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N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine compound, preparation method and application

A hydroxybenzophenanthridine and compound technology, applied in the field of natural medicines, can solve the problems of unsatisfactory DDC inhibitory activity, bond inactivation, etc., and achieve the effect of retaining DDC inhibitory activity

Active Publication Date: 2017-05-31
湖南省中药提取工程研究中心有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve technical problems such as the unsatisfactory DDC inhibitory activity of sanguinarine, which is easily deactivated by sulfhydryl compounds such as dithiothreitol, the invention discloses an N-methyl-2,3,7,8-tetra DDC inhibitors of hydroxytriphenanthridine compounds, designed to enhance DDC inhibitory activity

Method used

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  • N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine compound, preparation method and application
  • N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine compound, preparation method and application
  • N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine compound, preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0039] N-methyl-2,3,7,8-tetrahydroxytriphenylene quaternary ammonium salt (I) preparation (see equation 2):

[0040]

[0041] Accurately weigh 1g of sanguinarine chloride and equivalent phloroglucinol (phloroglucinol), add 30ml of 60% concentrated sulfuric acid, stir at 95°C, and stir at 5, 10, 15, 20, 25, 30, 38, 46, At 54 and 70 minutes, a small amount of reaction solution was dropped into a vial containing a small amount of ultrapure water, and the precipitate and supernatant were collected by centrifugation for HPLC-QTOF detection. Since sanguinarine has two methylenedioxy groups, removing one methylene group will give two phenolic hydroxyl derivatives (II), the reaction time is prolonged, and the conversion rate of the target product I is gradually increased. According to the concentration and time plotting of sanguinarine chloride, the bisulfate of compound I and the bisulfate of compound II in the products of different reaction times, obtain the conversion rate-react...

Embodiment 2

[0043] Separation and purification of N-methyl-2,3,7,8-tetrahydroxytriphenylene phenanthridine quaternary ammonium salt (I)

[0044] The reaction product of Example 1 was added to 200 mL of ultrapure water for centrifugation, the supernatant was discarded, and the precipitate was repeatedly washed with ultrapure water for 3 times to remove sulfuric acid. The precipitate was ultrasonically dissolved with 44% formic acid to prepare a sample solution for later use. Pack the pretreated AB-8 resin into a column with an inner diameter of 4cm, a resin height of 54cm, and a column volume of 1BV=678mL. The top of the resin is protected with absorbent cotton, and the resin column is pre-washed with 1BV44% formic acid at a flow rate of 3BV / h , when the liquid level above the resin column is 5cm away from the absorbent cotton, it is ready to load the sample. The flow rate of the sample is controlled at 2BV / h. Chromatography for detection, liquid chromatography detection conditions are: c...

Embodiment 3

[0051] Research on the inhibitory activity of sanguinarine and compound I (purified according to Example 2) on DDC

[0052] Sanguinarine was formulated as 2.29×10 according to the results of DDC inhibitory activity pre-test -6 mol / ml, the compound I concentration is 3.044×10 -7 mol / ml solution. The remaining components used in the enzymatic reaction system are: phosphate buffer solution is Na 2 HPO 4 -KH 2 PO 4 (0.02M, pH6.8), the concentration of human recombinant dopa decarboxylase (human recombinized DDC) phosphate buffer solution is 10 μg / mL, the concentration of PLP phosphate buffer solution is 5×10 -6 mol / mL, L-Dopa phosphate buffer solution is 2.5×10 -6 mol / ml. Under the premise of ensuring that the total volume of the reaction system is 2 mL and the DDC concentration is 40 ng / uL, 15 μL of PLP solution, phosphate buffer, different concentration gradients of sanguinarine or the phosphate buffer solution of compound (I) and DDC phosphate buffer solution, sealed at...

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Abstract

The invention belongs to the field of natural medicinal chemistry, and particularly relates to a preparation method of N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine quaternary ammonium salt used for inhibiting DDC (dopa decarboxylase), and application of the N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine quaternary ammonium salt to pharmacy. The DDC is also called as aromatic amino acid decarboxylase; mammal enteric microorganism and self secreted DDC can catalyze aromatic amino acid to generate decarboxylated degradation in intestinal tracts and peripheral tissues; the absorption and utilization rate of the aromatic amino acid is reduced. Compared with a commercial DDC inhibiter, the prepared N-methyl-2,3,7,8-tetrahydroxy benzophenanthridine quaternary ammonium salt has a fire-new DDC inhibition mechanism.

Description

technical field [0001] The invention belongs to the technical field of natural medicines, and in particular relates to the application of N-methyl-2,3,7,8-tetrahydroxytriphenylene quaternary ammonium salt in the preparation of drugs for inhibiting dopa decarboxylase. Background technique [0002] Dopa decarboxylase (Dopa decarboxylase, DDC), also known as aromatic amino acid decarboxylase, can catalyze the decarboxylation synthesis of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan. Physiologically active neurotransmitters dopamine and serotonin (Moore B M, et. al. J Biol. Chem, 1996, 271: 23954-23959.); at the same time, they can also catalyze the decarboxylation of some aromatic amino acids to generate corresponding biogenic amines. Decreased serotonin content in the brain will lead to common mood disorders such as depression and anxiety; the reduction of dopamine synthesis caused by substantia nigra and striatum lesions can also lead to the occurrence of P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/18C07D491/056A61K31/473A61P25/22A61P25/24A61P25/16
CPCC07D221/18C07D491/056
Inventor 程辟曾建国
Owner 湖南省中药提取工程研究中心有限公司
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