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Preparation method of triptolide derivatives and products and application of triptolide derivatives

A technology for triptolide and derivatives is applied in the preparation of triptolide derivatives, products and application fields, and can solve the problems of low conversion rate, poor selectivity, low yield of chemical synthesis method and the like

Active Publication Date: 2014-03-12
HUAQIAO UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although chemical modification provides broad prospects for the large-scale preparation of triptolide-related derivatives, the chemical synthesis method has some limitations, such as low yield, poor selectivity, many by-products, and complicated processes.
[0004] On the other hand, the use of microorganisms with biomimetic metabolism to directly transform biological triptolide through the special enzymatic action of microorganisms to produce a variety of in vivo metabolic and attenuated derivatives of triptolide has also achieved certain results. Effects, for example, Ning et al. used Cunninghamella blakesleeana to biotransform triptolide, and could simultaneously obtain 7 hydroxylated products of 1β, 2β, 5α, 15, 16, 19α, and 19β hydroxylation, and Various products have remarkable tumor-inhibiting activity, and their toxicity is less than that of triptolide. It is not difficult to find through comparison that although the transformation of Tripterygium compounds by the genus C. The metabolite 5α-hydroxytriptolide with the highest conversion rate is only 18%

Method used

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  • Preparation method of triptolide derivatives and products and application of triptolide derivatives
  • Preparation method of triptolide derivatives and products and application of triptolide derivatives
  • Preparation method of triptolide derivatives and products and application of triptolide derivatives

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preparation example Construction

[0044] The present invention relates to a kind of preparation method of triptolide derivative, comprising the following steps:

[0045] Step 1: Take a transformed strain stored at 4°C and cultivated on a potato slant medium, place it in a constant temperature incubator at 25°C for 7 days, and blow off the spores on the slope with an appropriate amount of sterile water to make a single Adjust the concentration of the spore suspension to 107-108 / mL to obtain the seed spore liquid;

[0046] Step 2: Inoculate the spore liquid obtained in step 1 on the potato liquid medium with an inoculum amount of 100ml and 5mL, and cultivate it for 12 hours at a pH of 6.0, a temperature of 30°C±1°C, and a shaking speed of 200r / min; press 0.1 ~4ug inoculum, add various combined elicitors in different proportions, continue to cultivate for 12 hours, then add triptolide according to the inoculum of 1~10ug, and then continue to cultivate for 5 days, detect various triptolide derivatives every day W...

Embodiment 1

[0080] Example 1: Preparation of Triptolide Derivatives

[0081] 1. Preparation of 6α-hydroxytriptolide

[0082] Inoculate 5mL (108 cells / mL) spore liquid of Cunninghamella blakesleana AS3.970 in 100mL potato liquid medium, under the condition of pH to 6.0, temperature 30℃±1℃, shaking speed 200r / min After incubation for 12 hours, add methyl jasmonate (MeJA, 0.35mmol / mL), dexamethasone (DXM) and β-cyclodextrose at a weight ratio of 0.2ug (3:2:1) (BCD, 0.51mmol / mL), continue to cultivate for 12 hours, then add triptolide according to the inoculum amount of 5%, then continue to cultivate for 5 days, stop the cultivation, and then centrifuge the filtrate at 8000r / min for 10min to remove the precipitate. The filtrate was extracted 3 times with an equal volume of ethyl acetate, and the extract was evaporated to dryness, dissolved in 2m L of acetone, and then separated by a chromatographic silica gel column. , 6:1, 4:1, 2:1, 1:1, 1:2, 1:4, 1:6, 1:8 petroleum ether: ethyl acetate, 1...

Embodiment 2

[0114] Embodiment two, pharmacodynamics evaluation experimental example

[0115] In the following experimental examples, the test sample is provided by the preparation method embodiment of the present invention, and the precursor compound triptolide is used as a positive control.

[0116] 1. The growth inhibitory effect of 12 compounds of the present invention on human lung cancer cell A549 cells cultured in vitro

[0117] Methods: Human A549 lung cancer cells were cultured in DMEM medium (Gibco, USA) containing 10% fetal bovine serum at 37°C, 5% CO 2 , tumor cells 0.7x10 4 / well was inoculated in a 96-well plate, and after 24 hours, the compound diluted with dimethyl sulfoxide (200uM) and PBS solution was added to make the final concentration of the culture medium 10 -4 、10 -5 、10 -6 、10 -7 、10 -8 M, after 72 hours of treatment, discard the culture medium, fix the cells with 10% cold trichloroacetic acid, stain with sulforhodamine B (SRB) solution, wash away the unbound...

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Abstract

The invention provides a preparation method of triptolide derivatives and products and application of the triptolide derivatives. According to the preparation method, the triptolide is taken as a microbial metabolism medicine, and microbial metabolism triptolide is processed by a special inducer, so as to simultaneously obtain a plurality of triptolide-based hydroxyl and / or methylation-modified triptolide derivatives with high productivities. These triptolide derivatives have good effects on inhibition of tumors, aids and hepatitis B viruses. The method disclosed by the invention is green and environment-friendly, strong in selectivity, and high in productivity, and the triptolide derivatives can be prepared at a large scale by using microorganisms.

Description

【Technical field】 [0001] The invention relates to a preparation method of a triptolide derivative, a product thereof and an application thereof. 【Background technique】 [0002] Tripterygium wilfordii Hook.F., a plant of the Euonymus family, was collected in "Southern Yunnan Materia Medica", and its production areas are mainly distributed in southern China, including Zhejiang, Hunan, Anhui, Yunnan, Fujian and Taiwan, among which Fujian The quality of Triptolide produced in Taining is the best (Zhou ZL, Yang YX, Ding J. et al Triptolide: structural modifications, structure–activity relationships, bioactivities, clinical development and mechanisms, Nat.Prod.Rep., 2012,29,457– 475.). Triptolide (Triptolide, TP, triptolide) is a diterpene epoxy compound and is one of the main active ingredients of Triptolide. and other aspects have shown outstanding pharmacological activity, and it has good antitumor activity to all 60 kinds of cancer cells listed by the National Cancer Institu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/20C07J73/00A61P35/00A61P35/02A61P31/18A61P31/20A61P1/16A61P31/22A61P31/16C12R1/685C12R1/67C12R1/785C12R1/80C12R1/645
Inventor 张景红谢深霞唐圆圆
Owner HUAQIAO UNIVERSITY
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