Norcantharidin monomer-acid monoester derivative and anti-tumor application thereof

A technology of norcantharidin and monoacid monoester, which is applied in the direction of antineoplastic drugs, drug combinations, and active ingredients of heterocyclic compounds, and can solve the structure and synthesis method of norcantharidin monoacid monoester derivatives that have not been reported yet. , low bioavailability, poor water solubility, etc.

Inactive Publication Date: 2016-11-09
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, both cantharidin and norcantharidin have been used clinically. Both of these two drugs have their own clinical characteristics, but the disadvantages are: the water solubility of these two drugs is poor, and the bioavailability is not high.
Chinese patents with applica

Method used

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  • Norcantharidin monomer-acid monoester derivative and anti-tumor application thereof
  • Norcantharidin monomer-acid monoester derivative and anti-tumor application thereof
  • Norcantharidin monomer-acid monoester derivative and anti-tumor application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0029] The preparation of embodiment 1.5-ene norcantharidin 1

[0030] Take out a certain amount of maleic anhydride from the reagent bottle, place it in a dry grinding body and grind it finely, then weigh 12.021g of the finely ground maleic anhydride with an electronic balance, put it in a dry three-necked flask, and plug it Stopper, add diethyl ether and stir, when the amount of diethyl ether is 90mL, the maleic anhydride is completely dissolved. After the maleic anhydride was completely dissolved, 13 mL of furan was slowly added through the dropping funnel for 13 minutes. The temperature was controlled to start the reaction at 38°C. After reacting for 1 h, white solids appeared in the solution, and the longer the time, the more white solids there were. After reacting for 24 hours, it was filtered with suction to obtain compound 1 as a white solid, that is, 5-enorcantharidin. The dry weight was 17.46g, and the yield was 85.8%. Melting point: 122-123°C, ratio shift Rf: 0....

Embodiment 2

[0031] Embodiment 2. The preparation of norcantharidin 2

[0032] Take 5-enenorcantharidin 1 (1.091g) in a Schlenk bottle, add 20ml of tetrahydrofuran to dissolve it, add 109mg of palladium carbon, remove the air in the flask by vacuum, then feed hydrogen, stir at 25°C to make it react, After the reaction was finished, palladium carbon was removed by suction filtration, and the resulting filtrate was rotary evaporated and dried to obtain norcantharidin (72.2%), 794.3 mg of white solid. 1 HNMR (DMSO-d 6 ): δ: 4.85 (s, 2H), 3.34 (d, J=20Hz, 2H), 1.65 (d, J=8Hz, 4H). 13 CNMR (DMSO-d 6 ): δ: 173.35, 80.08, 51.14, 40.35, 40.14, 39.93, 39.72, 27.90.

Embodiment 3

[0033] Embodiment 3. the synthesis of norcantharidin monoethyl ester (3, R=Et):

[0034] Steps: Take 672mg of norcantharidin in a flask, add 30ml of absolute ethanol to dissolve it, heat to reflux at 80°C, after 4.5 hours, the reaction is complete, rotary steam, use ethyl acetate as the eluent to pass through the silica gel column, spot the plate, The collected colored samples were rotary evaporated and dried to obtain norcantharidin monoacid ethyl ester (87%), 747.2 mg of white solid. 1 HNMR (CDCl3): δ: 4.91 (d, J = 24Hz, 2H), 4.11 (d, J = 8Hz, 2H), 2.99 (q, J = 12Hz, 3H), 1.81 (t, J = 4Hz, 2H) , 1.52 (d, J=8Hz, 2H), 1.21 (t, J=8Hz, 3H). 13CNMR (CDCl3): δ: 176.45, 170.87, 78.59, 78.29, 77.03, 76.71, 61.16, 52.27, 28.97, 13.94.

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Abstract

The invention provides a norcantharidin monomer-acid monoester derivative and an application thereof. The structural formula of the derivative is shown as the No.3 formula (please see the specification), wherein R is selected from alkyl or benzyl of C1 to C3. An activity test proves that the third designed and synthesized norcantharidin monomer-acid monoester derivative has good inhabitation activity in liver cancer tumor cells, stomach cancer tumor cells and colon cancer tumor cells, and can be expected to be applied to preparing medicine for resisting the three tumors.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to a novel norcantharidin monoacid monoester derivative and its antitumor application. Background technique [0002] Mylabris, also written as Mylabris, commonly known as banmiao, Spanish fly, etc., has been recorded in the earliest existing Chinese pharmacy monographs "Compendium of Materia Medica" and "Shen Nong's Materia Medica". Cantharidin is the dry body of the insects of the family Mythaceae, the southern large spot or the yellow-black small spot, which belongs to the insect of the order Coleoptera. It is one of the earliest medicinal materials with anti-cancer effects discovered in my country. Cantharidin is pungent, hot, and has strong nephrotoxicity. It also has the effects of removing blood stasis, removing stasis, reducing swelling, and attacking toxins and erosions. It is often used clinically for the treatment of malignant sores, stubborn ringwor...

Claims

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Application Information

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IPC IPC(8): C07D493/08A61K31/34A61P35/00A61P1/16A61P1/00
CPCC07D493/08
Inventor 王先恒赵长阔贾佳罗灿敏李晓飞
Owner ZUNYI MEDICAL UNIVERSITY
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