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Application of protoberberine-type compound with TDO selective inhibition activity in medicament preparation

A protoberberine and compound technology, which is applied in the field of protoberberine compounds and can solve problems such as no protoberberine compounds.

Inactive Publication Date: 2019-05-28
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] So far, in the prior art, there are no reports related to the application of the original berberine compounds of the present invention in the preparation of TDO inhibitors, and in the preparation of drugs for the treatment or prevention of TDO-mediated diseases

Method used

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  • Application of protoberberine-type compound with TDO selective inhibition activity in medicament preparation
  • Application of protoberberine-type compound with TDO selective inhibition activity in medicament preparation
  • Application of protoberberine-type compound with TDO selective inhibition activity in medicament preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of Compounds Tetrahydroepiberberine and Coryrydine Cheilanthifolin:

[0022]

[0023] Dried ivy (Sinomeniumacutum (Thunb.) Rehd.et Wils.) 10kg, crushed and extracted with methanol 3 times (30L×3) at room temperature, soaked for 24h each time. The extracts were combined, the organic solvent was recovered by distillation under reduced pressure, the pH value was adjusted to 1-2 with 3% hydrochloric acid, and extracted three times with ethyl acetate. The aqueous phase was adjusted to pH 9-10 with aqueous ammonia, extracted three times with chloroform, and concentrated to obtain 144 g of total alkali. The total alkali was eluted by basic alumina (100-200 mesh, 2kg), petroleum ether-acetone (7:1-1:1), chloroform-methanol (100:1-1:1) gradient elution, after detection Three fractions (Fr1-Fr3) were combined. Fraction 3 (26 g) was eluted with a gradient of 10-100% methanol / water through a medium-pressure MCI column, and 7 sub-fractions (Fr2.1-Fr2.7) with increas...

Embodiment 2

[0027] experimental method:

[0028] 1.1 Protein sample preparation for TDO

[0029] References for gene cloning, protein expression and purification of human TDO (Meng, Wu et al.2014). References for gene cloning, protein expression and purification of human IDO (Nelp, Kates et al. 2018). Based on literature reports, slightly adjusted according to experimental conditions.

[0030] Protein Concentration Determination

[0031] Using the bovine serum protein standard curve as a reference, the protein concentration was detected by BCA Protein Assay Kit. In each detection process, different dilution concentrations are used for detection at the same time to ensure the error in the concentration detection process.

[0032] 1.2 Activity experiment

[0033] The reaction system is 200uL, including 20uL of 0.5M potassium phosphate buffer (pH 6.5), 40uL of 0.2M ascorbic acid, 8uL of 0.5mM methylene blue, 8uL of 5mg / ml catalase, and 15uL of L-tryptophan , 120uL ddH 2 O. The final ...

Embodiment 3

[0049] Tablet: Mix 10 mg of the compound obtained in Example 1, add 180 mg of lactose, 55 mg of starch and other auxiliary materials and mix evenly, moisten it with water, make granules and dry, then add 5 mg of magnesium stearate and mix evenly, and then press into tablets. Tablets weigh approximately 250mg.

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Abstract

The invention discloses the application of a protoberberine-type compound in preparation of TDO inhibitors or in preparation of medicaments for treating or preventing TDO-mediated diseases. Results ofenzyme activity inhibition experiments show that compounds, including tetrahydroepiberberine and Cheilanthifolin, have the inhibitory effect on the tryptophan 2,3-dioxygenase, and can be used for preparing the TDO inhibitors and preparing the medicaments or derivatives for treating or preventing the TDO-mediated diseases, wherein the TDO-mediated diseases mainly include tumors such as liver cancer, spongioblastoma, mesothelioma, head and neck cancer, non-small cell lung cancer, bladder cancer and breast cancer, or metabolic disorders such as depression, organ transplant rejection, neuropathicdisorders and obesity, or autoimmune diseases, and in the diseases, the TDO expression is up-regulated or the activity is obviously enhanced.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a class of proberberine compounds, especially tetrahydroepiberberine and cordyline Cheilanthifolin in the preparation of TDO inhibitors or in the preparation of medicines for treating or preventing TDO-mediated diseases Applications. Background technique [0002] Tryptophan 2,3-dioxygenase TDO and indoleamine 2,3-dioxygenase IDO are the first rate-limiting enzymes in the metabolic pathway of kynurenine, which catalyze the formation of N- Formylkynurenine. 95% of tryptophan is metabolized through this pathway, and 5% of tryptophan is converted into 5-hydroxytryptamine through other pathways. TDO is mainly expressed in the liver, and its physiological functions mainly include regulating the level of tryptophan in the system and the concentration of kynurenine in the liver. In vivo and in vitro experiments confirmed that TDO plays an important role in promoting the ...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61P35/00A61P3/00A61P25/00A61P37/00A61P3/04A61P25/24A61P37/06A61P27/12
Inventor 赵勤实刘将新毕冉杨坤吴兴德彭丽艳
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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