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Carbazole-type indole alkaloids, and application thereof in preparation of anti-complement medicines

A technology of indole alkaloid and carbazole type is applied in the field of carbazole type indole alkaloid and in the field of preparing anti-complement drugs, which can solve the problems of lack of therapeutic drugs and the like

Active Publication Date: 2016-10-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still a lack of ideal therapeutic drugs for such diseases, so there is an urgent need for high-efficiency, low-toxicity, and specific new complement inhibitors in clinical practice.

Method used

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  • Carbazole-type indole alkaloids, and application thereof in preparation of anti-complement medicines
  • Carbazole-type indole alkaloids, and application thereof in preparation of anti-complement medicines
  • Carbazole-type indole alkaloids, and application thereof in preparation of anti-complement medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1 Preparation of carbazol-type indole alkaloids 1 and 2

[0018] Take 5kg of Qingdai powder, 95% ethanol reflux extraction 3 times (50L×3), 2h each time, combine the extracts and concentrate to get 0.25kg of extract, add water (4L) to suspend, add equal volume petroleum ether, ethyl acetate and n-butanol for 5 times, combined extracts and concentrated to dryness to obtain 50 g of ethyl acetate extract; the ethyl acetate extract was separated by silica gel (200-300 mesh) column chromatography, and dichloromethane-methanol (50 :1-0:1) gradient elution to obtain 8 fractions (Fr.1-8), of which Fraction Fr.7 (3g) was subjected to silica gel column chromatography (dichloromethane-methanol, 10:1,5 :1,3:1,1:1), Sephadex LH-20 column chromatography (chloroform-methanol, 1:1) and reverse phase HPLC (methanol-water, 20:80-80:20 gradient elution) and other means of purification , to obtain carbazol-type indole alkaloids 1 and 2.

Embodiment 2

[0019] Example 2 Anti-complement classical pathway test in vitro

[0020] Take 0.04ml of complement (guinea pig serum), add barbiturate buffer solution (BBS) to prepare a 1:10 solution, and double-dilute with BBS to 1:20, 1:40, 1:80, 1:160, 1:10 320, 1:640 and 1:1280 solutions. Take 1:1000 hemolysin, 0.1ml of 2% sheep red blood cell (SRBC) and 0.2ml of complement of each concentration, dissolve in 0.2ml BBS, mix well, put it into a low-temperature high-speed centrifuge after 30 minutes in a water bath at 37°C, and place it in a low-temperature high-speed centrifuge at 4000rpm, 4°C Centrifuge for 5 min under conditions. Take 0.2ml of the supernatant from each tube and place it in a 96-well plate, and measure its absorbance at 405nm. At the same time, a complete hemolysis group (0.1ml 2% SRBC, 0.1ml hemolysin dissolved in 0.4ml triple distilled water) was set up in the experiment. The absorbance of three-distilled water lysed blood vessels was used as the standard of total he...

Embodiment 3

[0023] Example 3 Anti-complement alternative pathway test in vitro

[0024]Take 0.2ml of complement (human serum), add AP diluent (barbital buffer, pH=7.4, containing 5mMMg 2+ ,8mM EGTA) was prepared as a 1:5 solution, and double-diluted into 1:10, 1:20, 1:40, 1:80, 1:160, 1:320 and 1:640 solutions. Take 0.15ml of complement of each concentration, 0.15ml of AP diluent and 0.20ml of 0.5% rabbit erythrocytes (RE), mix them well, put them in a low-temperature high-speed centrifuge at 4000rpm and 4℃ for 5min in a 37°C water bath for 30min. Take 0.2ml of the supernatant from each tube and place it in a 96-well plate, and measure the absorbance at 405nm. At the same time, a complete hemolysis group (0.20ml 0.5% RE dissolved in 0.3ml triple distilled water) was set up in the experiment. The absorbance of three-distilled water lysed blood vessels was used as the standard of total hemolysis, and the hemolysis rate was calculated. Plot the dilution of complement on the X-axis and the...

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Abstract

The invention belongs to the field of traditional Chinese medicine pharmacy and relates to an application of carbazole-type indole alkaloids in preparation of anti-complement medicines. The novel carbazole-type indole alkaloid compounds are separated from powder of indigo naturalis and have novel and unique structures. The invention, for the first time in nature, discloses the carbazole-type indole alkaloids in which a substituted group is introduced to a sixth locus. The carbazole-type indole alkaloids include the following two compounds: (1) 1-(5,7-dihydroxypyridino[3,2-b:5,6-b']bisindole-6-ethane-2-one and (2) N-(2-hydroxyphenyl)-5,7-dihydroxypyridino[3,2-b:5,6-b']-bisindole-6-formamide. A modern pharmacological researching method proves that the compounds have strong inhibition effects on both a classical pathway and a bypass pathway of a complement system, wherein the CH50 values of the compound (1) and the compound (2) are respectively 0.024 + / - 0.007 mg / ml and 0.032+ / - 0.009 mg / ml while the AP50 values are respectively 0.056 + / - 0.010 mg / ml and 0.072+ / - 0.014 mg / ml. The compound is used for preparing a complement inhibitor.

Description

technical field [0001] The invention belongs to the field of traditional Chinese medicine pharmacy, and relates to carbazole-type indole alkaloids and their application in preparing anti-complement drugs. Specifically related to two carbazole-type indole alkaloids 1-(5,7-dihydroxypyrido[3,2-b:5,6-b']bisindolyl-6-ethane-2- Ketone (1), N-(2-hydroxyphenyl)-5,7-dihydroxypyrido[3,2-b:5,6-b']-bisindolyl-6-carboxamide (2) Background technique [0002] It is disclosed in the prior art that excessive activation of the complement system can cause many major diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and acute respiratory distress syndrome (ARDS). The study of anti-complement drugs has been the focus and focus of the world's pharmaceutical research for many years. However, there is still a lack of ideal therapeutic drugs for such diseases at present, so there is an urgent need for high-efficiency, low-toxicity, and specific new complement inhibito...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/437A61P37/02
Inventor 陈道峰范明松黄成钢
Owner FUDAN UNIV
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