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Antitumor antibiotic ancomycin and its derivative

A technology of ancomycin and its derivatives, applied in the field of antitumor antibiotic ancomycin and its derivatives

Active Publication Date: 2011-11-23
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The ancomycin ester derivatives of the present invention and their antitumor effects have not been reported so far

Method used

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  • Antitumor antibiotic ancomycin and its derivative
  • Antitumor antibiotic ancomycin and its derivative
  • Antitumor antibiotic ancomycin and its derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 > Preparation of Ancomycin

[0047] Streptomyces strain C-9095 preserved in the glycerol tube was inoculated to the slant (glucose 1%, asparagine 0.1%, dipotassium hydrogen phosphate 0.05%, agar 1.5%, pH 7.2-7.4, sterilized, and cultivated at 28°C for 7-10 day) culture medium, cultivated in a constant temperature incubator at 28°C for 7-10 days. Inoculate the slant culture into 100ml primary seed medium (glucose 10g, soluble starch 15g, beef extract 5g, fish peptone 5g, soybean cake powder 10g, sodium chloride 3g, adjust pH to 7.0, double distilled water into 1000ml, autoclaved), 28 ℃ at 28 ℃ in the rotary shaker of 180 rev / min and cultivated for 48 hours, got the first-grade seeds that cultivated, and replanted in 100ml secondary seed culture medium by 10% inoculum size ( Seed culture medium of the same level), cultured on a rotary shaker at 28°C for 24 hours. Get the secondary seeds that have been cultivated, and replant in 1000ml fermentation medium by 1...

Embodiment 2

[0049] Example 2 > Preparation of Ancomycin Methyl Ester

[0050] Take 12ml of methanol in the reaction flask, slowly add thionyl chloride (SOCl 2 ) 3ml, the temperature was controlled below 0°C, and the reaction was continued for 1 hour at about 0°C after the dropwise addition was completed. Weigh 500 mg of ancomycin, dissolve in methanol-thionyl chloride solution, stir at room temperature, and track the reaction by TLC, solvent methanol: ethyl acetate: ammonia water (5:3:2), total reaction 48h, reduce Evaporate under pressure to obtain a yellow oily liquid. Dissolve 2ml of the yellow oily solution in methanol, then add 20ml of diethyl ether, a white solid is precipitated, and the solid is obtained by suction filtration under reduced pressure. The solid matter is separated with a preparative thin-layer silica gel chromatography plate, and the developing solvent is methanol: ammonia water=5: 1, and R f =0.50 band, eluting with the eluent of ethanol: water=3: 2, and the elu...

Embodiment 3

[0051] Example 3 > Preparation of Ancomycin Isopropyl Ester

[0052] Put 200 mg of ancomycin and 2 ml of dimethyl sulfoxide (DMSO) into the reaction bottle, stir until dissolved in a warm state, and slowly add 3 ml of aceton (aceton) dropwise without obvious turbidity. Then add 1ml iodoisopropane and 100mg K 2 CO 3 Powder, the reaction solution is slightly turbid, keep the internal temperature (50-55) ° C, stir and react overnight, and react for a total of 17 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a solid, which was separated by preparative thin-layer silica gel chromatography. The developing solvent was methanol: ethyl acetate: ammonia water = 2: 0.4: 0.1, and R f =0.35 band, eluted with methanol, and the eluate was evaporated to dryness under reduced pressure to obtain 28 mg of ancomycin isopropyl ester. ESI-MS m / z416[M+H] + (molecular formula C 16 h 25 N 5 o 8 , molecular weight is 415).

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Abstract

The invention relates to derivatives of a cytidine peptide compound, and specifically relates to ancomycin methyl ester, isopropyl ester and isopentyl ester. Wherein, carboxyl in position 5' of the hexose ring in the fermentation product ancomycin of streptomyces albulus C-9095 is connected with the methyl, isopropyl and isopentyl respectively for esterification through different chemosynthesis methods, thus obtaining the relevant ancomycin ester derivatives. Experimental research both in vivo and in vitro proves that the derivatives have inhibitory effects on relevant tumor cells, thus being hopeful to be developed as antitumor medicaments.

Description

Technical field: [0001] The present invention relates to derivatives of cytosine nucleoside peptide compounds and their preparation and application in antitumor. Background technique: [0002] In the process of screening anti-tumor antibiotics, a strain of Streptomyces albulus C-9095 was isolated from soil samples in Guanping County, Yunnan Province, my country. Species Preservation Management Committee General Microbiology Center, address: No. 3, Courtyard No. 1, Beichen West Road, Chaoyang District, Beijing, preservation number: CGMCC No.4831), and dipeptide nucleoside peptide compounds were extracted from the fermentation broth of the strain. The compound is isolated after acidification to obtain a single amino acid nucleoside compound, which is named ancomycin (ancomycin), and its molecular composition includes 3 parts: serine, cytosine and hexosamine (acid), and its chemical structure is as follows: 1) as shown. Previous studies in our laboratory found that ancomycin h...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00A61K31/7068A61P35/00
CPCC07H19/06C07H1/00A61P35/00
Inventor 张方博甄永苏许先栋刘秀均赵春燕李毅陈文君李电东胡继兰戚长菁
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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