Vancomycin compound

A vancomycin and compound technology, applied in the direction of drug combinations, glycopeptide components, peptides, etc., can solve the problems of inability to prepare oral drugs and affect the application of vancomycin, and achieve high stability effects

Active Publication Date: 2011-05-11
SHANGHAI LAIYI BIOMEDICAL RES & DEV CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, vancomycin is unstable under acidic conditions, especially strong acidic conditions, so it cannot be prepared into an oral drug, which affects the application of vancomycin, which makes the development of new drugs that are especially acidic in the stomach under acidic conditions. Stable vancomycin-like antibiotic compounds are of great interest under
[0004] In 2000, O'Brien et al. cloned the N-terminal methyltransferase of chloroeremomycin, and catalyzed the reaction with norvancomycin, nor-sugar-free vancomycin heptapeptide backbone, etc. In the catalyzed reaction of the glycovancomycin heptapeptide backbone as the substrate, a monomethylated sugar-free vancomycin heptapeptide backbone was obtained, but the study was not continued

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 , Inducible expression of N-methyltransferase

[0032] Pick a fresh single clone of the expression strain E.coli BL21(DE3) / pLYLH13, add it to LB medium supplemented with 50 μg / ml kanamycin, and culture overnight at 37°C. Take 1ml of bacterial liquid and add it to 100ml LB containing 50μg / ml kanamycin, cultivate to OD 600 After the temperature is 0.6-0.8, add IPTG with a final concentration of 1 mmol / L, and induce at 30°C for 6 hours. The bacterial cells were collected by centrifugation, and after ultrasonic disruption, the supernatant was collected by centrifugation to obtain a crude enzyme solution.

Embodiment 2

[0033] Example 2 , crude enzyme solution into sugar-free vancomycin

[0034] Using the crude enzyme solution obtained in Example 1, catalyze the reaction of sugar-free vancomycin solution for 24hrs at 25°C, the reaction conditions are as follows:

[0035] The reaction system is (1ml): adenosylmethionine (SAM) 2mmol / L 100μl; sugar-free vancomycin 0.5mg / ml 300μl; crude enzyme solution 100μl, 500μl 50mmol / L Tris / HCl at pH 7.5.

[0036] The solution obtained by the reaction is detected by HPLC, specifically as follows:

[0037] Mobile phase preparation: use 0.2% triethylamine solution and phosphoric acid to adjust the pH to 3.2 as a buffer. Mix the buffer solution with acetonitrile and tetrahydrofuran at a volume ratio of 92:7:1, shake well, and use it as solution A; mix the buffer solution with acetonitrile and tetrahydrofuran at a volume ratio of 39:60:1, shake it well, and use it as solution B. Gas for 20 minutes, set aside. During the elution process, the ratio of liquid ...

Embodiment 3

[0048] Example 3 , Reaction liquid purification

[0049]The reaction solution obtained in Example 2 was centrifuged and the supernatant was collected, and then the centrifuged supernatant was adsorbed using a macroporous adsorption resin Amberlite XAD-1600 column, and gradient eluted with water and ethanol aqueous solutions of different concentrations respectively, and each part was collected. The gradient effluent was detected by HPLC, the target components were combined, and the combined effluent was concentrated under reduced pressure and freeze-dried to obtain a purified crude product.

[0050] Then, 200 mg of the obtained crude product was dissolved in 20 ml of buffer solution C, and then the sample was loaded to the pre-equilibrated C with buffer solution C. 18 In the reverse-phase medium pressure preparative column (flow rate: 5ml / min), then use buffer solution C to elute, and collect the eluent, the effluent is detected by a 254nm ultraviolet absorption detector, and...

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Abstract

The invention provides a new vancomycin compound and an application thereof in preparation of antibiotic drugs. The compound provided by the invention is N-methyl sugar-free vancomycin. The N-methyl sugar-free vancomycin provided by the invention is a new vancomycin antibiotic, although the antimicrobial activity of the N-methyl sugar-free vancomycin is slightly lower than that of vancomycin, the water solution of the N-methyl sugar-free vancomycin can not only be more stable than the vancomycin under strong acidic condition, but also maintain high stability, so that the new vancomycin compound can be used for preparing oral antibiotic drugs.

Description

technical field [0001] The invention belongs to the field of glycopeptide compounds, in particular, it relates to a vancomycin compound. Background technique [0002] Vancomycin (Vancomycin) is a glycopeptide antibiotic against Gram-positive bacteria. It was isolated from the fermentation broth of Amycolatopsis orientalis by McCormick in 1956. It is currently used clinically to treat methoxy The drug of choice for severe infections caused by cillin-resistant Staphylococcus aureus (MRSA), has been praised by international antibiotic experts as "the last line of defense for humans against stubborn drug-resistant strains" and "the ace antibiotic". [0003] However, vancomycin is unstable under acidic conditions, especially strong acidic conditions, so it cannot be prepared into an oral drug, which affects the application of vancomycin. Stable vancomycin-like antibiotic compounds are of great interest under these conditions. [0004] In 2000, O'Brien et al. cloned the N-termin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00A61K38/14A61P31/00
Inventor 李航黄鹤阮林高杨晟郭兆霞姜卫红朱丽陈代杰罗敏玉
Owner SHANGHAI LAIYI BIOMEDICAL RES & DEV CENT
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