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Transformation method of hydroxylated capers diterpenoid derivatives and its use in the preparation of antitumor drugs

A technology for biotransformation and microbial transformation, applied in the field of biopharmaceuticals, and can solve problems such as reports on the microbial transformation of diterpenoids that have not yet been reported.

Active Publication Date: 2021-01-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, there has been no report on the microbial transformation of diterpenoids in capsularia

Method used

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  • Transformation method of hydroxylated capers diterpenoid derivatives and its use in the preparation of antitumor drugs
  • Transformation method of hydroxylated capers diterpenoid derivatives and its use in the preparation of antitumor drugs
  • Transformation method of hydroxylated capers diterpenoid derivatives and its use in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Preparation of 18-Hydroxy Capper Diterpene Alcohol (1) and 19-Hydroxy Capper Diterpene Alcohol (3)

[0027] The two-step activation method was used to activate the strains, and the obtained seed solution was inoculated at 1% volume ratio in a 1 L Erlenmeyer flask containing 250 mL of potato medium, and cultured in a shaker flask at 28 °C and 180 rpm for 48 h. Add 5 mg / mL ethanol solution of Capper diterpene alcohol to each bottle of activated bacterial liquid, and the final concentration is 0.1 mg / mL. After culturing under the same conditions for 72 h, the fermentation broth was suction-filtered, and the filtrate was extracted three times with ethyl acetate, and the ethyl acetate was recovered after merging to obtain the fermentation broth extract;

[0028] Dissolve the extract of the fermentation broth with a small amount of ethyl acetate, mix the sample with silica gel (100-200 mesh), load the sample on a silica gel column equipped with 40-50 g column chroma...

Embodiment 2

[0029] Example 2 Preparation of 7β, 18-dihydroxycapricorn diterpene alcohol (2)

[0030]The two-step activation method was used to activate the strains, and the obtained seed solution was inoculated at 1% volume ratio in a 1 L Erlenmeyer flask containing 250 mL potato medium, and cultured in a shaker flask at 28 °C and 180 rpm for 48 h. Add 5 mg / mL ethanol solution of 7β-hydroxycapricorn diterpene alcohol to each bottle of activated bacterial liquid, and the final concentration is 0.1 mg / mL. After 72 hours of culture under the same conditions, the fermentation liquid is suction-filtered, and ethyl acetate is added to the filtrate. Extracting 3 times, reclaiming ethyl acetate after merging, and obtaining the fermentation broth extract;

[0031] Dissolve the extract of the fermentation broth with a small amount of ethyl acetate, mix the sample with silica gel (100-200 mesh), load the sample into a silica gel column equipped with 40-50 g column chromatography silica gel (200-300 ...

Embodiment 3

[0035] Example 3 Preparation of 18-Nicotinyloxy Capper Diterpene Alcohol (4)

[0036] Take 10 mg of dry and anhydrous 18-hydroxyeuphorbia factor L3 (1) in a 50 mL round bottom flask, add 10-15 mL of anhydrous tetrahydrofuran, add 8 mL of triethylamine, a trace of 4-dimethylaminopyridine (DMAP ), stir and dissolve with a magnetic stirrer, add 1 equivalent of nicotinoyl chloride hydrochloride under ice bath conditions, stir and react together to room temperature for 8 hours, if the reaction is not complete, then reflux and heat for 1 to 3 hours;

[0037] Check whether the reaction is complete: use a capillary to absorb a small amount of reaction solution, spot on a silica gel thin-layer plate, and spot 18-hydroxycapricorn diterpene alcohol in parallel, and use dichloromethane-methanol (20:1) upward method to develop. Take it out to dry, and inspect it under a 254 nm ultraviolet light. The sign of the completion of the reaction is that there is no bright spot or only a faint brig...

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Abstract

The present invention relates to the field of biopharmaceuticals, in particular to a method for converting capricorn diterpene-type compounds. The present invention utilizes known microorganisms to carry out microbial conversion of capricorn diterpene alcohol and 7-hydroxy capricorn diterpene alcohol, and combines chemical Acylation, the preparation of Capella diterpenoid-type derivatives, especially with Mortierella ramannii Mortierella ramanniana Microorganisms carry out hydroxylation biotransformation of caperia diterpene alcohol, and further chemically acylate the hydroxylated product introduced at C-18 to produce 18-nicotinoyloxy caperia diterpene alcohol derivatives. The hydroxylation of the carbon site of the capricorn diterpene can increase the chemical modification sites of the capricorn diterpene alcohol and improve the druggability. Furthermore, the prepared capsaicin alkane diterpene derivative compound can be used to prepare anti-tumor multi-drug resistance drugs or pharmaceutical compositions.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and relates to a conversion method of caperia diterpene-type compounds, in particular to using known microorganisms to carry out microbial transformation of caperia diterpene alcohols and derivatives thereof, and further combining chemical acylation methods to prepare Capsella diterpene-type derivatives with anticancer activity. Background technique [0002] It is disclosed in the prior art that the diterpene-type compound of Caperia spp. belongs to the natural product of the diterpene skeleton, and has obvious anti-tumor activity and anti-tumor multidrug resistance (MDR). The study of structure-activity relationship shows that the difference of substituents on the core can obviously change the antitumor activity and MDR activity of this kind of compound. [0003] Capper spp. Euphorbia lathyris L. isolated from (TetrahedronLetters, 1971, 18: 1325-1328) Capricorn diterpene-type compounds; and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P15/00C07D213/80A61K31/122A61K31/435A61P35/00C12R1/645
CPCA61K31/122A61K31/435C07D213/80C12P15/00
Inventor 程志红吴亦晴
Owner FUDAN UNIV
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