CN111362962B - Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof - Google Patents
Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof Download PDFInfo
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- CN111362962B CN111362962B CN202010184573.XA CN202010184573A CN111362962B CN 111362962 B CN111362962 B CN 111362962B CN 202010184573 A CN202010184573 A CN 202010184573A CN 111362962 B CN111362962 B CN 111362962B
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Abstract
Tetrafluorobenzyl norcantharidin carboxylate and synthesis method and structure thereofThe structure formula is shown in a formula I,
the specific structure of the tetrafluorobenzyl norcantharidin carboxylate shown in the formula I comprises:
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a norcantharidin carboxylic acid tetrafluorobenzyl ester and a synthesis method thereof.
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
The invention aims to provide a norcantharidin carboxylic acid tetrafluorobenzyl ester and a synthesis method thereof.
A norcantharidin carboxylic acid tetrafluorobenzyl ester, the structural formula of which is shown in formula I,
the specific structure of the tetrafluorobenzyl norcantharidin carboxylate shown in the formula I comprises:
a synthetic method of tetrafluorobenzyl norcantharidinate carboxylate is characterized by comprising the following steps: the synthesis method comprises the following steps:
the side chain tetrafluorobenzyl alcohol (compound 5) and norcantharidin (compound 4) react in an organic solvent under the action of organic base at a certain temperature to obtain the norcantharidin carboxylic acid tetrafluorobenzyl ester shown in a formula I, and the synthetic route is as follows:
the tetrafluorobenzyl alcohol (compound 5) is 2,3,4, 5-tetrafluorobenzyl alcohol, 2,3,4, 6-tetrafluorobenzyl alcohol or 2,3,5, 6-tetrafluorobenzyl alcohol.
The organic base is triethylamine or 4-dimethylaminopyridine (4-DMAP for short); 4-DMAP is preferred.
The organic solvent is ethyl acetate, tetrahydrofuran or dichloromethane (abbreviation DCM); preferably DCM, and the temperature is preferably 60 ℃.
The preparation method of the norcantharidin (compound 4) 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 (compound 2) is added with hydrogen in an organic solvent to react to obtain the substrate norcantharidin (compound 4), and the synthetic route is 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) is carried out at room temperature.
In a preferred embodiment, the organic solvent used for the reaction in 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) 2 Palladium on carbon or platinum on carbon inclusive; 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 benzyl tetrafluoroborate shown in the formula I synthesized by the invention has good anti-tumor effect, especially on liver cancer. Half inhibitory concentration (IC50) on human liver cancer SMMC-7721 cells, compound 6-1 has an effect for 24h with an IC50 ═ 36.78 μ M, and for 48h with an IC50 ═ 25.07 μ M; compound 6-2 has an IC50 ═ 20.63 μ M for 24h and an IC50 ═ 18.32 μ M for 48 h; compound 6-3 acted 24h with an IC50 of 34.74 μ M and 48h with an IC50 of 22.09 μ M.
The inhibitory activity on human liver cancer Bel-7402 cells is that the compound 6-1 acts for 24h with the IC50 ═ 14.07 μ M, and acts for 48h with the IC50 ═ 16.53 μ M; compound 6-2 has an IC50 ═ 13.63 μ M for 24h and an IC50 ═ 16.76 μ M for 48 h; compound 6-3 has an IC50 ═ 12.94 μ M for 24h and an IC50 ═ 15.02 μ M for 48 h;
the activity of the compounds is stronger than that of norcantharidin and sodium norcantharidinate which are positive control medicaments, or the inhibiting activity is equivalent; can be used as cantharidin antineoplastic drugs to be applied clinically; therefore, the norcantharidin carboxylic acid tetrafluorobenzyl ester shown in the formula I is used for preparing the antitumor drug; preferably, the application of the compound in preparing anti-liver cancer drugs.
The beneficial effect of adopting above-mentioned technical scheme is:
the norcantharidin carboxylic acid tetrafluorobenzyl ester provided by the invention is a suitable candidate anti-tumor drug, and particularly serves as a candidate anti-liver cancer drug; compared with positive control drugs norcantharidin and sodium norcantharidinate, the compound of the invention introduces carboxyl in the molecular structure, thus improving the water solubility and stability; in addition, the introduction of fluorine-containing groups can significantly change the physical, chemical and biological properties of the parent molecule, thereby enhancing the pharmacokinetic efficacy. In addition, the synthesis method of the norcantharidin carboxylic acid tetrafluorobenzyl ester 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 protective scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Furan, maleic anhydride, 2,3,4, 5-tetrafluorobenzyl alcohol, 2,3,4, 6-tetrafluorobenzyl alcohol, 2,3,5, 6-tetrafluorobenzyl alcohol used in the present invention are available 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 (compound 4) of the invention,
the method specifically comprises the following steps:
1) placing maleic anhydride 1 into 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) and sequentially adding the obtained 5-alkene norcantharidin 3 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 is monitored by chromatography or chromatography-mass spectrometry. In the chromatography, thin layer chromatography can be used, and gas chromatography or liquid chromatography such as HPLC can be used instead.
The preparation method of the 5-alkene norcantharidin 3 comprises the following steps:
2.6g of maleic anhydride 1(26mmol) is placed in a round-bottom flask, 20mL of diethyl ether is added into the flask to completely dissolve the maleic anhydride 1, 22.9mL of furan (39mmol) is slowly dripped after complete dissolution, reaction is carried out for 24h at room temperature, suction filtration and drying are carried out to obtain a white solid compound 3, namely 5-alkene norcantharidin, the drying weight is 2.1g, and the yield is 48%. 1 HNMR(400Hz,DMSO-d 6 ):δ6.58(s,2H),5.35(s,2H),3.31(d,J＝4.0Hz,2H)。
The preparation method of norcantharidin (compound 4) comprises the following steps:
at room temperature, 1.7g of white solid compound 3, namely 5-alkene norcantharidin (10mmol) and 10% palladium-carbon (0.16g and 15 mmol%) are sequentially added into a 100mL three-necked bottle, the bottle is plugged, vacuum pumping is carried out, hydrogen is introduced, 30mL of ethyl acetate is added, and stirring is carried out for 24 hours at room temperature; 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 1.6g of white solid intermediate 4, namely the norcantharidin (compound 4), wherein the yield is 97%. 1 HNMR(400Hz,DMSO-d 6 ):4.86(s,2H),3.39(s,2H),1.65(s,4H)。
The preparation method of the norcantharidin carboxylic acid-2, 3,4, 5-tetrafluorobenzyl ester (compound 6-1) comprises the following steps:
norcantharidin (compound 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, 2,3,4, 5-tetrafluorobenzyl alcohol 5(2.0mmol, 240. mu.L) were added in that order and reacted at 60 ℃ for 14 hours. Cooling to room temperature after the reaction is finished, washing with HCl (1mol/L) and saturated saline solution for three times respectively, combining organic phases, drying the organic phases with anhydrous sodium sulfate, and performing flash column chromatography to obtain a white solid product, namely the norcantharidin carboxylic acid-2, 3,4, 5-tetrafluorobenzylEster (Compound 6-1) in 32.3% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.25(s,1H),7.48-7.41(m,1H),5.09(d,J＝12.8Hz,1H),5.00(d,J＝12.8Hz,1H),4.70(t,J＝4.4Hz,2H),3.05(s,2H),1.57-1.47(m,4H). 19 F NMR(376MHz,DMSO-d 6 )δ-139.61—-139.73(m,1F),-144.77—-144.82(m,1F),-156.94(t,J＝22.6Hz,1F),-158.54—-158.65(m,1F)。
The preparation method of the norcantharidin carboxylic acid-2, 3,4, 6-tetrafluorobenzyl ester (compound 6-2) comprises the following steps:
adding norcantharidin (compound 4) (1.0mmol,168mg) and 4-DMAP (1.0mmol,244mg) into a 25mL sealed tube respectively, replacing with argon for three times, sequentially adding 2.5mL of DCM and 2,3,4, 6-tetrafluorobenzyl alcohol 5(2.0mmol,240 mu L), and reacting at 60 ℃ for 14 h; 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 then subjected to flash column chromatography to obtain a white solid product, namely the norcantharidin carboxylic acid-2, 3,4, 6-tetrafluorobenzyl ester (compound 6-2), and the yield is 32.5%. 1 H NMR(400MHz,DMSO-d 6 )δ12.20(s,1H),7.58-7.51(m,1H),5.08(d,J＝12.4Hz,1H),5.00(d,J＝12.4Hz,1H),4.67(d,J＝3.6Hz,2H),3.01(dd,J＝15.2Hz,9.6Hz,2H),1.58-1.48(m,4H). 19 F NMR(376MHz,DMSO-d 6 )δ-121.33,-136.23,-139.66(d,J＝22.6Hz,1F),-170.09。
The preparation method of the norcantharidin carboxylic acid-2, 3,5, 6-tetrafluorobenzyl ester (compound 6-3) comprises the following steps:
adding norcantharidin (compound 4) (1.0mmol,168mg) and 4-DMAP (1.0mmol,244mg) into a 25mL sealed tube respectively, replacing with argon for three times, sequentially adding 2.5mL of DCM, 2,3,5, 6-tetrafluorobenzyl alcohol 5(2.0mmol,240 mu L), and reacting at 60 ℃ for 14 h; after the reaction is finished, cooling to room temperature,washing with HCl (1mol/L) and saturated saline solution for three times, combining organic phases, drying the organic phases with anhydrous sodium sulfate, and performing flash column chromatography to obtain a white solid product, namely the norcantharidin carboxylic acid-2, 3,5, 6-tetrafluorobenzyl ester (compound 6-3), wherein the yield is 21.1%. 1 H NMR(400MHz,DMSO-d 6 )δ12.24(s,1H),7.99-7.90(m,1H),5.15(d,J＝12.0Hz,1H),5.07(d,J＝12.4Hz,1H),4.67(s,2H),3.02(dd,J＝14.8Hz,9.6Hz,2H),1.57-1.49(m,4H). 19 F NMR(376MHz,DMSO-d 6 )δ-139.09,-139.39,-142.11,-144.38.
Activity test of Tetrafluorobenzyl norcantharidinate I
Cell lines:
human liver cancer SMMC-7721 cells;
human liver cancer Bel-7402 cells;
culturing the cells in RPMI1640 containing 10% fetal bovine serum;
solvent:
dimethylsulfoxide (abbreviated as DMSO).
The CCK-8 staining method for detecting the anti-tumor activity of the cells comprises the following steps:
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 EnoGeneCell TM Counting 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% CO 2 Culturing 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% CO 2 After 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 for human hepatoma SMMC-7721 cells
TABLE 2 IC50 of human hepatoma Bel-7402 cells
The experimental results in tables 1-2 show that the compounds of the present invention have very good in vitro anti-tumor activity. The inhibitory activity of the 3 compounds on human liver cancer cells SMMC-7721 is obviously stronger than that of norcantharidin and is equivalent to that of sodium norcantharidin; the inhibition activity of human liver cancer cell Bel-7402 is obviously stronger than that of norcantharidin and sodium norcantharidinate.
In addition, compared with a positive control norcantharidin, the compound introduces carboxyl 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 of the invention is a suitable candidate drug for resisting tumors, in particular to a candidate drug for resisting liver cancer.
Claims (2)
1. The tetrafluorobenzyl norcantharidin carboxylate is characterized in that: the structural formula is shown as a formula I,
the specific structure of the tetrafluorobenzyl norcantharidin carboxylate shown in the formula I comprises:
compound 6-1 norcantharidin carboxylic acid-2, 3,4, 5-tetrafluorobenzyl ester compound 6-2 norcantharidin carboxylic acid-2, 3,4, 6-tetrafluorobenzyl ester
The compound 6-3 norcantharidin carboxylic acid-2, 3,5, 6-tetrafluorobenzyl ester.
2. The tetrafluorobenzyl norcantharidin carboxylate according to claim 1, characterized in that: can be used for preparing anti-liver cancer medicine.
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