Synthesis and purpose of glycyrrhetinic acid derivative

A technology of glycyrrhetinic acid and derivatives, which is applied in the field of preparation of glycyrrhetinic acid derivatives, and can solve the problems of further research on liver targeting

Inactive Publication Date: 2015-09-23
INNER MONGOLIA MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Fan Feng et al. used norcantharidin as a raw material, modified with various small molecule amino acids, and underwent acylation, hydrogenolysis, glycosidation and deacetylation reactions to synthesize norcantharidin-galactose (NCTD-Gal) derivatives. It is expected to obtain a liver-targeted anticancer prodrug, and a preliminary anti-tumor experiment

Method used

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  • Synthesis and purpose of glycyrrhetinic acid derivative
  • Synthesis and purpose of glycyrrhetinic acid derivative
  • Synthesis and purpose of glycyrrhetinic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1. compound synthesis experiment

[0030] 1.1 Experimental materials

[0031] 1.1.1 Main experimental instruments

[0032]XT4A binocular micro melting point apparatus, temperature uncorrected; RE-52A rotary evaporator; CCA-20 circulating water pump; CL-2 magnetic stirrer; ZF-1 ultraviolet analyzer; KQ-250DE numerical control Ultrasonic cleaner; Agilent 1100LC-MSD-Trap-SL mass spectrometer; Bruker 400 nuclear magnetic resonance spectrometer and avanceIII 500 nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 or CDCl 3 , TMS is the internal standard.

[0033] 1.1.2 Main reagents and materials

[0034] Glycyrrhetinic acid (97% 18β-glycyrrhetinic acid), norcantharidin, tetrahydrofuran (anhydrous), triethylamine (anhydrous), acetic anhydride (anhydrous), N-methylmorpholine, oxalyl chloride, Anhydrous sodium carbonate, DCC (dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine), DMF (N,N-dimethylformamide), zinc powder, 4A molecular sieve, VLC...

Embodiment 2

[0062] Embodiment .2 compound pharmacological experiment

[0063] 2.1 Main reagents and materials

[0064] Human liver cancer cell line HepG2 was purchased from Shanghai Cell Bank Center, Chinese Academy of Medical Sciences, DMEM medium, fetal bovine serum (Hyclone, American Hyclone Company), trypsin (Huamei Bioengineering Company), dimethyl sulfoxide (Sigma Company) ), phosphate buffered solution (PBS), 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide (MTT), etc.

[0065] 2.2 Experimental operation

[0066] 2.2.1 Solution preparation

[0067] ①MTT solution (5g / L)

[0068] Weigh 250mg of MTT, put it into a small beaker, add 50mL of PBS (0.01mol / L, pH7.4) and stir on an electromagnetic stirrer for 30min, filter and sterilize with a 0.22μm microporous membrane, and dispense under aseptic conditions. Store at 4°C. Valid for two weeks.

[0069] ②10% fetal bovine serum DMEM culture medium

[0070] Aspirate 90mL DMEM culture solution, add 10mL fetal bovine serum, mi...

Embodiment 3

[0084] Embodiment 3: compound synthesis and pharmacological experiment result

[0085] Synthesized 13 target compounds that have not been reported in the literature, by proton nuclear magnetic resonance spectrum ( 1 H-NMR), carbon nuclear magnetic resonance spectrum ( 13 C-NMR), mass spectrometry (MS) confirmed the structural formula ( Figure 8 ). The obtained target compounds are easily soluble in tetrahydrofuran and ethyl acetate, soluble in methanol and ethanol, and almost insoluble in water.

[0086] 3.1 Analysis of Compound Spectrum

[0087] With target compound M-1-b (molecular formula C 39 h 56 o 8 , Molecular weight 652.40, structural formula see Figure 9 ) as an example to analyze its related spectral data.

[0088] 3.1.1 Proton NMR spectrum 1 H-NMR:

[0089] 1 H-NMR (400MHz, CDCl 3 )δ: 5.69 (1H, s, H-12), 4.89-5.05 (3H, m, 3CH), 4.52-4.54 (1H, m, CH), 4.13-4.15 (1H, m, H-3), 3.01 -3.08(3H,m,COOCH 3 ),2.37(1H,s,H-9),2.08(1H,m,H-18),1.86(2H,m,CH 2 ),1....

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Abstract

The invention designs and synthetizes a lead compound by using a glycyrrhetinic acid derivative as a carrier and being connected with norcantharidin and a derivative thereof through ester bonds, the obtained lead compound expects to have the advantages of having liver targeting action, prolonging action time, reducing toxic and side effects and improving the curative effect of resisting liver cancer, and a model compound is provided for the research of a liver targeting medicine for the liver cancer. Firstly, two positions of C11 and C30 in glycyrrhetinic acid molecules are reduced and synthetized respectively, methyl ester is chemically modified into glycyrrhetinic acid (GA) and 18 alpha-glycyrrhetinic acid as well as a derivative thereof, the glycyrrhetinic acid (GA) and 18 alpha-glycyrrhetinic acid as well as the derivative thereof are used as framework molecules, through a series of reactions, the framework molecules and the norcantharidin (NCTD) as well as a derivative thereof are condensed to form ester as a prodrug, a cell activity screening test is performed on 5 object compounds, 13 object compounds in 3 series are synthetized, and structural characterization is performed on a carbon spectrum, a hydrogen spectrum and a mass spectrum; the influence of different concentrations of 5 object compounds on HepG2 cell proliferation of the liver cancer is inspected by a method, results show that inhibitory action presents time-dose dependence, and the suppression ratio of 14 mu g/mL is the highest.

Description

technical field [0001] The invention relates to a preparation method and application of a glycyrrhetinic acid derivative, in particular to a liver-targeting anticancer drug of norcantharidin with glycyrrhetinic acid as a carrier. Background technique [0002] Licorice (Glycyrrhiza root) belongs to leguminous plants, distributed in western my country and European countries such as Russia, and widely used as medicine in many countries. Its main pharmacologically active substances are glycyrrhizic acid (GL for short) and its aglycone glycyrrhetinic acid (GA for short) etc. ( figure 1 ). Glycyrrhizic acid drugs are mainly hydrolyzed by gastric acid or decomposed into glycyrrhetinic acid by β-glucuronidase in the liver in the human body, and then partly generate 3-epi-glycyrrhetinic acid and a small amount of 3- dehydroglycyrrhetinic acid for pharmacological activity. Therefore, the effect of glycyrrhizic acid drugs is essentially the effect of glycyrrhetinic acid. GA has vari...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61P35/00
CPCC07J63/008
Inventor 杨慧赵岩布仁马宇衡杨丽敏米雪朱晓伟嘎鲁
Owner INNER MONGOLIA MEDICAL UNIV
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