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Synthesis and anti-tumor application of norcantharidin carboxylic acid perfluorobenzyl ester

A technology of methylcantharidin carboxylic acid and norcantharidin, which is applied in the synthesis of norcantharidin carboxylic acid perfluorobenzyl ester and its anti-tumor application field, to achieve easy availability of raw materials, enhanced pharmacokinetic efficacy, and easy operation The effect of implementation

Inactive Publication Date: 2020-06-09
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are few studies on the introduction of fluorine-containing groups into cantharidin. At the same time, in order to find anti-tumor drug candidates with better efficacy and less toxicity, and to expand the types of cantharidin anti-tumor drugs, we designed a fluorine-containing group The fluorine-containing derivatives of norcantharidin were synthesized, which laid the foundation for the subsequent screening of anticancer activity

Method used

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  • Synthesis and anti-tumor application of norcantharidin carboxylic acid perfluorobenzyl ester
  • Synthesis and anti-tumor application of norcantharidin carboxylic acid perfluorobenzyl ester
  • Synthesis and anti-tumor application of norcantharidin carboxylic acid perfluorobenzyl ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1、5

[0030] The preparation of embodiment 1,5-ene norcantharidin 3:

[0031] Take a certain amount of maleic anhydride 1 (26mmol, 2.6g), put it in a round-bottomed flask, add 20mL of ether into the bottle to completely dissolve the maleic anhydride, and after it is completely dissolved, slowly add 2.9mL of furan 2 (39mmol), reacted at room temperature for 24h, suction filtered, and dried to obtain white solid compound 3, namely 5-enenorcantharidin, which weighed 2.1g after drying, and the yield was 48%. 1 H NMR (400Hz, DMSO-d 6 ): δ6.58(s, 2H), 5.35(s, 2H), 3.31(d, J=4.0Hz, 2H).

[0032] The organic solvent used to dissolve maleic anhydride in step 1 of the above-mentioned embodiment 1 can be replaced by any one of dichloromethane, chloroform, and tetrahydrofuran in addition to diethyl ether.

Embodiment 2

[0033] Embodiment 2. The preparation of norcantharidin 4:

[0034] At room temperature, take compound 3 (10mmol, 1.7g) in step (1), and add 10% palladium carbon (0.16g, 15mmol%) into a 100mL three-necked bottle in turn, stopper and vacuumize, pass in hydrogen, and then add acetic acid Ethyl ester 30mL, stirred at room temperature for 24h. Suction filtration after the reaction was completed, the filter cake was rinsed 2-3 times with ethyl acetate, and the obtained filtrate was concentrated under reduced pressure to obtain white solid intermediate 4 (1.6 g), i.e. norcantharidin, with a yield of 97%. 1 H NMR (400Hz, DMSO-d 6 ): 4.86(s,2H), 3.39(s,2H), 1.65(s,4H).

Embodiment 3

[0035] Embodiment 3. The preparation of norcantharidin carboxylic acid perfluorobenzyl ester 6:

[0036]

[0037] Add norcantharidin 4 (1.0mmol, 168mg) and DMAP (1.0mmol, 244mg) to the 25mL sealed tube respectively, after argon replacement three times, then add DCM 2.5mL, pentafluorobenzyl alcohol 5 (2.0mmol, 274μL ), reacted at 60°C for 14h. After the reaction was finished, it was cooled to room temperature, washed three times with HCl (1mol / L) and saturated brine respectively, and the organic phase was combined. After drying the organic phase with anhydrous sodium sulfate, flash column chromatography obtained the white solid product 6, and the yield was 28.5%. %. 1 H NMR (400MHz, DMSO-d 6 )δ12.15(s,1H),5.11(s,2H),4.67(t,J=4.4Hz,2H),3.01(dd,J=16.8Hz,9.6Hz,2H),1.57-1.49(m, 4H). 19 F NMR (376MHz, DMSO-d 6 )δ-144.00(d, J=15.0Hz, 2F), -155.55(t, J=22.6Hz, 1F), -162.47—-162.58(m, 2F).

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Abstract

The invention provides synthesis and anti-tumor application of norcantharidin carboxylic acid perfluorobenzyl ester with a structural formula shown as I in the specification. Activity tests show thatthe norcantharidin carboxylic acid perfluorobenzyl ester obtained by synthesis is a candidate medicine suitable for resisting tumors, and particularly serves as a candidate medicine for resisting liver cancer. Compared with positive control drugs including norcantharidin and sodium norcantharidate, carboxyl is introduced into the molecular structure of the compound I, so that the water solubility,stability and anti-tumor activity are improved. Due to the introduction of a fluorine-containing group, the physical property, the chemical property and the biological activity of parent molecules can be remarkably changed, so that the pharmacokinetic efficacy can be enhanced. The synthesis method of the norcantharidin carboxylic acid perfluorobenzyl ester has the advantages that the raw materials are easy to obtain, and the operation and the implementation are very easy.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to the synthesis of a class of norcantharidin carboxylate perfluorobenzyl ester and its antitumor application. Background technique [0002] Cantharidin (cantharidin, CA) is an anti-cancer substance extracted from the body of Cantharis, an insect of the family Melanthaceae. It has good curative effects on liver cancer, ovarian cancer, esophageal cancer, etc., and has a special inhibitory effect on primary liver cancer. However, due to the severe toxicity of cantharidin, it can seriously stimulate the human urinary system and digestive system, so it has certain limitations in its clinical application. The artificially synthesized cantharidin derivative norcantharidin (Norcantharidin, NCTD) has the same configuration as cantharidin, but the 2 and 3 methyl groups are replaced by hydrogen, and the toxic and side effects are significantly reduced. It can not only s...

Claims

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Application Information

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IPC IPC(8): C07D493/08C07D493/18A61P35/00
CPCC07D493/08C07D493/18A61P35/00
Inventor 张新刚贺春阳李晓飞贾佳朱二林
Owner ZUNYI MEDICAL UNIVERSITY