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Bleomycin derivatives and anti-tumour activity thereof

A technology of bleomycin derivatives and derivatives, which is applied in the field of new bleomycin derivatives and their activities, and can solve the problems of low toxicity, low efficiency, and no activity of bleomycin derivatives

Active Publication Date: 2013-03-27
HAYAO CIHANG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the total chemical synthesis of bleomycin has been completed, a small amount of bleomycin derivatives obtained through traditional chemical modification did not show better activity or lower toxicity, while bleomycin and its complex molecules The structure also leads to cumbersome and inefficient synthetic processes, which cannot meet the needs of clinical research and the application of industrial production

Method used

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  • Bleomycin derivatives and anti-tumour activity thereof
  • Bleomycin derivatives and anti-tumour activity thereof
  • Bleomycin derivatives and anti-tumour activity thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Both Streptomyces chrysogenum SB9001 and the genetically engineered mutant strain obtained in the experiment were cultured on ISP4 agar solid medium at 30°C to obtain spores. Streptomyces verticillium ATCC15003 was grown in TSBY liquid medium containing 0.5% glycine at 28°C and 250 rpm to obtain genomic DNA. Escherichia coli was grown in LB liquid medium at 37°C and 250rpm for daily plasmid cloning and establishment of BAC library.

[0047] 1) Construction of Streptomyces chrysanthemum SB9025 mutant strain

[0048] A 10kb DNA fragment containing the complete zbmVIII gene was isolated from the cosmid containing a part of the zobermycin biosynthetic gene cluster zbm, and cloned into the Litmus 28 plasmid through BamHI and BglII restriction sites superior. The resulting plasmid was digested with SbfI to remove the insert fragment with a size of about 3.7 kb, and then the plasmid was self-ligated to complete the knockout of the zbmVIII gene. The modified DNA insert was d...

Embodiment 2

[0055] Separation, purification and detection of novel bleomycin analogs BLM S (CH102, compound 1) and 6'-dehydroxy-BLM S (CH103, compound 2)

[0056] The supernatant solution obtained after the fermentation broth was centrifuged was detected and analyzed by high-performance liquid phase (HPLC). The mobile phase A was 99.9% deionized water and 0.1% acetic acid, and the mobile phase B was 99.9% methanol and 0.1% acetic acid. The flow rate was 0.8mL / min, the UV detector wavelength is 300nm. The linear gradient analysis program was: 0-30 minutes, 100%A / 0%B to 0%A / 100%B. The rest of the supernatant was adjusted to pH 7.0 with 1N hydrochloric acid and loaded into Amberlite IRC50 (NH 4 +type) resin column, washed with 10 times column volume of deionized water, and then eluted with 2 liters of 20% ammonium acetate solution. The resulting eluate was mixed with Diaion HP-20 resin and gently shaken at room temperature for 45 minutes for adsorption, then the HP-20 resin was packed in...

Embodiment 3

[0068] BLM S (CH102, compound 1) and 6'-dehydroxy-BLM S (CH103, compound 2) DNA cleavage activity test

[0069] in Fe 2+ In the presence of conditions, respectively for BLM S, 6'-dehydroxy-BLM S and bleomycin A 2 (BLM A 2 ) to test and compare their biological activity. Based on the analysis of plasmid relaxation activity of supercoiled plasmid DNA pBluescript II SK(+), single-strand cleavage mediated by bleomycin family compounds first converts supercoiled plasmid DNA (form A) into open circular plasmid DNA (form B ), followed by double-strand cleavage to convert it into linear plasmid DNA (form C). The total reaction volume of the DNA cleavage activity test experiment was 10 μl, which contained 25 mM Tris-HCl buffer (pH 7.5), about 0.65 μg of pBluescriptSK II(+) plasmid DNA, 5 μM Fe(NH 4 ) 2 (SO 4 ) 2 ·6H 2 O (in 1mM H 2 SO 4 freshly prepared in solution) and a certain concentration of active compounds to be tested (BLM S, 6'-dehydroxy-BLM S and BLM A 2 ). After ...

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Abstract

The invention relates to the technical field of biological medicine, and particularly relates to novel bleomycin derivatives prepared from streptomycete flavoviridis SB9026 (having a preservation number of CCTCCM 2011292) and the anti-tumour activity thereof. The bleomycin derivatives disclosed by the invention have a chemical structure general formula shown in a formula (I), wherein R1 is selected from H, alkyl, amino, alkyl, acyl, sulfonyl, halogenated alkyl, heter-alkyl, hydroxyl alkyl, amino-alkyl or -(CH2)n-C(NH2)=NH, wherein n is equal to 1-6; and R2 is selected from H or -OH. Simultaneously, according to the invention, a preliminary test is performed on the biological activities of two specific bleomycin derivatives, and the preliminary test found that the DNA (deoxyribonucleic acid) cracking activity of the derivative compound BLM S (compound 1) is equivalent to the activity of the known bleomycin A2, and the DNA cracking activity of the derivative compound 6'-dehydroxylated-BLM S (compound 2) is at least 10 times as high as the activity of the bleomycin A2.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a novel bleomycin derivative and its activity. Background technique [0002] Bleomycin (BLM) is a class of glycopeptide antitumor antibiotics isolated from the fermentation product of Streptomyces verticillus in the 1960s. At present, more than ten natural components of bleomycin have been found, and their structures differ only in the terminal amino group, and the main components are bleomycin A2 (55%-70%) and bleomycin B2 ( 25% to 32%). In addition, natural products including Tallysomycin, Zorbamycin and Phleomycin are very similar in structure and activity to bleomycin, so they are collectively called bleomycin Glycopeptide antitumor antibiotics. [0003] Bleomycin has a unique molecular structure and biological activity, can mediate the activation of oxygen molecules, and selectively cause single-stranded and double-stranded DNA breaks to inhibit tumor cell...

Claims

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Application Information

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IPC IPC(8): C07K9/00C12N1/21C12N15/76A61K38/14A61P35/00A61P35/02A61P17/06C12R1/465
Inventor 沈奔段燕文
Owner HAYAO CIHANG PHARM CO LTD
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