CN108794564B - Hederagenin A-ring-and-pyrazine derivative as well as preparation method and application thereof - Google Patents
Hederagenin A-ring-and-pyrazine derivative as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a hederagenin A-cyclopopyrazine derivative with a novel structure and a preparation method thereof. The compounds of the present invention have the same in vivo drug resistance-reversing activity as in vitro, and can be directly administered in vivo. The invention also discloses a preparation method of the derivatives and application of the derivatives in preparing tumor drug resistance reversal agents directly applied to bodies.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a hederagenin A cyclo-pyrazine derivative with a novel structure, a preparation method thereof and application thereof in preparing a tumor drug resistance reversal agent directly applied to a human body.
Technical Field
Tumors seriously threaten human health, chemotherapy is an important means for clinical treatment of tumors, and the generation of tumor drug resistance is one of the main reasons for failure of chemotherapy. Statistics show that more than 50% of malignant tumors have drug resistance to traditional chemical drugs, and the number of people dying from malignant tumors every year worldwide exceeds 600 ten thousand. Therefore, the development of novel tumor drug resistance reversal agents is a problem which needs to be solved urgently in the research of tumor therapeutics and pharmacology. The natural product has the characteristics of rich structure types, small toxic and side effects and the like, so that the search of the tumor drug resistance reversal agent from the natural product becomes an important research direction for researchers.
Hederagenin (H) is derived from Hederagenin (Hederagenin, H) of Hedera of Araliaceae, is pentacyclic triterpene compound, and is derivative of oleanolic acid. In the pre-study of the subject group, it was found that hederagenin derivatives had tumor multidrug resistance reversing activity (see Yang YT, Guan DK, Lei L, et al. H6, a novel heideragenin derivative, reverts multidrug resistance in the video and in the video [ J ]. Toxicology & Applied Pharmacology,2018,341:98, hereinafter referred to as document 1). But at the same time the highlighted technical problem is: although the in vitro activity of the hederagenin derivative is obvious, the in vivo activity of the hederagenin derivative is poor, and the hederagenin derivative can have corresponding drug administration property only by preparing the hederagenin derivative into a liposome by a film dispersion method.
Disclosure of Invention
The invention aims to provide hederagenin A cyclopopyrazine derivatives and a preparation method thereof, and application of the hederagenin A cyclopopyrazine derivatives in preparation of tumor drug resistance reversal agent drugs directly applied to the body, and the hederagenin A cyclopopyrazine derivatives have obvious activity in the body.
The structural formula of the hederagenin A cyclo-pyrazine derivative provided by the invention is as follows:
wherein, the general formula I: r represents OR1Alkane-substituted or unsubstituted nitrogen-containing six-membered heterocyclic ring;
R1represents halogen substituted or unsubstituted benzene or hexatomic aromatic heterocyclic triazole,
Preferably, the hederagenin A cyclic pyrazine derivative is:
general formula I:
o- (23-hydroxy-olean-12-en-28-acyl [3,2-b ] pyrazine) -1-hydroxybenzotriazole;
o- (23-hydroxy-olean-12-ene-28-acyl [3,2-b ] pyrazine) -1-hydroxy-7-azo benzotriazole
O- (23-hydroxy-olean-12-en-28-oyl [3,2-b ] pyrazine) -3-dimethylamino-1-propanol;
o- (23-hydroxy-olean-12-en-28-oylo [3,2-b ] pyrazine) -4-amidobutyric acid methyl ester;
n- (23-hydroxy-olean-12-en-28-acyl [3,2-b ] pyrazine) -1-morpholine.
The invention relates to an application of hederagenin A cyclo-pyrazine derivative in preparing a tumor drug resistance reversal agent directly applied to the body.
The preparation route of the hederagenin A cyclo-pyrazine derivative provided by the invention is as follows:
the hederagenin A ring-shaped pyrazine derivative of the general formula I is prepared by the following synthesis method:
when R is OR1Alkane-substituted or unsubstituted nitrogen-containing six-membered heterocyclic ring; r1Is composed of
The preparation method comprises the following steps:
a. taking hederagenin as a raw material, and protecting carboxyl by benzyl bromide in the presence of inorganic base;
b. protecting the hydroxyl at the 23-position by using tert-butyldimethylsilyl chloride;
c. the intermediate product protected by TBS is oxidized with newly prepared pyridine chlorochromate to generate hydroxyl at the 3-position;
d. reacting with ethylenediamine under the catalysis of sulfur;
e. under the acidic condition, removing the 23-bit protecting group, protecting the 23-bit hydroxyl group by acid anhydride, and then carrying out hydrogen catalytic reduction;
f.28 site forming active acyl chloride to react with different amino acid hydrochlorides, heterocycles and other side chains;
g. under alkaline condition, removing the hydroxyl protecting group at the C-23 position.
When R is OR1；R1When the halogen substituted or unsubstituted benzene or hexabasic aromatic heterocyclic triazole is used, the preparation steps comprise:
a. taking hederagenin as a raw material, and protecting carboxyl by benzyl bromide in the presence of inorganic base;
b. protecting the hydroxyl at the 23-position by using tert-butyldimethylsilyl chloride;
c. the intermediate product protected by TBS is oxidized with newly prepared pyridine chlorochromate to generate hydroxyl at the 3-position;
d. reacting with ethylenediamine under the catalysis of sulfur;
e. under the acidic condition, removing a protecting group, and then carrying out catalytic reduction by hydrogen;
f. reacting with different triazole groups under the catalysis of EDCl.
The invention discloses a compound which has obvious tumor drug resistance reversion property in vivo.
Drawings
FIG. 1 is a graph showing the cell viability of the cells of examples 1-5 of the present invention when administered alone and in combination.
FIG. 2 is a Balb/c nude mouse KBV cell xenograft tumor model to examine the in vivo drug resistance reversal activity of example 3.
Detailed Description
Example 1 Synthesis and characterization of O- (23-hydroxy-olean-12-en-28-oyl [3,2-b ] pyrazine) -1-hydroxybenzotriazole
Dissolving compound hederagenin (472.0mg, 1.0mmol) in N, N-dimethylformamide (15.0mL), adding potassium carbonate (300.0mg, 2.1mmol) and benzyl bromide (0.2mL, 1.3mmol), and stirring at 50 deg.C for 6-10 h. Diluting the reaction solution with ethyl acetate (25.0mL), washing with water for three times, washing with saturated salt water for two times, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Petroleum ether:VEthyl acetate10:1-5:1) to give a white solid (470.0mg, 83.0%).
The above compound (460.0mg, 0.8mmol) was dissolved in 20.0mL of dichloromethane, 4-dimethylaminopyridine (122.0mg, 1.0mmol) and tert-butyldimethylsilyl chloride (360.0mg, 2.4mmol) were added, and the mixture was stirred at room temperature for 4-8 h. The dichloromethane was evaporated, diluted with ethyl acetate (20.0mL), washed acidic with 5% HCl, washed neutral with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (V)Petroleum ether:VEthyl acetate30:1-15:1) to give a white solid (383.0mg, 70.0%).
The above-mentioned compound (380.0mg, 0.6mmol) was dissolved in 15.0mL of dichloromethane, and fresh pyridinium chlorochromate (300.0mg, 1.3mmol) was added thereto and stirred at room temperature for 6 to 10 hours. Evaporating to remove dichloromethane, diluting with ethyl acetate (20.0mL), washing with water, washing with saturated salt water to neutral, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetate35:1-20:1) to give a white solid (319.0mg, 84.0%).
Dissolving the above compound (500.0mg, 0.7mmol) in morpholine (25.0mL), adding sulfur (0.3g, 10.0mmol) and ethylenediamine (0.3g, 4.5mmol), refluxing for 6-10h, diluting with ethyl acetate (30.0mL), washing with water three times, washing with saturated salt water twice, drying over anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetate30:1-10:1) to give a white solid (357.0mg, 68.0%).
Dissolving the above product (300.0mg, 0.4mmol) in acetone (20.0mL), adding 10% HCl (2.0mL), stirring at room temperature for 3-5h, diluting with ethyl acetate, washing with water to neutrality, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentratingColumn chromatography (V)Petroleum ether:VEthyl acetate5:1-8:1) to give H6(225.0mg, 89.0%) as a white solid.
Dissolving the above product (200.0mg, 3.0mmol) in methanol (30.0mL) in 100mL eggplant-shaped bottle, adding 10% Pd/C (68.0mg, 6.0mmol), hydrogenating at room temperature under normal pressure for 6 hr, vacuum filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetateWhen the ratio is 8:1) to give HBQ as a white solid (156.0mg, 92.3%).
Dissolving compound HBQ (56.0mg, 0.1mmol) in anhydrous dichloromethane (8.0mL) in a 25mL eggplant-shaped bottle, adding 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) (112.0mg, 0.6mmol) and 1-hydroxy-benzotriazole (156.0mg, 1.2mmol), reacting at room temperature for 3h, and performing silica gel column chromatography (V) after the reaction is finishedChloroform:VMethanol200: 1) white solid was obtained with a yield of 91.5%. m.p.136.6-138.7 ℃.1H-NMR(400MHz,CDCl3)δ:8.46(s,1H,H-pyrazine),8.42(s,1H,H-pyrazine),8.13(d,J＝8.4Hz,1H,H-Ar),7.61(t,J＝7.6Hz,1H,H-Ar),7.49(d,J＝7.6Hz,1H,H-Ar),7.46(d,J＝8.3Hz,1H,H-Ar),5.55(t,J＝3.2Hz,1H,H-12),3.91(d,J＝10.6Hz,1H,H-23a),3.60(d,J＝10.5Hz,1H,H-23b),3.10(d,J＝16.7Hz,2H,H-11),2.61(d,J＝16.6Hz,1H,H-18),1.41(s,3H,CH3),1.36(s,3H,CH3),1.10(s,3H,CH3),1.07(s,3H,CH3),1.04(s,3H,CH3),1.03(s,3H,CH3).
Example 2 Synthesis and characterization of O- (23-hydroxy-olean-12-en-28-oyl [3,2-b ] pyrazine) -1-hydroxy-7-azobenzotriazol
According to the preparation method of the compound in preparation example 1, the compound HBQ reacts with 1-hydroxy-7-azobenzotriazole to synthesize the compound, and silica gel column chromatography (V)Chloroform:VMethanol200: 1) white solid was obtained with a yield of 92.8%. m.p.161.9-164.8 ℃.1H-NMR(400MHz,CDCl3)δ:8.69(d,J＝3.8Hz,1H,H-Ar),8.38(s,1H,H-pyrazine),8.36(s,1H,H-pyrazine),8.32(s,1H,H-Ar),7.39(dd,J＝8.3,4.5Hz,1H,H-Ar),5.42(s,1H,H-12),3.81(d,J＝10.5Hz,1H,H-23a),3.50(d,J＝10.5Hz,1H,H-23b),3.01(d,1H,H-18),2.97(d,2H,H-11),1.32(s,3H,CH3),1.26(s,3H,CH3),0.99(s,3H,CH3),0.96(s,3H,CH3),0.95(s,3H,CH3),0.93(s,3H,CH3).
Example 3 Synthesis and characterization of O- (23-hydroxy-olean-12-en-28-oyl [3,2-b ] pyrazine) -3-dimethylamino-1-propanol
Dissolving compound H6(2.0g, 3.4mmol) in pyridine (30.0mL), adding acetic anhydride (16.0mL), stirring at room temperature for 8H, diluting with ethyl acetate, washing with water, washing with saturated saline twice, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetate20:1) to give a white solid (1.9g, 89.0%).
Dissolving the above compound (1.9g, 3.0mmol) in methanol (30.0mL), adding 10% Pd/C (0.6g, 6.0mmol), hydrogenating at room temperature under normal pressure for 6 hr, vacuum filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetateWhen the ratio is 8:1) this gave a white solid (1.5g, 92.3%).
Dissolving the above compound (50.0mg, 0.1mmol) in dry dichloromethane (6.0mL), placing in ice bath for 10min, adding oxalyl chloride (77.0 μ L), stirring at room temperature for 1h, evaporating to dryness, dissolving in dry dichloromethane (6.0mL), adding 3-dimethylamino-1-propanol (11.4mg, 0.2mmol) and triethylamine (38.0 μ L), stirring at room temperature for 2h, concentrating, diluting with ethyl acetate, washing with water and saturated saline solution twice, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetateWhen the ratio is 8:1) to give a yellow oil (83.9%).
Dissolving the yellow oily substance (40.0mg, 0.1mmol) in mixed solution (5.0mL) of tetrahydrofuran and methanol (3:2), adding 10% NaOH solution (0.1mL) dropwise, reacting at room temperature under stirring for 5h, concentrating the reaction solution, diluting with ethyl acetate, adjusting pH to acidity with 5% HCl, sequentially washing with water and saturated saline solution twice, drying with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (V)Chloroform:VMethanol25: 1) white solid was obtained with a yield of 93.5%. m.p.121.1-123.2 ℃.1H-NMR(400MHz,CDCl3)δ:8.34(d,J＝2.3Hz,1H,H-pyrazine),8.31(d,J＝2.5Hz,1H,H-pyrazine),5.34(t,J＝3.3Hz,1H,H-12),4.07(t,J＝6.1Hz,2H,OCH2),3.76(d,J＝10.6Hz,1H,H-23a),3.45(d,J＝10.6Hz,1H,H-23b),2.85(d,J＝14.4Hz,1H,H-18),2.76(d,J＝11.0Hz,2H,NCH2),2.57(s,6H,2×NCH3),1.29(s,3H,CH3),1.15(s,3H,CH3),0.90(s,3H,CH3),0.90(s,3H,CH3),0.88(s,3H,CH3),0.78(s,3H,CH3).
Example 4 Synthesis and characterization of methyl O- (23-hydroxy-olean-12-en-28-oylo [3,2-b ] pyrazine) -4-amidobutyrate
According to the method of the present application for the preparation of the compound of example 3, silica gel column chromatography (V)Petroleum ether:VEthyl acetate5:1) white solid was obtained with a yield of 50.2%. m.p.128.3-129.8 ℃.1H-NMR(400MHz,CDCl3)δ:9.07(s,1H,NH),8.35,8.33(each 1H,ds,J＝2.3Hz,H-pyrazine),5.39(s,1H,H-12),3.77(d,J＝10.5Hz,1H,H-23a),3.68(s,3H,OCH3),3.46(d,J＝10.5Hz,2H,H-23b),3.93-2.86(m,1H,H-18),2.68(t,J＝6.7Hz,2H,NHCOCH2),2.59-2.43(m,2H,OCOCH2),1.30(s,3H,CH3),1.17(s,3H,CH3),0.92(s,6H,2×CH3),0.89(s,3H,CH3),0.80(s,3H,CH3).
Example 5 Synthesis and characterization of N- (23-hydroxy-olean-12-en-28-oyl [3,2-b ] pyrazine) -1-morpholine
According to the method of the present application for the preparation of the compound of example 3, silica gel column chromatography (V)Petroleum ether:VEthyl acetateWhen the ratio is 8:1) white solid was obtained with a yield of 90.3%. m.p.147.1-149.3 ℃.1H-NMR(400MHz,CDCl3)δ:8.34(d,J＝8.0Hz,2H,H-pyrazine),5.34(s,1H,H-12),3.78(d,J＝10.6Hz,1H,H-23a),3.75-3.54(m,8H,4×NCH2),3.47(d,J＝10.6Hz,1H,H-23b),3.10(d,J＝11.2Hz,1H,H-18),2.99(d,J＝16.6Hz,1H,H-11a),2.49(d,J＝16.7Hz,1H,H-11b),1.30(s,3H,CH3),1.18(s,3H,CH3),0.93(s,6H,2×CH3),0.89(s,3H,CH3),0.83(s,3H,CH3).
Example 6
The following are the results of pharmacological experiments with some of the compounds of the invention.
1 experimental method: examples 1-5 detection of the survival Rate of the antitumor drug paclitaxel in KBV resistant Strain cells
Cell plating: taking KBV drug-resistant strain cells with good growth state in logarithmic phase, adding culture medium after trypsinization, and gently blowing and beating to obtain single cell suspension. After cell counting, the cell concentration is diluted to 3-4 multiplied by 10 by using a culture medium4cells/mL were seeded in a 96-well cell plate culture plate at a volume of 100. mu.L/well, and were left to stand in a carbon dioxide incubator.
Cell administration: after 24h of cell plating, 10. mu.M of each of the different compounds was added in combination with 100nM of Paclitaxel and corresponding solvent control cultures. Each set of 3 parallel wells. And (4) after the medicine is added, placing the 96-well plate in an incubator, and performing static culture for 72 hours.
MTT detection: after the cells were cultured for 72 hours after administration of the corresponding drugs, the cell viability was examined.
Balb/c nude mouse xenograft tumor model the effect of example 3 on the proliferation of KBV cells in vivo was observed.
Nude mice (6-8 weeks old, Balb/c, male) were used to establish xenograft tumors. Briefly, KBV cells (5X 10) were injected subcutaneously6) Inoculated on the back of nude mice. The tumor to be transplanted grows to 100-200mm3Nude mice were randomly divided into four groups, and as a control, paclitaxel (30mg/kg), example 3(50mg/kg) and paclitaxel (30mg/kg) and paclitaxel were combined with example 3(50mg/kg), five mice per group. Paclitaxel was administered to the animals twice a week by intraperitoneal injection and the sodium hydroxymethyl cellulose solution of example 3 was administered directly by gavage. Body weight was weighed twice a week and tumor size was measured. Tumor volume was calculated according to the following formula: volume (V) ═ a × b2And/2 (a: long diameter, b: short diameter). And (5) drawing a tumor proliferation curve, and comparing the growth conditions of the tumors in each group. At the end of the experiment, the animals were sacrificed by removing the cervical vertebrae and the tumors were removed, the animal body weight and the tumor weight were weighed, and the tumor growth inhibition ratio (%) was calculated.
2, experimental results:
examples 1-5 cell viability when administered alone and in combination is shown in figure 1 and table 1.
Examples 1-5 survival assay of antitumor drug paclitaxel in KBV resistant strain cells:
the survival rate evaluation results of KBV drug-resistant strain cells of the derivatives show that the examples 1-5 have better tumor drug resistance reversal activity, wherein the activity is the best example 3.
TABLE 1 cell viability of examples 1-5 when administered alone and in combination
Balb/c nude mouse KBV cell xenograft tumor model tested the in vivo drug resistance reversal activity of example 3.
Consistent with the results of the in vitro study, paclitaxel was not active against KBV xenograft tumors in nude mice (figure 2). Co-treatment of example 3 with paclitaxel at a dose of 50mg/kg significantly increased the tumor suppressive activity of paclitaxel without increasing toxicity, wherein example 3 alone did not show significant anti-tumor activity (fig. 2). Compared with the control group, the tumor inhibition rate of the paclitaxel (30mg/Kg) group is about 11.14%, and the tumor inhibition rate of the paclitaxel and the example 3 combined treatment group is as high as 49.38%. We thus see that example 3 has a significant enhancement of the in vivo antitumor activity of paclitaxel in the KBV xenograft tumor model. Wherein example 3 alone did not show significant antitumor activity. The compounds of the present invention have the same in vivo drug resistance-reversing activity as in vitro and can be directly administered in vivo.
The present invention provides a compound which is the greatest difference from the closest prior art (document 1) in that the obtained novel compound has a remarkable drug resistance reversal property in vivo while maintaining the activity. The problem of document 1 is that although the compound provided has drug resistance reversal activity proved by in vitro experiments, the compound has poor in vivo activity and does not have drug administration in vivo, and the compound needs to be prepared into liposome by film dispersion assistance to have corresponding drug administration.
Claims (2)
1. HederageninA-ring-and-pyrazine derivative and medically acceptable salt thereof, characterized in that the hederagenin A-ring-and-pyrazine derivative isO- (23-hydroxy-olean-12-en-28-oylo [3, 2-)b]Pyrazine) -3-dimethylamino-1-propanol.
2. The use of the hederagenin A-cyclopopyrazine derivative of claim 1 and the pharmaceutically acceptable salts thereof for the preparation of a tumor drug resistance reversal agent for direct application in vivo.
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| CN112076200B (en) * | 2020-10-28 | 2022-01-11 | 烟台大学 | Application of hederagenin polyethylene glycol derivative |
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