Triptolide derivatives, and preparation method and applications thereof

A technology of triptolide and derivatives, applied in the pharmaceutical field, can solve the problems of large toxic and side effects hindering development and research, poor metabolic stability, increased poisoning, etc., so as to reduce physical, psychological and economic burdens, prolong half-life, and reduce clearance rate. Effect

Inactive Publication Date: 2018-10-19
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Due to the broad-spectrum and high-efficiency anti-tumor activity of triptolide, it is very likely to become a promising new drug for clinical application, but its further development and research are hindered by the severe side effects, and the toxicity of triptolide is Dose-dependent, and its poor metabolic stability and short half-life require frequent administration, which increases the possibility of poisoning

Method used

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  • Triptolide derivatives, and preparation method and applications thereof
  • Triptolide derivatives, and preparation method and applications thereof
  • Triptolide derivatives, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of Triptolide Derivatives

[0026] Add 50 mg of triptolide, 1.5 ml of morpholine, and 3.6 mg of ether magnesium bromide in a 25 ml reaction tube, and the reaction is carried out under solvent-free conditions. Stirring overnight at room temperature, the progress of the reaction was detected by thin-layer chromatography on a silica gel plate, the chromogen was kedde reagent, and triptolide and its derivatives were purple-red. After 48 hours of reaction, the reaction was complete, and ethyl acetate and deionized water were added for washing. The ethyl acetate phase was collected, dehydrated by adding anhydrous sodium sulfate, filtered, and concentrated to obtain a solid.

[0027] The solid was dissolved with a small amount of dichloromethane, separated and purified with a silica gel column, and eluted with petroleum ether: ethyl acetate = 5:1 as eluent. Use thin-layer chromatography to detect and collect the chromogenic fraction. Concentrate under reduced pr...

Embodiment 2

[0031] Triptolide derivatives inhibit cell viability curve and IC 50 Determination.

[0032] In this embodiment, the MTT method is used to measure the influence of triptolide derivatives on the proliferation of various cancer cells, and the specific operations are as follows:

[0033] (1) Digest the cells in the logarithmic growth phase with trypsin, add the medium, centrifuge and collect after the digestion is terminated, and make a cell suspension, and adjust the concentration to 5-10×10 by cell counting 4 individual / ml.

[0034] (2) Mix the cell suspension evenly, add 100 microliters to each well, the cell density in each well is 5000-10000 / well, and fill the edge wells with sterile PBS.

[0035] (3) Put the inoculated cells into the incubator and cultivate overnight, add drugs with different concentration gradients, and set three duplicate holes.

[0036] (4) 5% carbon dioxide, culture at 37 degrees Celsius for 72 hours, observe the cell viability with an inverted micro...

Embodiment 3

[0042] Determination of Half-life of Triptolide Derivatives

[0043] In this embodiment, the substrate elimination method under liver microsomes in vitro is adopted, and the specific operation is as follows:

[0044] (1) Add 1 μl of substrate to a 1.5ml EP tube, take a tris-HCl 15ml centrifuge tube, and take a certain amount of human liver microsomes (20mg / ml)

[0045] (2) Add alamethicin (2.5 μg / ml), vortex for 5 seconds, and ice-bath for 15 minutes to make holes for the microsomes.

[0046] (3) Magnesium chloride hexahydrate solution (100 mM), D-glucose-6-phosphate disodium salt (10 mM), and glucose-6-phosphate dehydrogenase (10 unit / ml) were added in sequence. Vortex for 10 sec to mix well.

[0047] (4) Take a certain amount of the mixed solution from the 15ml centrifuge tube and add it to each EP tube. Put it into a constant temperature mixer at 37°C, and pre-incubate for 10 minutes to balance.

[0048] (5) Add β-nicotinamide adenine dinucleotide phosphate (10 mM) and ...

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Abstract

The invention belongs to the technical field of pharmacy, and provides triptolide derivatives, and a preparation method and applications thereof. The structural formula of triptolide derivatives is represented in the description, and R represents an amine ring compound group, more specifically, a cyclohexane group, a morpholine group, or an aniline group. The preparation method comprises followingsteps: taking triptolide as the raw material, adding an amine ring reagent and a catalyst into triptolide, wherein the mole ratio of triptolide to the amine ring reagent is 1:1-6, and the mole ratioof triptolide to the catalyst is 1:0.1-0.4; carrying out reactions for 24-48 hours in the absence of solvent; after reactions, carrying out a post treatment: washing the reaction liquid by ethyl acetate, then washing the ethyl acetate phase by deionized water for many times, drying, dehydrating, and drying; and purifying triptolide derivates: adopting an adsorbent as a stationary phase to carry out separation and purification, and recovering and drying the eluent to obtain triptolide derivates. The triptolide derivates can inhibit thyroid cancer cells, human prostatic cancer cells, and colon cancer cells.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and provides a triptolide derivative, a preparation method and an application. Background technique [0002] Triptolide, also known as triptolide ketone, is mainly extracted from the roots and rhizomes of Tripterygium wilfordii and Kunming Begonia. Pharmacological studies have shown that triptolide has various pharmacological activities, including anti-tumor, anti-inflammatory and immunosuppressive activities, and its pharmacological effects are extremely strong. At the same time, the anti-tumor activity of triptolide is also very broad-spectrum, including human leukemia, lymphoma, breast cancer, gastric cancer, pancreatic cancer, liver cancer, cervical cancer, ovarian cancer, lung cancer, and fibrosarcoma. More studies have shown that triptolide can inhibit the proliferation of 60 tumor cell lines commonly used by the American Institute of Cancer Research at very low concentrations, with an av...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61P35/00
CPCA61P35/00C07J73/003
Inventor 刘勇孙明申刘亚军姜丽丽夏杨柳
Owner DALIAN UNIV OF TECH
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