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Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor

A dioxygenase and compound technology, applied in the field of medicine, can solve the problems of difficulty in meeting research and clinical medication, long separation process, low extraction rate, etc., and achieve the effect of good potential for research and development of new drugs

Inactive Publication Date: 2013-04-24
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although tryptanthrin can be extracted from indigo plants such as Polygonum indigo, Isatis indigo, and other blue-producing plants and metabolites of microorganisms, the separation process is long and the extraction rate is low, which is difficult to meet the needs of research and clinical medicine.

Method used

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  • Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor
  • Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor
  • Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1: the preparation of 8-nitrotryptanthrin

[0022]

[0023]First add 1ml of concentrated sulfuric acid to the reaction flask, under ice cooling, add tryptanthrin (248mg, 1mmol) in batches, then add dropwise (0.15ml) concentrated nitric acid, and react for 1h. After the reaction, it was poured into ice water and drained to obtain a yellow-green 8-nitrotryptanthrin solid. Yield 90%. The characterization data are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ= 8.86(d, 1H), 8.75(d, 1H), 8.69(m, 1H), 8.49(m, 1H), 8.09(d, 1H), 7.95(m, 1H), 7.76(d, 1H).

Embodiment 2

[0024] Example 2: Preliminary detection of IDO inhibitory activity

[0025] The construction, expression, extraction and purification of the plasmid containing human IDO gene were carried out according to the method reported by Littlejohn et al. (Protein Exp Purif, 2000. 19(1): 22-9). The inhibitory activity of compounds against IDO was tested according to the method introduced. Mix 50 mM potassium phosphate buffer (pH 6.5), 40 mM vitamin C, 400 μg / ml catalase, 20 μM methylene blue, substrate L-tryptophan and the sample to be tested, and incubate the mixture at 37 °C for 5 minutes , then add IDO enzyme to the above mixture, react at 37 °C for 30 minutes, add 200 μl of 30% (w / v) trichloroacetic acid to terminate the reaction, and heat the reaction system at 65 °C for 15 minutes to complete from The conversion of formylkynurenine to kynurenine was followed by centrifugation at 12,000 rpm for 10 min, and the supernatant was mixed with an equal volume of 2% (w / v) p-dimethylaminob...

Embodiment 3

[0027] Example 3: Determination of whether it is reversible inhibition

[0028] In the case of a fixed inhibitor concentration, a series of different concentrations of the enzyme are reacted with the inhibitor and the reaction rate is determined. Plot the reaction speed against the enzyme concentration (ν~[E]), and judge whether it is a reversible inhibitor or not according to the characteristics of the curve.

[0029] Reaction conditions: In a 500 μl reaction system, first add 50 mM potassium phosphate buffer (pH 6.5), 40 mM vitamin C, 400 μg / ml catalase, 20 μM methylene blue, 300 mM substrate L-tryptamine Acid or 100 mM inhibitor (8-nitrotryptanthrin) was added at the same time, and the mixture was incubated at 37 °C for 5 minutes, and then different volumes of IDO enzyme were added to the above mixture (for 8-nitrotryptanthrin, the amount of enzyme added The volumes were 0.5, 1, 2, 3, 4, 5, 6, 7 μl), the reaction was carried out at 37 °C for 30 minutes, and 200 μl of 30% (...

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PUM

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Abstract

The invention belongs to the medicinal field, and concretely relates to a use of a 8-nitrotryptanthrin compound as an IDO inhibitor. The 8-nitrotryptanthrin compound is a reversible IDO inhibitor, has an inhibition constant Ki of 0.054muM, has in-vitro and cell-based median effective inhibition concentrations IC50 of 0.103muM and 1.80*10<-5>muM respectively, and has an inhibition effectiveness obviously better than a present inhibitor 1-methyltryptophan (Ki of 34muM and IC50 of 340muM). 8-nitrotryptanthrin disclosed in the invention can effectively lower the abnormally-increasing IDO activity in a tumor animal model as the IDO inhibitor, and also has tumor treatment effects comprising tumor growth delaying, tumor volume reduction and in-vitro tumor cell killing. 8-nitrotryptanthrin disclosed in the invention has a wide application prospect, and can be used for treating serious diseases having the IDO mediated tryptophan metabolism approach pathology characteristics, such as cancers, the Alzheimer disease, tristimania, cataract and the like as the IDO inhibitor.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the use of a tryptanthrin compound as an indoleamine 2,3-dioxygenase inhibitor. Background technique [0002] Indoleamine 2, 3-dioxygenase (Indoleamine 2, 3-dioxygenase, IDO) is an enzyme containing heme in cells, and it is the only enzyme outside the liver that can catalyze the metabolism of tryptophan to make it along the path of kynurenine Rate-limiting enzyme in the acid pathway to generate a series of metabolites including quinolinic acid (MacKenzie, C. R. et. al. Current Drug Metabolism , 2007, 8: 237-244). [0003] IDO is related to many physiological and pathological processes. Studies on pregnant mouse models have found that syncytiotrophoblast cells and antigen-presenting cells at the maternal-fetal interface can synthesize IDO, and the dynamic changes in IDO expression are consistent with embryogenesis. If the effect of IDO is specifically blocked, it can lead to ...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61P35/00A61P25/28A61P25/24
Inventor 杨青匡春香
Owner FUDAN UNIV
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