CN111233883A - Norcantharidin fluorine-containing benzyl ester salt derivative, synthesis method and anti-tumor application - Google Patents
Norcantharidin fluorine-containing benzyl ester salt derivative, synthesis method and anti-tumor application Download PDFInfo
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Abstract
A norcantharidin fluorine-containing benzyl ester salt derivative, a synthesis method and anti-tumor application thereof,
the specific structure of the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I comprises:
Description
Technical Field
The invention belongs to the field of new drug design and synthesis, and particularly relates to synthesis and anti-tumor application of a norcantharidin fluorine-containing benzyl ester salt derivative.
Background
Cantharidin (CA) is an anticancer substance extracted from Mylabris (Mylabris phalerata Linnaeus) of family Meloidae, and has good therapeutic effects on hepatocarcinoma, ovarian cancer, esophageal cancer, etc., especially on primary hepatocarcinoma. However, cantharidin has severe toxicity and serious irritation to urinary system and digestive system of human body, and has certain limitation in clinical application. The artificially synthesized cantharidin derivative Norcantharidin (NCTD) has the same configuration as that of cantharidin, but 2 and 3 methyl groups are replaced by hydrogen, so that the toxic and side effects are obviously reduced, the Norcantharidin derivative Norcantharidin can stimulate bone marrow to have the effect of increasing white blood cells, and has the effects of protecting liver cells and enhancing immunity, but because the Norcantharidin has short detention time in a human body, adverse reactions occur when the Norcantharidin is slightly excessive, and the limitation of the dosage greatly prevents the medicine from exerting curative effects. The sodium norcantharidinate is prepared by hydrolyzing norcantharidin under alkaline conditions, the toxicity of the compound is obviously reduced, the pharmacological action is clear, and the compound can be applied to clinic.
Therefore, the synthesis of the high-efficiency low-toxicity norcantharidin derivative and the development of the variety of cantharidin anticancer drugs have great significance, and the synthesis of the norcantharidin derivative becomes an antitumor research hotspot of modern Chinese medicaments. "fluorine" is a highly surprising atom with a small atomic radius (between the hydrogen and oxygen atoms) and a maximum electronegativity, so that the selective introduction of a fluorine atom or fluorine-containing group into a drug lead molecule can produce significant changes in the physical, chemical, and biological properties of the parent molecule. According to the statistics of pharmacologists, the introduction of fluorine into the drug lead molecules can improve the drug success rate by ten times, 30-40% of pesticides contain fluorine at present, and 20% of marketed drugs contain fluorine, so that the efficient synthesis of fluorine-containing analogues of some bioactive molecules is an effective means for obtaining high-activity drug lead molecules, and is one of important ways for developing new drugs.
At present, research on introducing fluorine-containing groups into cantharidin is less, and in order to search candidates of antitumor drugs with better drug effect and lower toxicity and expand the types of cantharidin antitumor drugs, the fluorine-containing groups are introduced into norcantharidin, so that the fluorine-containing derivatives of norcantharidin are synthesized, and a foundation is laid for subsequent screening of anticancer activity.
Disclosure of Invention
On one hand, the invention provides a norcantharidin fluorine-containing benzyl ester salt derivative, the structural formula of which is shown as a formula I,
the specific structure of the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I comprises:
on the other hand, the invention provides a synthesis method of the norcantharidin fluorine-containing benzyl ester salt derivative I, which comprises the following steps: 1) reacting side chain fluorine-containing benzyl alcohol 5 (compound 5) with norcantharidin (compound 4) in an organic solvent at a certain temperature under the action of organic base to obtain a compound 6, namely fluorine-containing benzyl norcantharidin carboxylate; 2) compound 6 with hydroxide (NaOH, Mg (OH)2) The neutralization reaction is carried out to obtain the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I, and the synthetic route is shown as follows:
in a specific embodiment, the fluorinated benzyl alcohol (compound 5) in step 1) is 3-fluorobenzyl alcohol and 3, 5-difluorobenzyl alcohol, respectively.
In a preferred embodiment, the organic base described in step 1) above is selected from triethylamine, 4-dimethylaminopyridine (4-DMAP for short) and the like, preferably 4-DMAP.
In a preferred embodiment, the solvent of step 1) above is selected from ethyl acetate, tetrahydrofuran, dichloromethane and the like, preferably dichloromethane (abbreviated as DCM), preferably at a temperature of 60 ℃.
In a specific embodiment, the hydroxides in step 2) above are sodium hydroxide and magnesium hydroxide, respectively.
In a preferred embodiment, the solvent of step 2) above is selected from dichloromethane and alcoholic solutions, preferably methanol.
In a preferred embodiment, when the hydroxide in the step 2) is NaOH, the temperature is preferably room temperature; when the hydroxide is Mg (OH)2When the temperature is higher than the reflux temperature, the reflux temperature is preferable.
In another aspect, the invention also provides a substrate 4 for synthesizing the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I and a preparation method thereof, wherein the method comprises the following steps: a) furan is used as a raw material and reacts with maleic anhydride (compound 1) in an organic solvent to obtain 5-alkene norcantharidin (compound 2); b) the 5-alkene-norcantharidin 2 and hydrogen are subjected to addition reaction in an organic solvent to obtain a substrate norcantharidin (compound 4), and the synthetic route is shown as follows:
in a preferred embodiment, the organic solvent used in step a) is an ethereal solvent or a halogenated hydrocarbon, such as: diethyl ether, tetrahydrofuran, dichloromethane or chloroform.
In a preferred embodiment, step a) can be carried out at room temperature, or with suitable heating; preferably room temperature.
In a preferred embodiment, the organic solvent used for the reaction of step b) is ethyl acetate, tetrahydrofuran or dichloromethane;
in a preferred embodiment, the catalyst used in the catalytic hydrogenation of step b) is selected from the group consisting of Pd/C, and Pd (OH)2Palladium carbon and platinum carbon including/C; Pd/C is preferred.
In the above synthesis and preparation methods, the reaction temperature may be appropriately selected according to the type of reaction. The reaction time can be obtained by tracking the reaction condition through monitoring means such as thin layer chromatography TLC, high performance liquid chromatography HPLC or LC-MS liquid mass spectrum combination and the like.
Activity tests prove that the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I, which is designed and synthesized by the invention, has a good anti-tumor effect, especially aiming at liver cancer; in an inhibitory activity test of human liver cancer SMMC-7721 cells, the compound I-1 acts for 24h with the IC50 being 19.89 mu M, and acts for 48h with the IC50 being 16.52 mu M; compound I-2 acted 24h with IC50 ═ 11.51 μ M, 48h with IC50 ═ 10.97 μ M; compound I-3 has an IC50 of 22.66 μ M for 24h and an IC50 of 14.38 μ M for 48 h; compound I-4 acted 24h with an IC50 of 8.67 μ M and 48h with an IC50 of 8.34 μ M.
The activity test of human liver cancer Bel-7402 cells shows that the compound I-1 acts for 24h with the IC50 being 15.36 mu M and the IC50 being 15.01 mu M; compound I-2 with IC50 ═ 10.62 μ M for 24h and IC50 ═ 9.98 μ M for 48 h; compound I-3 has an IC50 ═ 12.84 μ M for 24h and an IC50 ═ 12.01 μ M for 48 h; compound I-4 acted 24h with an IC50 of 7.21 μ M and 48h with an IC50 of 6.69 μ M. The activity of the compound is obviously stronger than that of positive control drugs norcantharidin and sodium norcantharidinate; can be used as cantharidin antineoplastic agent in clinic.
Therefore, the fourth aspect of the invention provides the application of the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I in preparing antitumor drugs; preferably, the application of the compound in preparing anti-liver cancer drugs.
The invention has the advantages that: the invention provides a norcantharidin fluorine-containing benzyl ester salt derivative shown in a formula I, which is a suitable candidate anti-tumor medicament, and is particularly used as a candidate anti-liver cancer medicament. Compared with norcantharidin serving as a positive control medicament, the compound I introduces metal sodium ions and magnesium ions into the molecular structure, so that the water solubility and the stability are improved; compared with sodium norcantharidinate, the compound I has the advantages that the molecular structure of the compound I is introduced with the fluorine-containing group, so that the physical property, the chemical property and the biological activity of parent molecules can be obviously changed, and the pharmacokinetic efficacy can be enhanced. In addition, the synthesis method of the norcantharidin fluorine-containing benzyl ester salt derivative has the advantages of easily available raw materials and easy operation and implementation.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Without departing from the inventive concept, a person skilled in the art may make modifications or combinations of the parameters or conditions of the claims, which modifications or combinations shall also be considered as the protective scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Furan, maleic anhydride, 3-fluorobenzyl alcohol, 3, 5-difluorobenzyl alcohol, sodium hydroxide, magnesium hydroxide used in the present invention were from sahn chemical technology (shanghai) ltd; the solvent used is from Shanghai Tantake technology, Inc. The reagents used are all chemically pure, unless otherwise specified.
The synthesis method of the lead compound norcantharidin 4 of the invention,
the method specifically comprises the following steps:
1) placing maleic anhydride in a dry round-bottom flask, adding diethyl ether for dissolving, dropwise adding furan 2 after complete dissolution, reacting at room temperature for 24h, performing suction filtration, and drying to obtain a white solid intermediate 5-alkene norcantharidin 3 for later use;
2) sequentially adding the 5-alkene norcantharidin 3 obtained in the step 1) and 10% palladium carbon into a 100mL three-necked bottle, vacuumizing, introducing hydrogen, adding 30mL of ethyl acetate, stirring at room temperature for 24h, filtering after the reaction is finished, and concentrating under reduced pressure to obtain a white solid product norcantharidin 4. In the above reaction, the progress of the reaction can be monitored by chromatography or HPLC-MS. In the chromatography, thin layer chromatography can be used, and gas chromatography or liquid chromatography such as HPLC can be used instead.
Example 1.preparation of 5-Endecamethylcantharidin 3:
putting a certain amount of maleic anhydride 1(26mmol,2.6g) into a round-bottom flask, adding 20mL of diethyl ether into the flask to completely dissolve the maleic anhydride, slowly dropwise adding 22.9 mL (39mmol) of furan after complete dissolution, reacting at room temperature for 24h, performing suction filtration, and drying to obtain a white solid compound 3, namely 5-alkene norcantharidin, wherein the dry weight is 2.1 g, and the yield is 48%.1HNMR(400Hz,DMSO-d6):δ6.58(s,2H),5.35 (s,2H),3.31(d,J＝4.0Hz,2H)。
The organic solvent used for dissolving maleic anhydride in step 1 of example 1 may be replaced with any one of dichloromethane, chloroform, and tetrahydrofuran, in addition to diethyl ether.
Example 2 preparation of norcantharidin 4:
at room temperature, the compound 3(10mmol,1.7g) in the step (1) and 10% palladium carbon (0.16g,15 mmol%) are sequentially added into a 100mL three-necked bottle, the bottle is plugged and vacuumized, hydrogen is introduced, then 30mL of ethyl acetate is added, and the mixture is stirred at room temperature for 24 hours. After the reaction is finished, suction filtration is carried out, a filter cake is washed by ethyl acetate for 2-3 times, and the obtained filtrate is decompressed and concentrated to obtain a white solid intermediate 4(1.6g), namely the norcantharidin, with the yield of 97%.1H NMR(400 Hz,DMSO-d6):4.86(s,2H),3.39(s,2H),1.65(s,4H)。
Example 3 preparation of 3-fluorobenzyl norcantharidinate carboxylate (Compound 6-1):
norcantharidin 4(1.0mmol,168mg), 4-DMAP (1.0mmol,244mg) were added to 25mL of the sealed tube, and after three times of replacement with argon, 2.5mL of DCM, 5-1(2.0mmol, 217. mu.L) of 3-fluorobenzyl alcohol were added in that order, and the mixture was reacted at 60 ℃ for 14 hours. After the reaction is finished, the reaction product is cooled to room temperature, the reaction product is washed for three times by HCl (1mol/L) and saturated saline solution respectively, organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, and the white solid product 6-1 is obtained by flash column chromatography, wherein the yield is 30.7%.1HNMR(400MHz,DMSO-d6) δ12.32(s,1H),7.41(q,J＝8.0Hz,1H),7.21-7.13(m, 3H),5.04(d,J＝13.2Hz,1H),4.94(d,J＝13.2Hz,1 H),4.76-4.68(m,2H),3.07(dd,J＝14.8Hz,9.6Hz,2H),1.59-1.51(m,4H).19F NMR(376MHz,DMSO-d6)δ-117.76 —-117.88(m,1F).
Example 4 preparation of 3, 5-difluorobenzyl norcantharidinate carboxylate (Compound 6-2):
norcantharidin 4(1.0mmol,168mg), 4-DMAP (1.0mmol,244mg) were added to each 25mL sealed tube, and after three times of replacement with argon, 2.5mL of DCM, 3, 5-difluorobenzyl alcohol 5-2(2.0mmol, 227. mu.L) were added in that order, and the mixture was reacted at 60 ℃ for 14 hours. After the reaction is finished, the reaction product is cooled to room temperature, the reaction product is washed for three times by HCl (1mol/L) and saturated saline solution respectively, organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, and the white solid product 6-2 is obtained by flash column chromatography, wherein the yield is 44.8%.1H NMR(400MHz,DMSO-d6) δ12.34(s,1H),7.18(t,J＝9.6Hz,1H),7.09(d,J＝6.4Hz,2H),5.05(d,J＝13.6Hz,1H),4.96(d,J＝13.6 Hz,1H),4.73(dd,J＝12.4Hz,2.0Hz,2H),3.09(dd, J＝16.0Hz,9.6Hz,2H),1.59-1.50(m,4H).19F NMR(376 MHz,DMSO-d6)δ-109.39(t,J＝7.5Hz,2F).
Example 5 preparation of norcantharidin-3-fluorobenzyl ester sodium salt I-1:
50mg (1.0equiv) of Compound 6-1 obtained in example 3 was weighed in a round-bottomed flask, dissolved in 15mL of methanol, added with 7.6mg (1.2equiv) of NaOH, stirred at room temperature, and stopped after disappearance of the starting material by TLC. Removing the solvent under reduced pressure, and performing column chromatography to obtain a white solid product, namely the target product norcantharidin-3-fluorobenzyl ester sodium salt, with the yield of 67%.1H NMR(400MHz,D2O)δ7.39(q,J＝8.0 Hz,1H),7.19(q,J＝7.6Hz,2H),7.089(t,J＝8.8Hz, 1H),5.09(d,J＝12.8Hz,1H),5.00(d,J＝12.8Hz,1 H),4.87-4.86(m,2H),3.02(dd,J＝37.2Hz,10.0Hz,2 H),1.71-1.67(m,2H),1.57-1.52(m,2H).
Example 6 preparation of norcantharidin-3, 5-difluorobenzyl ester sodium salt I-2:
62.4mg (0.2mmol,1.0equiv) of the compound 6-2 obtained in example 4 was weighed in a round-bottomed flask, dissolved in 10mL of methanol,8.0mg (0.2mmol,1.0equiv) of NaOH was added thereto, the reaction was stirred at room temperature, and the reaction was stopped after disappearance of the starting material by TLC. The solvent is removed under reduced pressure, and a white solid product, namely the target product norcantharidin-3, 5-difluoro benzyl ester sodium salt is obtained after column chromatography, wherein the yield is 70%.1H NMR (400MHz,DMSO-d6)δ7.17(t,J＝8.4Hz,1H),7.09(d, J＝7.2Hz,2H),5.04(d,J＝13.2Hz,1H),4.96(d, J＝13.2Hz,1H),4.73(d,J＝11.6Hz,2H),3.08(dd, J＝14.0Hz,8.8Hz,2H),1.55-1.49(m,4H)。
Example 7 preparation of magnesium norcantharidin-3-fluorobenzyl ester I-3:
50mg (1.0equiv) of Compound 6-1 obtained in example 3 was weighed in a round-bottomed flask, dissolved by adding 15mL of methanol, and 9.9mg (1.2equiv) of Mg (OH) was added thereto2Heating and refluxing for reaction, and stopping the reaction after TLC detection shows that the raw materials disappear. Removing the solvent under reduced pressure, and performing column chromatography to obtain a white solid product, namely the target product norcantharidin-3-fluorobenzyl ester magnesium salt, with the yield of 38%.1H NMR(400MHz,D2O)δ 7.45-7.33(m,1H),7.20-7.05(m,3H),5.05(dd,J＝27.6Hz,12.0Hz,2H),4.89-4.77(m,2H),3.14-3.07(m,2H), 1.70(s,2H),1.57(s,2H)。
Example 8 preparation of magnesium salt of norcantharidin-3, 5-difluorobenzyl ester I-4:
62.4mg (0.2mmol) of the compound 6-2 obtained in example 4 was weighed in a round-bottomed flask, dissolved by adding 10mL of methanol, and 11.6mg (0.2mmol) of Mg (OH) was added thereto2Heating and refluxing for reaction, and stopping the reaction after TLC detection shows that the raw materials disappear. Removing the solvent under reduced pressure, and performing column chromatography to obtain a white solid product, namely the target product norcantharidin-3, 5-difluoro benzyl ester magnesium salt, wherein the yield is 36%.1H NMR(400MHz,DMSO-d6) δ7.18(t,J＝9.2Hz,1H),7.07(d,J＝10.0Hz,2H), 5.04(d,J＝13.6Hz,1H),4.96(d,J＝13.6Hz,1H), 4.73(d,J＝12.4Hz,2H),3.09(dd,J＝15.2Hz,10.0 Hz,2H),1.56-1.50(m,4H).
Example 9 Activity test of fluorine-containing benzyl ester salt derivatives of norcantharidin
Cell line and solvent
Human liver cancer SMMC-7721 cells;
human liver cancer Bel-7402 cells;
culturing the cells in RPMI 1640 containing 10% fetal bovine serum;
solvent: dimethylsulfoxide (abbreviated as DMSO).
Embodiment for detecting anti-tumor activity of cells by CCK-8 staining method
Selecting the cells with the ratio of the tumor living cells to be detected being more than 90 percent for experiment. Cell proliferation inhibition assay Using EnoGeneCellTMCounting Kit-8 (CCK-8 for short) cell viability detection Kit. Taking human liver cancer SMMC-7721 and Bel-7402 cells in logarithmic growth phase, discarding culture solution, washing with PBS for 2 times, digesting with pancreatin, centrifuging, re-suspending and mixing the cells uniformly in culture solution, 8000 cells/hole, and inoculating in 96-well plate in parallel. The 96-well plate was placed at 37 ℃ in 5% CO2Culturing in incubator for 24 hr, taking out, adding 100 μ L culture solution containing compound to be tested into each well, and simultaneously establishing negative control group, solvent control group, and positive control group (the positive control group respectively adopts norcantharidin and sodium norcantharidinate). 3 replicates per group at 37 ℃ with 5% CO2After the culture is continued for 24 or 48 hours in the incubator, 10 mu L of CCK-8 solution is added into each hole, the culture plate is incubated in the incubator, an enzyme-labeling instrument is used for measuring the light absorption value (OD value) at 450nm, the experiment group and the control group are repeated for 3 times, and the IC50 of each compound acting on the human liver cancer cell SMMC-7721 and the human liver cell Bel-7402 is calculated. The experimental results are detailed in tables 1-2.
TABLE 1 IC50 of human liver cancer SMMC-7721 cells
TABLE 2 IC50 of human hepatoma Bel-7402 cells
The experimental results in tables 1-2 show that the compound I of the present invention has good in vitro anti-tumor activity. The norcantharidin fluorine-containing benzyl ester salt derivatives have obviously stronger inhibitory activity on human liver cancer cells SMMC-7721 and human liver cancer cells Bel-7402 than norcantharidin and sodium norcantharidinate.
In addition, compared with a positive control norcantharidin, the compound I introduces metal sodium ions and magnesium ions into the molecular structure, so that the water solubility and the stability are improved; compared with positive reference products of norcantharidin and sodium norcantharidinate, the biological activity of the norcantharidin and sodium norcantharidinate is obviously changed due to the introduction of fluorine-containing groups. Therefore, the compound I is a suitable candidate drug for resisting tumors, particularly as a candidate drug for resisting liver cancer.
Claims (10)
1. The norcantharidin fluorine-containing benzyl ester salt derivative has a structural formula shown in a formula I:
the specific structure of the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I comprises:
2. the method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 1, comprising the following steps:
the method comprises the following steps: the side chain contains fluorobenzyl alcohol 5, namely a compound 5, and norcantharidin, namely a compound 4, and the compound 6, namely the fluorine-containing benzyl norcantharidinate is obtained by reacting under the action of organic base in an organic solvent at a certain temperature;
step two: compound 6 with hydroxide, i.e. NaOH, Mg (OH)2Carrying out neutralization reaction to obtain the fluorine-containing benzyl ester salt derivative of norcantharidin shown as a formula I;
the synthetic route is shown as follows:
3. the method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 2, which is characterized in that: the compound 5 is fluorobenzyl alcohol, and the fluorobenzyl alcohol is 3-fluorobenzyl alcohol and 3, 5-difluorobenzyl alcohol respectively.
4. The method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 2, which is characterized in that: the organic base is selected from triethylamine or 4-dimethylaminopyridine.
5. The method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 2, which is characterized in that: the organic solvent is selected from ethyl acetate, tetrahydrofuran, dichloromethane, alcohol solution or methanol, and the temperature condition is 60 ℃.
6. The method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 2, which is characterized in that: the hydroxide is sodium hydroxide and magnesium hydroxide respectively.
7. The method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 2, which is characterized in that: the preparation method for synthesizing the compound 4 of the norcantharidin fluorine-containing benzyl ester salt derivative shown in the formula I comprises the following steps:
step a: furan is used as a raw material and reacts with maleic anhydride, namely a compound 1, in an organic solvent to obtain 5-alkene norcantharidin, namely a compound 2;
step b: the 5-alkene-norcantharidin 2 is added with hydrogen in an organic solvent to react to obtain norcantharidin, namely a compound 4, and the synthetic route is as follows:
8. the method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 7, which is characterized in that: the organic solvent used in step a) is an ether solvent or a halogenated hydrocarbon, for example: diethyl ether, tetrahydrofuran, dichloromethane or chloroform; the step a) may be carried out at room temperature, or may be suitably heated.
9. The method for synthesizing norcantharidin fluorine-containing benzyl ester salt derivative I according to claim 7, which is characterized in that: the organic solvent used in the reaction in the step b) is ethyl acetate, tetrahydrofuran or dichloromethane; the catalyst used in the step b) catalytic hydrogenation reaction is selected from Pd/C, Pd (OH)2Palladium carbon and platinum carbon including/C; Pd/C is preferred.
10. The application of the fluorine-containing benzyl cantharidin salt derivative according to claim 1, wherein the fluorine-containing benzyl cantharidin salt derivative is characterized in that: norcantharidin fluorine-containing benzyl ester salt derivatives can be used for treating hepatocarcinoma.
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