CN114853810A - Curcumin derivative and preparation method and application thereof - Google Patents
Curcumin derivative and preparation method and application thereof Download PDFInfo
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- CN114853810A CN114853810A CN202210494273.0A CN202210494273A CN114853810A CN 114853810 A CN114853810 A CN 114853810A CN 202210494273 A CN202210494273 A CN 202210494273A CN 114853810 A CN114853810 A CN 114853810A
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Abstract
The invention relates to the field of natural medicinal chemistry, and discloses a curcumin derivative and a preparation method and application thereof. Curcumin derivatives shown as formula (I) and pharmaceutically acceptable salts thereof, wherein R is H or
X is halogen; n is 2 to 5. The curcumin derivative can enter tumor cells and mitochondria thereof in a targeted manner, induces apoptosis by influencing mitochondrial membrane potential, and improves the anti-tumor curative effect.
Description
Technical Field
The invention relates to the field of natural medicinal chemistry, and particularly relates to a curcumin derivative and a preparation method and application thereof.
Background
Tumors are one of the prominent public health problems worldwide today, and are a serious threat to human health and life. The common methods for treating tumors include surgery, chemotherapy, radiotherapy, immunotherapy and the like, wherein the chemotherapy is a common systemic treatment method, but the nonspecific treatment method has serious toxic and side effects on normal tissues. Therefore, the development of high-selectivity antitumor drugs is of great significance.
Mitochondria are one of the most important organelles in the cell and are involved in a variety of physiological or pathological processes. Mitochondria are the core of cellular metabolism, are the main sites for synthesizing Adenosine Triphosphate (ATP) through oxidative phosphorylation, participate in processes such as cell differentiation, cell information transmission and apoptosis, and have the capability of regulating cell growth and cell cycle. The outer mitochondria can also play a role in signal transduction and apoptosis by interfering with electron transfer, regulating cellular redox potential, releasing or activating apoptosis-related proteins, and the like. When mitochondria function disorderly, permeability of the outer mitochondrial membrane is altered, pro-apoptotic proteins such as Bax are activated and form multimeric pores in the mitochondrial membrane, releasing cytochrome c (cytochrome c). After the cytochrome C enters cytoplasm, the cytochrome C is combined with an apoptosis protease activating factor-1 (APAF1) and caspase9 to form an apoptosis corpuscle, caspase 3 is further activated, and apoptosis is induced. Research shows that the characteristics of unlimited proliferation, apoptosis escape, metabolism enhancement and the like of tumor cells are closely related to mitochondrial dysfunction. Compared with the normal cell mitochondrial membrane potential (-160mv), the tumor cell mitochondrial membrane potential (-220mv) is lower, and the positively charged molecules can enter and concentrate in mitochondria more easily, thereby deriving a mitochondria-targeted therapeutic strategy. Triphenylphosphine (TPP) is a delocalized lipophilic cation whose good lipophilicity and electropositivity enable rapid transmembrane transport to mitochondria.
Curcumin is an electrophilic polyphenol compound extracted from Curcuma longa, Curcuma aromatica, Curcuma zedoaria, etc. of Zingiberaceae. The molecular formula of curcumin is C 21 H 20 O 6 The relative molecular weight was 368.39, and the appearance was an orange crystalline powder. Curcumin has wide antitumor spectrum, and has inhibitory effect on various cancer cells, such as hepatocarcinoma and cancer noduleIntestinal cancer, breast cancer, ovarian cancer, etc. Curcumin can inhibit the formation, proliferation, and metastasis of tumor cells by modulating a variety of signaling such as NF-. kappa. B, P-gp, VEGF, COX-2, STAT3, PTEN, Bcl-2, MMPs, and the like. Research has shown that the mechanism of curcumin inducing tumor cell apoptosis is closely related to the damage of mitochondrial function. Curcumin can induce apoptosis of cells by reducing Glutathione (GSH), generating excessive Reactive Oxygen Species (ROS), destroying the redox homeostasis in mitochondria, reducing mitochondrial membrane potential. Curcumin is considered as an excellent candidate drug with antitumor activity, but has limited clinical application due to the defects of extremely low water solubility, easy degradation, short biological half-life, low bioavailability, lack of selectivity on tumor cell mitochondria and the like.
In order to improve some defects of the curcumin, Momekova and the like prepare a mixed block micelle with a mitochondrion targeting function to load the curcumin, and researches show that the micelle can increase the accumulation of the curcumin at tumor mitochondrion, so as to more effectively induce apoptosis. The triphenylphosphorus group and curcumin are coupled through ether bond to prepare the mitochondrion targeting curcumin derivative, so that the uptake efficiency of tumor cells to the compound is improved. Compared with the original zingiberin, the new compound has better anti-tumor curative effect. However, in these methods, the synthesis methods required for the mitochondrial targeting agent and the mitochondrial targeting derivative are complicated and require many steps.
Disclosure of Invention
The invention aims to overcome the problems of multiple synthesis steps, complex preparation method and the like of a mitochondrion targeting preparation and a mitochondrion targeting derivative in the prior art, and provides a curcumin derivative and a preparation method and application thereof.
In order to achieve the above object, the present invention provides a curcumin derivative represented by formula (I) and a pharmaceutically acceptable salt thereof,
whereinR is H or
X is halogen; n is 2 to 5.
Preferably, X is Br, Cl or I.
Preferably, the structural formula of the curcumin derivative is as follows:
in a second aspect of the present invention, there is provided a method for producing the curcumin derivative described above, the method comprising: curcumin and a compound shown as a formula (II) are subjected to condensation reaction in the presence of a condensing agent and a catalyst,
wherein n is 2-5; x is as defined in any one of claims 1 to 2.
Preferably, the method comprises the steps of:
(1) dissolving curcumin, a compound shown in formula (II) and a catalyst in an organic solvent;
(2) dissolving a condensing agent in an organic solvent;
(3) adding the solution obtained in the step (2) into the solution obtained in the step (1) under an ice bath condition, and reacting for 1-48 h at 0-80 ℃ under the protection of inert atmosphere;
(4) washing the solution obtained in the step (3) by using a dilute hydrochloric acid solution and a saturated sodium chloride solution in sequence, then drying, and separating and purifying by using a silica gel column chromatography;
wherein the molar ratio of the curcumin to the compound shown in the formula (II) is 1: 1-2.
Preferably, the condensing agent is selected from dicyclohexylcarbodiimide and/or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
Preferably, the catalyst is selected from N-hydroxysuccinimide and/or 4-dimethylaminopyridine.
The third aspect of the invention provides an antitumor drug composition with a mitochondrion targeting function, which contains a drug active component and a pharmaceutically acceptable auxiliary material, wherein the drug active component is the curcumin derivative and pharmaceutically acceptable salts thereof.
The fourth aspect of the invention provides the use of the curcumin derivative and pharmaceutically acceptable salts thereof in preparing medicaments for treating tumor diseases.
Preferably, the neoplastic disease is ovarian cancer, liver cancer or colon cancer.
The invention discloses a curcumin derivative with a mitochondrion targeting function. The curcumin derivative is a mono-substituted or di-substituted compound, is yellow solid powder at normal temperature, and is easily soluble in organic solvents such as methanol, dichloromethane and the like. Compared with curcumin, the curcumin derivative has the advantages of reduced melting point, improved water solubility, increased efficiency of entering mitochondria of tumor cells, and remarkably enhanced apoptosis induction and anti-tumor curative effect, thereby providing a research basis for industrial production and clinical application of the curcumin derivative. The curcumin derivative can enter tumor cells and mitochondria thereof in a targeted manner, induces apoptosis by influencing mitochondrial membrane potential, and improves the anti-tumor curative effect. The curcumin derivative has the advantages of high efficiency of targeting mitochondria, good anti-tumor curative effect, simple preparation method, easy operation, convenience for subsequent development and industrialization and the like.
Drawings
FIG. 1 is a photograph of the product of example 1 1 H-NMR chart;
FIG. 2 is of the product of example 1 13 C-NMR chart;
FIG. 3 is of the product of example 2 1 H-NMR chart;
FIG. 4 is of the product of example 2 1 H-NMR chart;
FIG. 5 is the mass spectrometric detection of the product of example 2;
FIG. 6 shows the results of infrared detection in test example 3;
FIG. 7 shows mitochondrial co-localization of CUR-2T in ovarian cancer cells in test example 5, in which (A) 40. mu.M CUR, (B) 60. mu.M CUR, (C) 40. mu.M CUR-2T, (D) 60. mu.M CUR-2T;
FIG. 8 is a result of measurement of the effect of CUR-2T on the membrane potential of ovarian cancer cells in test example 6;
FIG. 9 is a result of measurement of the effect of CUR-2T on the level of Reactive Oxygen Species (ROS) in ovarian cancer cells in test example 7;
FIG. 10 is a graph showing the results of the CUR-2T-induced apoptosis test in test example 8;
FIG. 11 is a result of measurement of inhibition of ATP synthesis by CUR-2T in ovarian cancer cells in test example 9.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The invention provides a curcumin derivative shown as a formula (I) and pharmaceutically acceptable salts thereof in a first aspect,
wherein R is H or
X is halogen; n is 2 to 5.
In a preferred embodiment, X is Cl, Br or I.
Further preferably, X is Br.
In the present invention, n may be 2, 3, 4 or 5.
Further preferably, the structural formula of the curcumin derivative is as follows:
a second aspect of the present invention provides a method of the curcumin derivative described above, wherein the method comprises: curcumin and a compound shown as a formula (II) are subjected to condensation reaction in the presence of a condensing agent and a catalyst,
wherein n is 2-5; x is as defined above.
Preferably, the method comprises the steps of:
(1) dissolving curcumin, a compound shown as a formula (II) and a catalyst in an organic solvent;
(2) dissolving a condensing agent in an organic solvent;
(3) adding the solution obtained in the step (2) into the solution obtained in the step (1) under an ice bath condition, and reacting for 1-48 h at 0-80 ℃ under the protection of inert atmosphere;
(4) washing the solution obtained in the step (3) by using a dilute hydrochloric acid solution and a saturated sodium chloride solution in sequence, then drying, and separating and purifying by using a silica gel column chromatography;
wherein the molar ratio of the curcumin to the compound shown in the formula (II) is 1: 1-2.
In the process according to the invention, the organic solvent used is preferably dichloromethane, chloroform or tetrahydrofuran.
In the method of the present invention, the inert atmosphere is preferably helium or nitrogen.
In the method of the present invention, in the step (3), specifically, the reaction temperature may be 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or 80 ℃; the reaction time may be 1h, 5h, 10h, 15h, 20h, 25h, 30h, 35h, 40h, 45h or 48 h.
In a preferred embodiment, the condensing agent is selected from dicyclohexylcarbodiimide and/or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
In the invention, the dilute hydrochloric acid solution refers to a hydrochloric acid solution with a molar concentration of 0.01-0.1 mol/L.
In a preferred embodiment, the catalyst is selected from N-hydroxysuccinimide and/or 4-dimethylaminopyridine.
The third aspect of the invention provides an antitumor drug composition with a mitochondrion targeting function, which contains a drug active component and a pharmaceutically acceptable auxiliary material, wherein the drug active component is the curcumin derivative and pharmaceutically acceptable salts thereof.
The fourth aspect of the invention provides the use of the curcumin derivative and pharmaceutically acceptable salts thereof in preparing medicaments for treating tumor diseases.
Preferably, the neoplastic disease is ovarian cancer, liver cancer or colon cancer.
The invention discloses a curcumin derivative with a mitochondrion targeting function. The curcumin derivative is a mono-substituted or di-substituted compound, is yellow solid powder at normal temperature, and is easily soluble in organic solvents such as methanol, dichloromethane and the like. Compared with curcumin, the curcumin derivative has the advantages of reduced melting point, improved water solubility, increased efficiency of entering mitochondria of tumor cells, and remarkably enhanced apoptosis induction and anti-tumor curative effect, thereby providing a research basis for industrial production and clinical application of the curcumin derivative. The curcumin derivative can enter tumor cells and mitochondria thereof in a targeted manner, induces apoptosis by influencing mitochondrial membrane potential, and improves the anti-tumor curative effect. The curcumin derivative has the advantages of high efficiency of targeting mitochondria, good anti-tumor curative effect, simple preparation method, easy operation, convenience for subsequent development and industrialization and the like.
The present invention will be described in detail below by way of examples, but the scope of the present invention is not limited thereto.
Example 1
Preparing curcumin derivative CUR-T, which has the following structure:
the specific process comprises the following steps:
(1) a clean, dry, 100mL, clear, colorless three-necked flask was taken, charged with 1.00g (2.71mmol) curcumin, 1.24g (2.71mmol) 5-carboxypentyl triphenylphosphine bromide (i.e., X is Br, n ═ 5), 165.3mg (1.35mmol) 4-Dimethylaminopyridine (DMAP), and dissolved with 40mL dichloromethane;
(2) 800.8mg (4.06mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) are weighed out and dissolved with 10mL of dichloromethane;
(3) dropwise adding the solution obtained in the step (2) into the solution obtained in the step (1) under an ice bath condition, and reacting at room temperature (25 ℃) for 24 hours under the protection of nitrogen;
(4) washing the solution obtained in step (3) three times with dilute hydrochloric acid, then three times with saturated sodium chloride solution, and finally drying the organic phase over night with anhydrous sodium sulfate, and separating by silica gel column chromatography to obtain curcumin derivative (787.3mg, yield 35.9%).
Example 2
Preparing curcumin derivative CUR-2T, which has the following structure:
the preparation process comprises the following steps:
(1) a clean, dry, 100mL, clear, colorless three-necked flask was weighed and charged with 1.00g (2.71mmol) curcumin, 2.47g (5.42mmol) 5-carboxypentyl triphenylphosphine bromide (i.e., X is Br, n ═ 5), 330.6mg (2.71mmol) 4-dimethylaminopyridine and dissolved in 50mL dichloromethane;
(2) 1.60g (8.13mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are weighed out and dissolved completely with 10mL of dichloromethane;
(3) dropwise adding the solution obtained in the step (2) into the solution obtained in the step (1) under an ice bath condition, and reacting at room temperature (25 ℃) for 24 hours under the protection of nitrogen;
(4) washing the solution obtained in step (3) with dilute hydrochloric acid three times, then washing with saturated sodium chloride solution three times, finally drying the organic phase with anhydrous sodium sulfate overnight, and separating by silica gel column chromatography to obtain curcumin derivative (1.06g, 31.4% yield).
Test example 1
The products prepared in the examples were characterized by means of a nuclear magnetic resonance apparatus (Bruker, Avance III 400MHz, Switzerland). The detection process comprises the following steps: and (3) placing a sample to be detected in a nuclear magnetic tube, adding 0.5mL of deuterated dimethyl sulfoxide for dissolution, and detecting by using Tetramethylsiloxane (TMS) as a displacement reference substance.
In example 1 1 H NMR and 13 the C NMR spectrum is shown in FIGS. 1 and 2.
1 HNMR(400MHz,DMSO-d 6 )δ9.82(s,1H),8.03-7.66(m,15H),7.60(dd,J＝15.9,3.8Hz,2H),7.51(s,1H),7.38-7.24(m,2H),7.14(dd,J＝25.0and 8.2Hz,2H),6.98(d,J＝15.9Hz,1H),6.83(dd,J＝24.2and 11.9Hz,2H),6.14(s,1H),3.83(s,6H),3.69-3.58(m,2H),2.54(d,J＝6.7Hz,2H),1.63(d,J＝32.7Hz,6H).
13 CNMR(101MHz,DMSO-d 6 )δ185.37,181.88,171.30,151.64,150.17,148.51,142.07,141.23,139.43,135.38,135.35,134.30,134.15,134.04,130.77,130.65,125.10,123.81,123.70,121.75,121.58,119.48,118.62,116.24,112.48,112.02,101.78,56.52,56.22,33.31,29.68,29.51,24.11,21.98,20.94,20.44.
In example 2 1 H NMR and 13 the C NMR spectrum is shown in FIGS. 3 and 4.
1 H NMR(400MHz,DMSO-d 6 )δ8.02-7.73(m,30H),7.66(d,J＝15.8Hz,2H),7.57-7.51(m,2H),7.39-7.31(m,2H),7.13(d,J＝8.1Hz,2H),7.04(d,J＝15.9Hz,2H),6.23(s,1H),3.83(s,6H),3.66(dt,J＝14.5and 7.1Hz,4H),2.56(t,J＝7.0Hz,4H),1.63(dd,J＝27.9,6.4Hz,12H).
13 C NMR(101MHz,DMSO-d 6 )δ183.69,171.30,140.30,135.38,135.35,134.16,134.06,130.77,130.65,125.14,123.74,121.94,119.49,118.64,112.61,56.56,33.31,29.68,29.51,24.11,22.03,21.99,20.95,20.45.
Therefore, according to the above characterization results, CUR-T, CUR-2T has been successfully synthesized.
Test example 2
The product obtained in example 1 was detected by a mass spectrometer (Aglient, 7250& JEOL-JMS-T100 LPACuTOF, Japan) and the positive ion mode was selected.
As shown in fig. 5, the actual measurement result was 727.28172, and the theoretical value was 727.28. Therefore, from the above characterization results, it can be seen that the structural formula of the product CUR-T prepared in example 2 is consistent with the expected design.
Test example 3
The products obtained in examples 1 and 2, as well as Curcumin (CUR) and 5-carboxypentyl triphenylphosphine bromide (TPP), were examined using Fourier Infrared Spectroscopy (Thermo, Nicolet 6700, USA). The detection process comprises the following steps: weighing a proper amount of sample to be detected, dropwise adding the sample on a potassium bromide sheet, drying, and detecting in a Fourier infrared spectrometer within the detection range of 500-4500cm -1 。
The results are shown in FIG. 6, which shows that: curcumin is 1627cm -1 The peak appears in the position of the absorption peak of stretching vibration of C ═ C double bond, and the TPP is 1720cm -1 Absorption of stretching vibration of carboxyl group C ═ O, 690cm -1 The position is the absorption of the bending vibration of the mono-substituted C-H surface of the benzene ring. Example 1(CUR-T) and example 2(CUR-2T) at 1751cm -1 All the C ═ O stretching vibration absorption peak of ester bond appears at 1627cm -1 When C ═ C double bond stretching vibration absorption occurs, 690cm -1 A benzene ring monosubstituted absorption peak appears. The hydroxyl absorption peak of CUR-2T is weaker than that of CUR-T because both phenolic hydroxyl groups are esterified leaving only the hydroxyl absorption peak in the enol-structure. The change of the infrared characteristic peak indicates that the compound CUR-T, CUR-2T is successfully synthesizedAnd (4) obtaining.
Test example 4
The melting points of the products prepared in examples 1 and 2 and curcumin were examined. The detection steps are as follows: taking a sample to be detected which is dried to constant weight, grinding the sample into fine powder by using an agate mortar, preparing a sample by using a glass capillary for measuring a melting point, enabling the powder to be tightly aggregated at a melting-sealed end of the capillary by free fall, and then placing the capillary in a melting point instrument (a microcomputer melting point instrument, WRS-2, Shanghai) for detection. The results are shown in Table 1.
TABLE 1
As can be seen from Table 1, the melting points of the products of examples 1 and 2 are reduced relative to curcumin, and the change of the melting points shows that the melting points of the curcumin are reduced after the triphenyl-phosphorus groups are introduced into the curcumin structure.
Test example 5
Co-localization of CUR-2T to mitochondria in ovarian cancer cells
A2780 cells in the logarithmic growth phase are digested and counted, then the cells are inoculated into a glass bottom dish (35mm) at the speed of 2 multiplied by 104 per hole, and the cells are cultured in an incubator for 24 hours to be fully attached. The CUR group and the CUR-2T group were set, each group was set at two concentrations, 40. mu.M and 60. mu.M, and after 4 hours of action, the cells were washed three times with PBS, 1mL of a mitochondrial dye (Mitotrack Red, 60nM) was added to each dish, incubated in an incubator for 25min, washed three times with PBS, 1mL of 4% paraformaldehyde was added to fix the cells for 10min, washed three times with PBS, and finally 1mL of a nuclear dye, Hoechst33342 (10. mu.g/mL) was added to each dish, stained for 10min, washed three times with PBS, and observed under a confocal laser microscope (Olympus, FV-3000, Japan).
In order to investigate whether CUR-2T has a mitochondrial targeting function, the distribution of CUR and CUR-2T in A2780 cells was investigated in this experiment. In FIG. 7, (A) - (B) are 40 μ M and 60 μ M CUR groups, (C) - (D) are 40 μ M and 60 μ M CUR-2T groups, 1-3 columns are blue cell nucleus, green drug (CUR or CUR-2T) and red mitochondrion, 4 columns are superposition of blue, green and red pictures, wherein red and green are superposed to form orange yellow. As can be seen from FIG. 7, after incubating CUR and CUR-2T and A2780 for 4 hours, both the CUR and CUR-2T entered the cells in proportion to the dose administered, but the green fluorescence of 40. mu.M CUR-2T was significantly stronger than that of 60. mu.M CUR, indicating that the amount of CUR-2T entered the cells was greater. In addition, mitochondria stained with Mitotracker Red fluoresced Red and overlaid with green fluorescence to appear orange, indicating entry of the drug into the mitochondria. As can be seen from the figure, the orange color of 60 μ M CUR-2T is most evident, and 40 μ M CUR-2T times, indicating that CUR-2T can enter mitochondria of A2780 cells and is dose-dependent.
Test example 6
Effect of CUR-2T on ovarian cancer cell Membrane potential
And (3) qualitative detection: JC-1 is used as a fluorescent dye to detect the influence of CUR-2T on the mitochondrial membrane potential of A2780 ovarian cancer cells. A2780 ovarian cancer cells in a logarithmic growth phase are digested and counted, then the cells are inoculated into a 6-well plate at the density of 3 multiplied by 104 per well, and the cells are cultured in an incubator for 24 hours to be fully attached. The control group, CUR group and CUR-2T group were set, wherein the concentration of CUR was 5. mu.M, 10. mu.M and 20. mu.M, respectively, and the concentration of CUR-2T was 5. mu.M and 10. mu.M, respectively. Adding culture medium containing the above drugs into each well, culturing for 24 hr, discarding the culture medium, washing with PBS, adding 1mL JC-1 dye (60nM), mixing well, and incubating in incubator for 40 min. After the incubation was completed, the supernatant was discarded, washed 2 times with pre-cooled JC-1 staining buffer, and finally 2mL of the medium was added and observed under a fluorescent inverted microscope (Olympus, IX73, Japan).
And (3) quantitative detection: a2780 ovarian cancer cells in logarithmic growth phase are digested and counted at 3X 10 4 The density of each hole is inoculated in a 6-hole plate, and the cells are fully attached to the wall after being cultured for 24 hours in an incubator. Blank control group, CUR group and CUR-2T group were set, the concentration of CUR was 5. mu.M, 10. mu.M and 20. mu.M, and the concentration of CUR-2T was 5. mu.M and 10. mu.M. After 24h of action, the medium was aspirated, washed once with PBS, trypsinized for 4min, and centrifuged at 1200rpm for 5miAnd n, collecting bottom cell sediment, performing centrifugal washing once by using PBS, adding 1mL JC-1 staining working solution, fully and uniformly mixing, and incubating for 40min in an incubator. After the incubation was completed, the cells were washed 2 times by centrifugation with pre-cooled JC-1 staining buffer, and 500. mu. LPBS was added to each sample for resuspension and detection by flow cytometry.
JC-1 dye is a fluorescent probe for detecting Mitochondrial membrane potential (Mitochondrial membrane potential, MMP,. DELTA.. PSI.m) in which JC-1 aggregates to form a polymer in the Mitochondrial matrix and emits orange-red fluorescence, and JC-1 can only exist in the cytosol in monomeric form when the membrane potential is decreased or lost after Mitochondrial damage, producing green fluorescence, FIG. 8A is the results of detection of the effects of a blank control group (A1-A3), a 5. mu.M CUR group (A4-A6), a 10. mu.M CUR group (A7-A9), a 20. mu.M CUR group (A10-A12), a 5. mu.M CUR-2T group (A13-A15) and a 10. mu.M CUR-2T group (A16-A18) on the Mitochondrial potential of A2780 cells, where the first to third rows are photographs of the green fluorescence field, and the first row of A8 A.B field, respectively, normal A2780 cells had the morphological characteristics of epithelioid cells, mostly circular or polygonal, and when treated with 10. mu.M CUR-2T, the cells decreased in size and volume, and decreased in number (FIG. 8A 16). As shown in FIGS. 8A 2-A3, JC-1 in the cells of the control group mainly exists in a polymer form, red fluorescence is emitted, and green fluorescence is very weak; when CUR-treated cells were administered at concentrations of 5. mu.M, 10. mu.M and 20. mu.M, respectively, a slight decrease and increase in red and green fluorescence, respectively, was observed, indicating that the CUR was able to cause a slight decrease in MMP (FIGS. 8A 4-A12); when CUR-2T treatment was administered at concentrations of 5 μ M and 10 μ M, respectively, it was observed that the red fluorescence almost disappeared while the apparent green fluorescence appeared, and was dose-dependent, indicating that CUR-2T could target to mitochondria and significantly reduce MMPs (fig. 8a 13-a 18). Normal MMPs are a prerequisite for maintaining mitochondria to undergo oxidative phosphorylation and generate adenosine triphosphate, and MMP decline causes a series of apoptosis cascades such as opening of Permeability Transition Pore (PTP), suggesting that CUR-2T may promote apoptosis of ovarian cancer cells by lowering MMPs. FIG. 8B shows the ratio of the green/red fluorescence intensity measured by flow cytometry, and the trend of the results is consistent with the fluorescence photograph, and the two concentrations of CUR-2T are very significantly different from the control group. (compare control group, P < 0.1;. P < 0.01;. P < 0.001;. P < 0.0001;. compare CUR 20. mu.M, # #, P < 0.0001;. n;. 3)
Test example 7
Effect of CUR-2T on ovarian cancer cell Reactive Oxygen Species (ROS) levels
And (3) qualitative detection: and detecting the influence of CUR-2T on the ROS level in the A2780 ovarian cancer cells by adopting a reactive oxygen species detection kit. After digestion and counting A2780 cells in logarithmic growth phase, 2X10 cells were used 4 One/well density was seeded in 6-well plates at 37 ℃ with 5% CO 2 Culturing for 24h in the environment to ensure that the cells are fully attached to the wall. Control group, CUR group and CUR-2T group were set, wherein the concentration of CUR was 5, 10, 20. mu.M, and the concentration of CUR-2T was 5, 10. mu.M. Kit A fluid (1: 1000) was diluted with a medium containing no Fetal Bovine Serum (FBS) to give dichlorofluorescent yellow diacetate (DCFH-DA, 10mM) at a final concentration of 10. mu.M. The plates were removed from the incubator at 6-well, aspirated and washed once with 1mL PBS per well. Add 1mL DCFH-DA to each well and incubate for 20min in an incubator. After removal, cells were washed three times with FBS-free medium to sufficiently remove DCFH-DA that did not enter the cells. And observing under a laser micro-confocal microscope after the treatment is finished.
And (3) quantitative detection: a2780 cells in logarithmic growth phase were counted after digestion at 2X10 4 Cell/well Density seeded in 6-well plates at 37 ℃ 5% CO 2 The cells are fully attached by culturing for about 24 hours in the environment. Setting blank control group, CUR group and CUR-2T group, wherein the concentration of CUR is 5, 10, 20 μ M, and the concentration of CUR-2T is 5, 10 μ M. Kit A fluid (1: 1000) was diluted with a medium containing no Fetal Bovine Serum (FBS) to give a final DCFH-DA concentration of 10. mu.M. The 6-well plate was removed from the incubator, the culture broth was aspirated, and the plate was washed once per well at 1ml PBS. Trypsinize for 4min, centrifuge at 1200rpm for 5min to collect the bottom cell pellet, centrifuge and wash once with PBS, add 1mL DCFH-DA to each sample, incubate for 20 min. After removal, cells were washed three times with FBS-free medium to sufficiently remove DCFH-DA that did not enter the cells. Adding 500 mu LPBS into each sample for resuspension, and detecting by flow cytometryAnd (6) measuring.
DCFH-DA is an indicator of oxidative stress for the detection of ROS levels in cytoplasm and organelles (e.g., mitochondria). DCFH-DA is non-fluorescent and has cell membrane permeability, and can be hydrolyzed and deacetylated by cell esterase after entering cells to generate 2 ', 7' -Dichlorodihydrofluorescein (DCFH) and further rapidly oxidized to generate a fluorescent product 2 ', 7' -Dichlorofluorescein (DCF), and the DCF can be detected by fluorescence spectrum (Ex/Em: 504/529 nm). As can be seen from FIG. 9, the control groups (A1-A2) and the CUR 10. mu.M group (A3-A4) exhibited darker green fluorescence, indicating lower intracellular ROS levels. When treated with 5 μ M (A5-A6) and 10 μ M (A7-A7) of CUR-2T, the green fluorescence intensity of these two groups was significantly increased compared to the group of CUR 10M, indicating that the CUR-2T can induce apoptosis by increasing intracellular ROS content and is dose-dependent as compared to the CUR. FIG. 9B shows the results of flow assay, which showed a trend consistent with the results of the fluorescent photographs. (compare control group, P < 0.0001; compare CUR 10. mu.M, # #, P < 0.0001; n ═ 3)
Test example 8
CUR-2T-induced apoptosis in ovarian cancer cells
And detecting the apoptosis condition of the CUR-2T induced A2780 ovarian cancer cells by adopting an apoptosis detection kit and flow cytometry. A2780 cells in logarithmic growth phase were counted after digestion at 3X 10 5 The density of each well was seeded in 6-well plates at 37 ℃ with 5% CO 2 Culturing for about 24h in the environment to ensure that the cells are fully attached to the wall. A blank control group, a CUR group and a CUR-2T group were set, wherein the concentration of CUR was 10. mu.M, and the concentration of CUR-2T was 5. mu.M and 10. mu.M. Adding culture medium containing the above drugs into each well, culturing for 24h, washing cells with PBS 3 times, digesting with trypsin for 4min, centrifuging at 1200rpm for 5min, collecting bottom cell precipitate, adding 195 μ L binding solution for resuspension, adding 5 μ L LannexinV-FITC and 10 μ L PI, and dyeing in dark for 15 min. And detecting by using a flow cytometer after dyeing is finished.
In normal cells, phosphatidylserine is distributed on the inner side of cell membrane, and when the cell undergoes early apoptosis, the phosphatidylserine is everted to the outer side of the cell membrane, and the change occurs earlier than the apoptosis phenomena such as cell shrinkage, chromatin condensation, DNA fragmentation and increase of cell membrane permeability. Annexin V is a phospholipid binding protein and has high affinity with phosphatidylserine, and Annexin V-FITC with green fluorescence can be combined with phosphatidylserine exposed outside a cell membrane of early withering to be used as an indicator for the early withering reaction. Propidium Iodide (PI) is a nucleic acid dye that is impermeable to intact cell membranes, but can penetrate the cell membranes of apoptotic mid-late and dead cells with increased membrane permeability and stain red in such nuclei. Annexin v in combination with PI can be used to detect the number of cells at different apoptosis stages. As shown in FIG. 10, the control group (A1), CUR 10. mu.M (A2), CUR-2T 5. mu.M (A3), and CUR-2T 10. mu.M (A4) exhibited apoptosis rates of 4.25%, 6.27%, 7.9%, and 17.48%, respectively, and the results showed that the efficiency of inducing apoptosis by CUR-2T was significantly increased and dose-dependent as compared to the CUR. (compare with control group, P < 0.001;. P < 0.0001;. compare with CUR 10. mu.M, ##, P < 0.01; ###, P < 0.0001;. n;. 3)
Test example 9
CUR-2T inhibits ATP synthesis in ovarian cancer cells
And (3) detecting the influence of CUR-2T on ATP synthesis in A2780 cells by adopting an ATP content detection kit and flow cytometry. A2780 cells in logarithmic growth phase were counted after digestion at 3X 10 5 The density of each well was seeded in 6-well plates at 37 ℃ with 5% CO 2 Culturing for 24h in the environment to ensure that the cells are fully attached to the wall. A blank control group, a CUR group and a CUR-2T group were set, wherein the concentration of CUR was 10. mu.M, and the concentration of CUR-2T was 5. mu.M and 10. mu.M. The culture medium containing the above drugs was added to each well and the culture was continued for 24h, and the cells were washed 3 times with PBS, digested with trypsin for 4min, collected and counted. Centrifuging, discarding supernatant, adding 1mL of extractive solution into each group of cells, resuspending, performing ice bath ultrasonication for 1min (200W, 2s interval per ultrasonic treatment for 1s), centrifuging at 4 deg.C at 10000r/min for 10min, collecting supernatant to EP tube, adding 500 μ L chloroform into 1mL supernatant, shaking, mixing, centrifuging at 4 deg.C at 10000r/min for 3min, and collecting supernatant on ice for testing. Respectively adding 20 μ L of the supernatant to be detected, 128 μ L of the reagent I and 52 μ L of the working solution into a 96-well plate, fully mixing uniformly, immediately placing into an enzyme-labeling instrument, measuring the absorbance value A1 at the 10 th s at 340nm, and then putting the sample into a 3-well plateReacting in a thermostat at 7 ℃ for 3min, immediately measuring the absorbance value A2 at 3min for 10s, and calculating the ATP generation amount according to the formula given in the kit. ATP content (. mu.mol/10) 6 cell) 0.125 Δ a assay/Δ a standard.
The ATP content in the cells is detected, and the energy metabolism state of the tumor cells can be reflected. Intracellular Hexokinase (HK) can catalyze ATP and glucose to synthesize glucose-6-phosphate, the substance can be further catalyzed by glucose-6-phosphate dehydrogenase (G6PD) to generate reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH), the generated NADPH is proportional to the ATP content and has a characteristic absorption peak at 340nm, and therefore the ATP content can be reflected. As a result, as shown in FIG. 11, there was no significant change in ATP content in the group of CUR 10. mu.M, compared to the blank control group, after administering different concentrations of the CUR and CUR-2T-treated cells for 24 hours. However, both the CUR-2T 5 μ M and 10 μ M groups were significantly reduced compared to the blank control, CUR 10 μ M group. The result shows that CUR-2T can inhibit ATP synthesis in A2780 cells and is dose-dependent, which is probably because CUR-2T breaks mitochondria of A2780 cells to reduce ATP content and finally triggers apoptosis.
Test example 10
Cytotoxicity of CUR, CUR-T, CUR-2T on A2780 (human ovarian cancer cell), HepG2 (human liver cancer cell), HCT-8 (human colon cancer cell).
The inhibition of the proliferation of A2780 (human ovarian cancer cells) by CUR and CUR-T, CUR-2T was examined by the MTT method. A2780 cells in a logarithmic growth phase are digested, uniformly dispersed into a cell suspension, and inoculated to a 96-well plate by 1 × 104 cells after counting and dilution, and a control group and a blank group are arranged, and cultured for 24 hours to make the cells adhere to the wall. After discarding the medium, the medium containing different concentrations of CUR and CUR-T, CUR-2T was added to the medium and cultured for 24 hours. After the medium was discarded, 20. mu.L of MTT solution was added to each well, followed by culturing for 4 hours, and the supernatant was aspirated and 150. mu.L of DMSO was added to each well to dissolve MTT-formazan crystals. Absorbance (OD value) was measured at 570nm using a microplate reader (BIO-RAD, xMark, USA), and half lethal concentrations (IC50) of the three drugs were calculated by prism software. The cell viability calculation formula is as follows: cell viability (%) (OD experimental-OD blank)/(OD control-OD blank).
The cytotoxicity test method of CUR and CUR-T, CUR-2T on HepG2 and HCT-8 is the same as above.
Table 2 shows the results of cytotoxicity tests of CUR and CUR-T, CUR-2T on A2780, HepG2 and HCT-8 cells.
TABLE 2
As can be seen from Table 2, the IC50 of CUR was 64.11. + -. 1.09. mu.M, 112.20. + -. 4.32. mu.M and 68.43. + -. 0.69. mu.M in the three tumor cells, IC50 of CUR-T was 10.41. + -. 0.55. mu.M, 19.54. + -. 1.05. mu.M and 17.96. + -. 0.72. mu.M, and IC50 of CUR-2T was 6.17. + -. 0.56. mu.M, 12.59. + -. 0.64. mu.M and 11.21. + -. 0.66. mu.M, respectively. Compared with the CUR, the inhibition rate of the TPP modified CUR-T, CUR-2T on the proliferation of tumor cells is obviously increased. CUR-2T linked to two TPPs is more toxic to tumor cells than CUR-T linked to one TPP. Compared with IC50 of the CUR in three cells, the CUR-T is about 16.24%, 17.42% and 26.25% of the CUR, and the CUR-2T is about 9.62%, 11.22% and 16.38% of the CUR, which indicates that the CUR-T and the CUR-2T can induce apoptosis of three tumor cells by targeting mitochondria and causing change of membrane potential, thereby increasing the inhibition rate of cell proliferation.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A curcumin derivative shown in formula (I) and pharmaceutically acceptable salt thereof,
wherein R is H or
X is halogen; n is 2 to 5.
2. A curcumin derivative represented by formula (I) and a pharmaceutically acceptable salt thereof according to claim 1, wherein X is Br, Cl or I.
3. A curcumin derivative represented by the formula (I) and a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural formula of the curcumin derivative is as follows:
4. a process for preparing a curcumin derivative of claims 1 to 3, wherein the process comprises: curcumin and a compound shown as a formula (II) are subjected to condensation reaction in the presence of a condensing agent and a catalyst,
wherein n is 2-5; x is as defined in any one of claims 1 to 2.
5. The method according to claim 4, wherein the method comprises the steps of:
(1) dissolving curcumin, a compound shown as a formula (II) and a catalyst in an organic solvent;
(2) dissolving a condensing agent in an organic solvent;
(3) adding the solution obtained in the step (2) into the solution obtained in the step (1) under an ice bath condition, and reacting for 1-48 h at 0-80 ℃ under the protection of inert atmosphere;
(4) washing the solution obtained in the step (3) by using a dilute hydrochloric acid solution and a saturated sodium chloride solution in sequence, then drying, and separating and purifying by using a silica gel column chromatography;
wherein the molar ratio of the curcumin to the compound shown in the formula (II) is 1: 1-2.
6. A process according to claim 4 or 5, wherein the condensing agent is selected from dicyclohexylcarbodiimide and/or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
7. The process according to claim 4 or 5, wherein the catalyst is selected from N-hydroxysuccinimide and/or 4-dimethylaminopyridine.
8. An antitumor drug composition with a mitochondrion targeting function, which comprises a drug active component and a pharmaceutically acceptable auxiliary material, wherein the drug active component is the curcumin derivative and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3.
9. Use of a curcumin derivative according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the preparation of a medicament for the treatment of a neoplastic disease.
10. The use according to claim 9, wherein the tumor disease is ovarian cancer, liver cancer or colon cancer.
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| CN116496277A (en) * | 2023-06-14 | 2023-07-28 | 齐泽(云南)生物科技有限公司 | Curcumin 2, 6-diaminopurine derivative compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104856980A (en) * | 2014-02-21 | 2015-08-26 | 沈阳药科大学 | Medical uses of tetrahydrocurcumin |
| CN106344513A (en) * | 2016-10-27 | 2017-01-25 | 烟台大学 | Mitochondrion-targeted micelle material and curcumin micelle preparation prepared from material |
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| Publication number | Priority date | Publication date | Assignee | Title |
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Non-Patent Citations (1)
| Title |
|---|
| FEIYANG JIN等: "Sialic Acid-Functionalized PEG−PLGA Microspheres Loading Mitochondrial-Targeting-Modified Curcumin for Acute Lung Injury Therapy" * |
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| CN116444522A (en) * | 2023-06-14 | 2023-07-18 | 齐泽(云南)生物科技有限公司 | Curcumin adenine derivative compound |
| CN116496277A (en) * | 2023-06-14 | 2023-07-28 | 齐泽(云南)生物科技有限公司 | Curcumin 2, 6-diaminopurine derivative compound |
| CN116444522B (en) * | 2023-06-14 | 2023-08-25 | 齐泽(云南)生物科技有限公司 | Curcumin adenine derivative compound |
| CN116496277B (en) * | 2023-06-14 | 2023-08-25 | 齐泽(云南)生物科技有限公司 | Curcumin 2, 6-diaminopurine derivative compound |
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