from hydrogen atom, formyl group and acetyl group.
3. Use according to claim 2, characterized in that the compound is selected from:
4. use according to claims 1-3, characterized in that the compound or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for inhibiting the activity of a specific dessumoylated protease 1.
5. Use according to claim 4, characterized in that the compound or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for increasing the sensitivity of tumor cells to irradiation.
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Cited By (4)
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| CN111346099A (en) * | 2020-03-11 | 2020-06-30 | 郑州大学第一附属医院 | Medical application of lactone compound in preparing esophageal cancer radiotherapy sensitivity enhancing medicine |
| WO2021078150A1 (en) * | 2019-10-23 | 2021-04-29 | 中国科学院上海药物研究所 | Pentacyclic triterpene tgr5 receptor agonist and preparation method therefor and uses thereof |
| WO2021178663A1 (en) * | 2020-03-04 | 2021-09-10 | The George Washington University | Compositions and methods for treatment of platinum-based chemotherapeutic resistant tumors |
| CN113908163A (en) * | 2021-09-30 | 2022-01-11 | 中国医学科学院放射医学研究所 | Application of pentacyclic triterpenoid natural product in reversing tumor platinum drug resistance |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021078150A1 (en) * | 2019-10-23 | 2021-04-29 | 中国科学院上海药物研究所 | Pentacyclic triterpene tgr5 receptor agonist and preparation method therefor and uses thereof |
| WO2021178663A1 (en) * | 2020-03-04 | 2021-09-10 | The George Washington University | Compositions and methods for treatment of platinum-based chemotherapeutic resistant tumors |
| CN111346099A (en) * | 2020-03-11 | 2020-06-30 | 郑州大学第一附属医院 | Medical application of lactone compound in preparing esophageal cancer radiotherapy sensitivity enhancing medicine |
| CN111346099B (en) * | 2020-03-11 | 2021-02-02 | 郑州大学第一附属医院 | Medical application of lactone compound in preparing esophageal cancer radiotherapy sensitivity enhancing medicine |
| CN113908163A (en) * | 2021-09-30 | 2022-01-11 | 中国医学科学院放射医学研究所 | Application of pentacyclic triterpenoid natural product in reversing tumor platinum drug resistance |
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