CN113527405B - Application of hederagenin polyethylene glycol modified derivative in preparation of tumor drug resistance reversal agent - Google Patents
Application of hederagenin polyethylene glycol modified derivative in preparation of tumor drug resistance reversal agent Download PDFInfo
- Publication number
- CN113527405B CN113527405B CN202110705045.9A CN202110705045A CN113527405B CN 113527405 B CN113527405 B CN 113527405B CN 202110705045 A CN202110705045 A CN 202110705045A CN 113527405 B CN113527405 B CN 113527405B
- Authority
- CN
- China
- Prior art keywords
- hederagenin
- polyethylene glycol
- pyrazine
- drug resistance
- modified derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
- C07J71/0047—Nitrogen only at position 2(3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an application of a hederagenin polyethylene glycol modified derivative in preparation of a tumor drug resistance reversal agent. The hederagenin polyethylene glycol modified derivative and the optical isomer of the compound or the pharmaceutically acceptable solvate thereof. The compound or the salt thereof with effective dose and the medicinal carrier are used for treating diseases or symptoms such as oral epithelial cancer, gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer and the like by being combined with clinical common antitumor medicaments. The hederagenin polyethylene glycol modified derivative and the application of the medical acceptable salt thereof are used for preparing a tumor drug resistance reversal agent and/or a medicinal carrier for treating mammals, preferably human diseases or symptoms.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to application of a hederagenin polyethylene glycol modified derivative with a novel structure in preparation of a tumor drug resistance reversal agent.
Technical Field
Recent cancer data from the international agency for research on cancer (IARC) show: in 2020, the number of newly added cancers is estimated to be 1930 ten thousand in total, and the number of cancer death cases is estimated to be 1000 ten thousand in total. Once Multidrug Resistance (MDR) occurs, the chemotherapeutic effect of the drug will be significantly reduced, and thus, tumor MDR has become one of the major obstacles to chemotherapy, and the development of tumor MDR reversal agents is imminent. Natural products and derivatives thereof with various structural types have been reported to have tumor drug resistance reversing activity and become an important source of tumor drug resistance reversing agents.
Hederagenin (H) is a pentacyclic triterpene compound separated from Hederagenin leaves and other plants. In the previous studies, alpha-Hederagenin (H) is found to have the biological Activity of resisting tumors, and the structural modification study of pentacyclic triterpene A ring splicing heterocycle is reported in the literature, and a plurality of heterocycle derivatives with better biological Activity are obtained (see Milan Urban, jan Sarek, miroslav Kvassinica, et al. Triterpenta Pyrazines and Benzopyrazines with Cytotoxic Activity [ J ]. J Nat prod. 2007, 70, 526-532.). But the prior research simultaneously highlights the technical problems that: how to obtain the hederagenin derivative which has excellent tumor drug resistance reversion activity and higher water solubility simultaneously enables the drug resistance reversion activity and the water solubility of the obtained hederagenin derivative to be obviously improved, and the hederagenin derivative has the drug property.
Disclosure of Invention
The invention aims to provide application of a hederagenin polyethylene glycol modified derivative in preparation of a tumor drug resistance reversal agent. The invention further provides a pharmaceutical composition for treating oral epithelial cancer, gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer and the like by combining with clinical common antitumor drugs.
In order to solve the technical problems, the invention provides the following technical scheme:
the application of the hederagenin polyethylene glycol modified derivative shown in the general formula I in preparing the tumor drug resistance reversal agent is characterized in that the structural formula of the hederagenin polyethylene glycol modified derivative shown in the general formula I is as follows:
wherein the content of the first and second substances,
n =2-13, and n is a natural number.
Preferably, some of the compounds of the present invention are:
general formula I:
N- (23-hydroxy-olean-12-en-28-oyl [3,2-b]Pyrazine) -4-aminobutanoic acid diethylene glycol ester;
N- (23-hydroxy-olean-12-en-28-oyl [3,2-b]Triethyl pyrazine) -4-aminobutyric acidA glycol ester;
N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Pyrazine) -4-aminobutyric acid tetraethylene glycol ester;
N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Pyrazine) -4-aminobutanoic acid pentaethylene glycol ester;
N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Pyrazine) -4-aminobutanoic acid hexaethylene glycol ester;
N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Pyrazine) -4-aminobutyric acid heptaethylene glycol ester.
Preferably, the hederagenin polyethylene glycol modified derivative shown in the general formula I is used for preparing a tumor drug resistance reversal agent and/or a medicinal carrier for treating mammals, and further preferably treating human diseases or symptoms.
The preparation route of the hederagenin polyethylene glycol derivative provided by the invention is as follows:
the C-28 polyethylene glycol modified hederagenin derivative with the general formula I is synthesized and prepared by the following method:
a. taking hederagenin as a raw material, and protecting carboxyl by benzyl bromide in the presence of inorganic base;
b. protecting hydroxyl at the C-23 position by using tert-butyldimethylsilyl chloride;
c. the intermediate product protected by TBS is oxidized by chloropyridine chromate to obtain C-3 hydroxyl;
d. reacting with ethylenediamine under the catalysis of sulfur;
e. under the acidic condition, removing a C-23 protecting group;
f. under the catalysis of palladium-carbon, with H 2 Reacting to remove C-28 benzyl;
g. reacting with oxalyl chloride to prepare acyl chloride, and reacting with methyl 4-aminobutyrate under the catalysis of triethylamine;
h. under the catalysis of DMAP and EDCI, reacting with diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol and heptaethylene glycol to obtain a crude product;
i. and purifying the crude product by using a dialysis method and a column chromatography method in sequence to obtain the target compound.
The C-28 polyethylene glycol modified hederagenin derivative shown in the general formula I and the pharmaceutically acceptable salt thereof have excellent tumor drug resistance reversion activity and high water solubility, so that the drug resistance reversion activity and the water solubility of the obtained hederagenin derivative are remarkably improved, and the hederagenin derivative has drug properties.
Detailed Description
The invention is characterized in that the C-28 polyethylene glycol modified derivative of hederagenin in the general formula I and the medically acceptable salt thereof have the advantages that compared with the existing hederagenin derivative, the tumor drug resistance reversal activity is improved, the water solubility is also obviously improved, and the hederagenin derivative has good drug forming property.
The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.
Example 1 N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Synthesis and characterization of pyrazine) -4-aminobutyric acid diethylene glycol (H628 + D + P100)
The compound hederagenin (472.0 mg,1.0 mmol) is dissolved in N, N-dimethylformamide (15.0 mL), potassium carbonate (300.0 mg,2.1 mmol) and bromobenzyl (0.2 mL,1.3 mmol) are added, and stirring is carried out at 50 ℃ for 6-10 h. Diluting the reaction mixture with ethyl acetate (25.0 mL), washing with water for three times, washing with saturated salt water for two times, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and subjecting to silica gel column chromatography (V) Petroleum ether :V Acetic acid ethyl ester 1-5:1) to yield a white solid (470.0 mg, 83.0%).
The above compound (460.0 mg,0.8 mmol) was dissolved in 20.0 mL dichloromethane, 4-dimethylaminopyridine (122.0 mg,1.0 mmol) and tert-butyldimethylsilyl chloride (360.0 mg,2.4 mmol) were added and the mixture was stirred at room temperature for 4-8 h. Evaporating dichloromethane, diluting with ethyl acetate (20.0 mL), washing with 5% HCl solution until acidic, washing with saturated sodium chloride solution until neutral, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V) Petroleum ether :V Ethyl acetate 1-15) to give a white solid (383.0 mg, 70.0%).
The above compound (380.0 mg,0.6 mmol) was dissolved in 15.0 mL dichloromethane, fresh pyridinium chlorochromate (300.0 mg,1.3 mmol) was added and stirred at room temperature for 6-10 h. Evaporating dichloromethane, diluting with ethyl acetate (20.0 mL), washing with water, washing with saturated saline to neutrality, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V) Petroleum ether :V Ethyl acetate 1-20).
Dissolving the above compound (500.0 mg,0.7 mmol) in morpholine (25.0 mL), adding sulfur (0.3 g,10.0 mmol) and ethylenediamine (0.3 g,4.5 mmol), refluxing for 6-10 h, diluting with ethyl acetate (30.0 mL), washing with water three times, washing with saturated saline twice, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V) Petroleum ether :V Ethyl acetate 1-10) to give a white solid (357.0 mg, 68.0%).
Dissolving the above product (300.0 mg,0.4 mmol) in acetone (20.0 mL), adding 10% HCl (2.0 mL), stirring at room temperature for 3-5 h, diluting with ethyl acetate, washing with saturated saline solution to neutrality, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V) Petroleum ether :V Ethyl acetate = 5:1-8:1) to give H6 as a white solid (225.0 mg, 89.0%).
Dissolve H6 (1.0 g,1.7 mmol) in methanol: tetrahydrofuran =2:3 (20 mL) mixed solution, 10% of Pd/C (802.0 mg,7.5 mmol) was added, and H was passed through the reaction system 2 And stirring the mixture at room temperature for reaction for 5 to 8 hours. And (3) after the reaction is finished, carrying out vacuum filtration to obtain filtrate, and concentrating to obtain a crude product H6-Bn which can be directly used for the next reaction without further purification.
Dissolving H6-Bn (1.0 g,1.98 mmol) in anhydrous dichloromethane (15 ml), placing in an ice bath for 10 min, adding oxalyl chloride (2.68 mL), stirring at room temperature for 30 min, evaporating, dissolving with anhydrous dichloromethane (15 ml), adding methyl 4-aminobutyric acid hydrochloride (1.52 g,9.88 mmol) and triethylamine (1.01 mL), stirring at room temperature for 3H, concentrating, diluting with dichloromethane, washing with water once, washing with saturated common salt twice, drying with anhydrous sodium sulfate, concentrating to obtain white solid H628+ D-OCH3 (0.96 g, 93.77%).
Dissolving H628+ D-OCH3 (800 mg,1.32 mmol) in a mixed solution (40 ml) of tetrahydrofuran and methanol (3:2), dropwise adding a 10% NaOH solution (8 ml), stirring at room temperature for 1H, concentrating, EA diluting, adjusting pH to acidity with 5% HCl, washing with water and saturated brine in this order three times, drying over anhydrous sodium sulfate, and concentrating to obtain H628+ D (632 mg, 80.92%) as a white solid.
H628+ D (120 mg,0.20 mmol) was dissolved in dry DCM (6 ml), diethylene glycol (319. Mu.L, 4 mol) was added, DMAP (471 mg,3.8 mmol) and EDCI (466 mg,2.4 mmol) were added and 9H was stirred at room temperature, the reaction was concentrated and redissolved in methanol (4 mL) at the end of the reaction, the solution was dialyzed against deionized water (MWCO 500 Da) 28H, and the dialysate was changed every 7H. Concentrating the solution under reduced pressure, and performing silica gel column chromatography (V) DCM :V MA = 90). 1 H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 2.2 Hz, 1H, H-pyrazine), 8.34 (d, J = 2.4 Hz, 1H, H-pyrazine), 6.11 (t, J = 5.5 Hz, 1H, NH), 5.48 (t, J = 3.3 Hz, 1H, H-12), 4.30-4.21 (m, 2H, CH 2 O PEG group), 3.80 (d, J = 10.5 Hz, 1H, H-23a), 3.75-3.69 (m, 4H, CH 2 O PEG group), 3.62-3.58 (m, 2H, CH 2 O PEG group), 3.50 (d, J = 10.5 Hz, 1H, H-23b), 3.41 (dq, J = 13.6, 7.2 Hz, 1H, N-CH 2 a), 3.08 (dq, J = 13.4, 6.9 Hz, 1H, N-CH 2 b), 3.00 (d, J = 16.5 Hz, 1H, H-1a), 2.58 (dd, J = 12.8, 3.5 Hz, 1H, H-18), 2.52 (d, J = 16.6 Hz, 1H, H-1b), 2.39 (t, J = 7.2 Hz, 2H, CH 2 ), 2.10 (dd, J = 8.8, 3.3 Hz, 2H CH 2 ), 1.31 (s, 3H, CH 3 ), 1.21 (s, 3H, CH 3 ), 0.95 (s, 3H, CH 3 ), 0.93 (s, 3H, CH 3 ), 0.92 (s, 3H, CH 3 ), 0.86 (s, 3H, CH 3 ).
Example 2 N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Synthesis and characterization of triethylene glycol 4-aminobutyric acid (H628 + D + P150)
Referring to the synthesis of example 1, H628+ D was reacted with triethylene glycol, dialyzed (MWCO 500 DA), and subjected to silica gel column chromatography (V) Methylene dichloride : V Methanol = 85). 1 H NMR (400 MHz, Chloroform-d)δ 8.38 (s, 1H, H-pyrazine), 8.34 (s, 1H, H-pyrazine), 6.15 (t, J = 5.3 Hz, 1H, NH), 5.48 (t, J = 3.3 Hz, 1H, H-12), 4.29-4.21 (m, 2H, CH 2 O PEG group), 3.80 (d, J = 10.6 Hz, 1H, H-23a), 3.71 (dt, J = 9.2, 4.6 Hz, 4H, CH 2 O PEG group), 3.68-3.64 (m, 4H, CH 2 O PEG group), 3.63-3.55 (m, 2H, CH 2 O PEG group), 3.50 (d, J = 10.5 Hz, 1H, H-23b), 3.40 (dq, J = 13.5, 7.0 Hz, 1H, N-CH 2 a), 3.08 (dt, J = 13.2, 6.4 Hz, 1H, N-CH 2 b), 3.00 (d , J = 16.5 Hz, 1H, H-1a), 2.60 (d, J = 9.8 Hz, 1H, H-18), 2.52 (d, J= 16.5 Hz, 1H, H-1b), 2.39 (t, J = 7.2 Hz, 2H, CH 2 ), 2.10 (dd, J = 8.6, 2.9 Hz, 2H, CH 2 ), 1.31 (s, 3H, CH 3 ), 1.21 (s, 3H, CH 3 ), 0.95 (s, 3H, CH 3 ), 0.93 (s, 3H, CH 3 ), 0.92 (s, 3H, CH 3 ), 0.86 (s, 3H, CH 3 ).
Example 3N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Synthesis and characterization of tetraethylene glycol 4-aminobutyrate (H628 + D + P200)
Referring to the synthesis of example 1, H628+ D was reacted with tetraethylene glycol, dialyzed (MWCO 500 DA) and subjected to silica gel column chromatography (V) Methylene dichloride : V Methanol = 80). 1 H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 1.8 Hz, 1H, H-pyrazine), 8.36 (d, J = 1.8 Hz, 1H, H-pyrazine), 6.13 (t, J = 5.6 Hz, 1H, NH), 5.47 (t, J = 3.3 Hz, 1H, H-12), 4.28-4.20 (m, 2H, CH 2 O PEG group), 3.80 (d, J = 10.6 Hz, 1H, H-23a), 3.74-3.68 (m, 4H, CH 2 O PEG group), 3.67-3.64 (m, 8H, CH 2 O PEG group), 3.62-3.59 (m, 2H, CH 2 O PEG group), 3.50 (d, J = 10.6 Hz, 1H, H-23b), 3.41 (dt, J = 13.5, 6.8 Hz, 1H, N-CH 2 a), 3.12-3.05 (m, 1H, N-CH 2 b), 3.02 (d, J= 16.6 Hz, 1H, H-1a), 2.60 (d, J = 8.4 Hz, 1H, H-18), 2.53 (d, J = 16.6 Hz, 1H, H-1b), 2.39 (t, J = 7.6 Hz, 2H, CH 2 ), 2.13-2.07 (m, 2H, CH 2 ), 1.33 (s, 3H, CH 3 ), 1.21 (s, 3H, CH 3 ), 0.96 (s, 3H, CH 3 ), 0.93 (s, 3H, CH 3 ), 0.92 (s, 3H, CH 3 ), 0.86 (s, 3H, CH 3 ).
Example 4 N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Synthesis and characterization of pyrazine) -4-aminobutyric acid pentaglycerol ester (H628 + D + P240)
Referring to the synthesis method of example 1, H628+ D was reacted with pentaethylene glycol, dialyzed (MWCO 500 DA), and subjected to silica gel column chromatography (V) Methylene dichloride : V Methanol = 75). 1 H NMR (400 MHz, Chloroform-d) δ8.38 (s, 1H, H-pyrazine), 8.35 (s, 1H, H-pyrazine), 6.15-6.08 (m, 1H, NH), 5.48 (t, J = 3.1 Hz, 1H, H-12), 4.28-4.20 (m, 2H, CH 2 O PEG group), 3.80 (d, J = 10.6 Hz, 1H, H-23a), 3.71 (dd, J = 9.2, 4.4 Hz, 4H, CH 2 O PEG group), 3.67-3.65 (m, 12H, CH 2 O PEG group), 3.60 (dd, J = 5.2, 3.8 Hz, 2H, CH 2 O PEG group), 3.50 (d, J = 10.6 Hz, 1H, H-23b), 3.40 (dq, J = 13.7, 7.1 Hz, 1H, N-CH 2 a), 3.09 (dd, J = 11.7, 6.8 Hz, 1H, N-CH 2 b), 3.01 (d, J= 16.6 Hz, 1H, H-1a), 2.60 (dd, J = 13.1, 2.4 Hz, 1H, H-18), 2.52 (d, J = 16.7 Hz, 1H, H-1b), 2.39 (t, J = 7.1 Hz, 2H, CH 2 ), 2.10 (dd, J = 8.8, 3.2 Hz, 2H, CH 2 ), 1.32 (s, 3H, CH 3 ), 1.21 (s, 3H, CH 3 ), 0.95 (s, 3H, CH 3 ), 0.93 (s, 3H, CH 3 ), 0.92 (s, 3H, CH 3 ), 0.86 (s, 3H, CH 3 ).
Example 5 N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Synthesis and characterization of pyrazine) -4-aminobutyric acid hexaethylene glycol ester (H628 + D + P280)
Referring to the synthesis of example 1, H628+ D was reacted with hexaethylene glycol, dialyzed (MWCO 500 DA) and subjected to silica gel column chromatography (V) Methylene dichloride : V Methanol = 70). 1 H NMR (400 MHz, Chloroform-d) δ 8.39 (s, 1H, H-pyrazine), 8.38-8.33 (m, 1H, H-pyrazine), 6.10 (t, J = 5.4 Hz, 1H, NH), 5.48 (t, J = 3.4 Hz, 1H, H-12), 4.28-4.20 (m, 2H, CH 2 O PEG group), 3.80 (d, J = 10.6 Hz, 1H, H-23a), 3.71 (m, 4H, CH 2 O PEG group), 3.68-3.63 (m, 16H, CH 2 O PEG group), 3.63-3.58 (m, 2H, CH 2 O PEG group), 3.50 (d, J = 10.6 Hz, 1H, H-23b), 3.39 (dt, J = 13.6, 6.8 Hz, 1H, N-CH 2 a), 3.12-3.04 (m, 1H, N-CH 2 b), 3.01 (d, J = 16.4 Hz, 1H, H-1a), 2.59 (dd, J = 12.9, 4.0 Hz, 1H, H-18), 2.52 (d, J = 16.5 Hz, 1H, H-1b), 2.39 (t, J = 7.5 Hz, 2H, CH 2 ), 2.10 (dd, J = 8.8, 3.3 Hz, 2H, CH 2 ), 1.32 (s, 3H, CH 3 ), 1.21 (s, 3H, CH 3 ), 0.96 (s, 3H, CH 3 ), 0.93 (s, 3H, CH 3 ), 0.92 (s, 3H, CH 3 ), 0.86 (s, 3H, CH 3 ).
Example 6 N- (23-hydroxyolean-12-en-28-oylo [3,2-b]Synthesis and characterization of heptaethylene glycol pyrazine) -4-aminobutyric acid (H628 + D + P330)
Referring to the synthesis of example 1, H628+ D was reacted with heptaglycol, dialyzed (MWCO 500 DA) and subjected to silica gel column chromatography (V) Methylene dichloride : V Methanol = 60). 1 H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 2H, H-pyrazine), 6.15 – 6.09 (m, 1H, NH), 5.47 (t, J = 3.5 Hz, 1H, H-12), 4.30-4.19 (m, 2H, CH 2 O PEG group), 3.80 (d, J= 10.5 Hz, 1H, H-23a), 3.78-3.71 (m, 4H, CH 2 O PEG group), 3.71-3.66 (m, 20H, CH 2 O PEG group), 3.65-3.62 (m, 2H, CH 2 O PEG group), 3.50 (d, J = 11.4 Hz, 1H, H-23b), 3.40 (dt, J = 13.6, 6.8 Hz, 1H, N-CH 2 a), 3.12-3.04 (m, 1H, N-CH 2 b), 2.59 (dd, J = 13.4, 4.5 Hz, 1H, H-18), 2.53 (d, J = 16.9 Hz, 1H, H-1b), 2.39 (t, J = 7.0 Hz, 2H, CH 2 ), 2.11 (dd, J = 8.6, 2.9 Hz, 2H, CH 2 ), 1.33 (s, 3H, CH 3 ), 1.21 (s, 3H, CH 3 ), 0.96 (s, 3H, CH 3 ), 0.93 (s, 3H, CH 3 ), 0.92 (s, 3H, CH 3 ), 0.86 (s, 3H, CH 3 ).
The following are the pharmacological tests and data for some of the compounds of the invention.
The experimental method comprises the following steps: examples 1-6 detection of the survival of the antitumor drug paclitaxel in KBV resistant strain cells
KBV cells in logarithmic phase are digested with 0.25% pancreatin to prepare single cell suspension with certain concentration. Based on the difference in cell growth rate, the cells were seeded at 4000 wells in a 96-well plate, and 100. Mu.L of cell suspension was added to each well. 24 After h, different concentrations of compound and 100 nM of paclitaxel and corresponding solvent control complete medium were added. Add 100. Mu.L (DMSO final concentration < 0.1%) per well, set 3 parallel wells per group, continue culturing at 37 ℃ for 72 h, and discard the supernatant. mu.L of complete medium containing 0.5 mg/mL MTT was added to each well, 4 h was further cultured, after the supernatant was discarded, 150. Mu.L DMSO was added to each well to dissolve MTT formazan precipitate, after shaking and mixing well in a micro shaker, the Optical Density (OD) was measured with a microplate reader at a reference wavelength of 450 nm and a detection wavelength of 570 nm. Using tumor cells treated by solvent control as a control group, and calculating the survival rate of different tumor cells under the action of each compound by using the following formula; tumor cells treated by solvent control are used as a control group, the inhibition rate of the compound on the tumor cells is calculated by the following formula, and the IC is calculated according to the middle effect equation 50 。
Cell survival rate (%) = average OD value of administration group/average OD value of control group × 100%
IC 50 = (control mean OD value-administration mean OD value)/control mean OD value × 100%
2. The experimental results are as follows:
examples 1-6 cell viability when administered alone and in combination is shown in table 1.
TABLE 1 cell viability in examples 1-6 when administered alone and in combination
Examples 1-6 analysis of the viability of anti-tumor drug paclitaxel in KBV resistant strain cells.
The survival rate evaluation results of KBV drug-resistant strain cells of the derivatives show that examples 1-6 have better tumor drug resistance reversal activity and can obviously increase the sensitivity of the drug-resistant KBV cells to paclitaxel, wherein the activity of examples 3-6 is superior to that of an equal-dose positive control drug verapamil, and the action strength of the examples 5 and 6 with the best activity is superior to that of a leader H6.
The following are solubility determination tests and data for some of the compounds of the present invention.
The experimental method comprises the following steps: solubility tests were performed on examples 1-6
The excess compound was added to 4 mL, respectively, in deionized water, and the suspension was placed in a constant temperature shaker, shaken at 37 ℃ for 24 hours, and then centrifuged at 14,000 r/min in a centrifuge for 5 minutes. The supernatant was filtered through a 0.45 μm microporous membrane, diluted appropriately, and the concentration of the compound was measured by UV-visible spectrophotometry to obtain the solubility of the compound in water.
The experimental results are as follows:
examples 1-6 solubility data are shown in table 2.
TABLE 2 examples 1-6 solubility
The solubility measurement results of examples 1 to 6 show that the water solubility of the hederagenin C-28 polyethylene glycol modified derivative is remarkably improved compared with that of the lead compound H6, and the water solubility of the hederagenin C-28 polyethylene glycol modified derivative is improved by about 90 times in example 6.
Pharmacological tests and solubility determination tests prove that the C-28 polyethylene glycol modified hederagenin derivative provided by the invention improves water solubility while maintaining or improving tumor drug resistance reversal activity, and the water solubility is also obviously improved while improving the tumor drug resistance reversal activity in examples 5 and 6, can be used for preparing a tumor drug resistance reversal agent, is combined with common antitumor drugs, and exerts good antitumor activity.
The experiments show that the polyethylene glycol modification method is introduced into the C-28 position structural modification of H6, and the polyethylene glycol is connected to the H6 through the connecting chain 4-aminobutyric acid, so that the hederagenin C-28 position polyethylene glycol modified derivative with improved tumor drug resistance reversal activity and remarkably improved water solubility and a novel structure is obtained, namely the structural modification of the hederagenin C-28 position polyethylene glycol modified derivative with the general formula I and the medically acceptable salt thereof is successful, the water solubility is remarkably improved on the premise of having good tumor drug resistance reversal effect and the activity superior to that of the primer H6, and the hederagenin polyethylene glycol derivative with the general formula I and the medically acceptable salt thereof have good drug forming properties.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent changes may be made within the technical spirit of the present invention, and the technical scope of the present invention is also covered by the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (1)
1. The application of the hederagenin polyethylene glycol modified derivative in preparing the tumor drug resistance reversal agent is characterized in that the hederagenin polyethylene glycol modified derivative is as follows:
n- (23-hydroxyolean-12-en-28-oyl [3,2-b ] pyrazine) -4-aminobutanoic acid diethylene glycol ester;
triethylene glycol N- (23-hydroxyolean-12-en-28-oyl [3,2-b ] pyrazine) -4-aminobutyrate;
tetraethylene glycol N- (23-hydroxyolean-12-en-28-oylo [3,2-b ] pyrazine) -4-aminobutyrate;
n- (23-hydroxy olean-12-en-28-oyl [3,2-b ] pyrazine) -4-aminobutanoic acid pentaglycerol ester;
n- (23-hydroxy olean-12-en-28-oyl [3,2-b ] pyrazine) -4-aminobutanoic acid hexa-ethylene glycol ester;
n- (23-hydroxy olean-12-en-28-acyl [3,2-b ] pyrazine) -4-amino butyric acid hepta-ethylene glycol ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110705045.9A CN113527405B (en) | 2021-06-24 | 2021-06-24 | Application of hederagenin polyethylene glycol modified derivative in preparation of tumor drug resistance reversal agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110705045.9A CN113527405B (en) | 2021-06-24 | 2021-06-24 | Application of hederagenin polyethylene glycol modified derivative in preparation of tumor drug resistance reversal agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113527405A CN113527405A (en) | 2021-10-22 |
| CN113527405B true CN113527405B (en) | 2022-12-20 |
Family
ID=78096608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110705045.9A Active CN113527405B (en) | 2021-06-24 | 2021-06-24 | Application of hederagenin polyethylene glycol modified derivative in preparation of tumor drug resistance reversal agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113527405B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749494B (en) * | 2017-02-06 | 2019-03-12 | 烟台大学 | With the active α of tumor drug resistance reversal-hederagenin derivative and its preparation method and application |
| CN108794564B (en) * | 2018-08-03 | 2021-01-19 | 烟台大学 | Hederagenin A-ring-and-pyrazine derivative as well as preparation method and application thereof |
-
2021
- 2021-06-24 CN CN202110705045.9A patent/CN113527405B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113527405A (en) | 2021-10-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101139347B (en) | Banisterine derivative compound and uses thereof | |
| US8796279B2 (en) | 4′-demethylepipodophyllotoxin derivative, preparation method and use thereof | |
| CN106916236A (en) | A kind of cyclodextrin camptothecin supermolecule chemotherapeutics and its preparation and application | |
| KR20220038601A (en) | Camptothecin drug and antibody conjugate thereof | |
| CN112076200B (en) | Application of hederagenin polyethylene glycol derivative | |
| CN113234117A (en) | Hederagenin C-28 polyethylene glycol modified derivative and preparation method thereof | |
| CN113527405B (en) | Application of hederagenin polyethylene glycol modified derivative in preparation of tumor drug resistance reversal agent | |
| CN110642740B (en) | Isostaviolamide derivative and preparation method thereof | |
| WO2024066548A1 (en) | β-ELEMENE DERIVATIVE CONTAINING PHOTOAFFINITY GROUP DIAZIRINE, PREPARATION METHOD THEREFOR, AND USE THEREOF AS PHOTOAFFINITY MOLECULAR PROBE | |
| JPH01275581A (en) | Antitumor substance sf2582 derivative | |
| CN112175037B (en) | Hederagenin polyethylene glycol derivative and preparation method thereof | |
| CN110201182B (en) | paclitaxel-DHA-dextran coupling polymer and synthetic method and application thereof | |
| CN114835759A (en) | Melatonin-platinum (IV) -carbon nitrogen long-chain complex, preparation method and application thereof in tumor drugs | |
| CN110759961B (en) | Ursolic acid indolyquinone amide derivatives and preparation method and application thereof | |
| CN113880855A (en) | Preparation of 9-fluoro camptothecin derivative and application of 9-fluoro camptothecin derivative in anti-tumor aspect | |
| CN110167917B (en) | Compound with anticancer effect and preparation method and application thereof | |
| CN115057850B (en) | Aloe-emodin derivative and preparation method and application thereof | |
| CN109422759B (en) | Micromolecule modified taxane water-soluble prodrug and medicinal application thereof | |
| CN114890995B (en) | Icaritin PROTACs and preparation method and application thereof | |
| CN116143758B (en) | Azaflavonoid targeting protein chimera and application thereof in preparation of antitumor drugs | |
| CN114478566B (en) | Derivative for eliminating hydroxyl at 1-position of oridonin and application thereof | |
| CN116102567B (en) | 7-substituted camptothecin derivative, synthesis method and application thereof as antitumor drug | |
| CN109575051B (en) | Natural medicine component modified derivative and anti-tumor application thereof | |
| KR102162351B1 (en) | Drug-conjugated compound and uses thereof | |
| CN110577552A (en) | Camptothecin-glycine-5, 6-didehydro norcantharidin conjugate and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |