Bleomycin derivative and preparation method and application thereof

A technology of bleomycin and its derivatives, which is applied in the field of bleomycin derivatives and its preparation, can solve the problems of short half-life, poor enrichment and toxicity of bleomycin, and achieve little harm and strong accumulation in the body. Effect of reducing binding force and adverse reactions

Inactive Publication Date: 2017-12-05
国科戎安生物科技(北京)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the simple mixing of bleomycin and (111) indium does not bring good curative effect, and there are some disadvantages: 1. The half-life of bleomycin is short, and it degrades quickly after entering the body; 2. In-Bleomyci

Method used

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  • Bleomycin derivative and preparation method and application thereof
  • Bleomycin derivative and preparation method and application thereof
  • Bleomycin derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The preparation method of bleomycin derivative comprises the steps:

[0070] (1) Strain activation: prepare Gaoshi No. 1 medium: dissolve 10 g of soluble starch, 0.5 g of potassium chloride, 1 g of potassium dihydrogen phosphate, 0.5 g of magnesium sulfate, 2 g of sodium nitrate, and 2 g of ferrous sulfate in 1 liter of water , inoculate Streptomyces verticillium into the culture medium, culture at 28°C for 7 days; harvest monospore suspension, concentration 10 8 a / ml;

[0071] (2) Secondary fermentation: preparation of fermentation medium: glucose 10g, soybean cake powder 30g, corn steep liquor 30g, industrial starch 30g, maltose 20g, sodium chloride 3g, dipotassium hydrogen phosphate 1g, zinc sulfate 0.5g, soybean peptone 5g, dissolved in 1000ml water, inoculated Streptomyces verticillium activated in step (1) into the culture medium, cultured at 28°C for 5 days; Molecule, dropwise, control the highest concentration to 3μm / l;

[0072] (3) Tertiary fermentation: pre...

Embodiment 2

[0077] 111 The preparation method of the chelate of indium-bleomycin derivative: get N 2 Add 1mg of dried bleomycin derivative dry powder to 80μl 111 InCl 3 In the solution, use 1M NaCl solution to adjust the ionic strength at 250-300mOsm / kg·H 2 Between 0 and 20-30°C, stir gently for more than 30 minutes to dissolve the bleomycin derivative to obtain a mixed solution. During the stirring process, the pH value of the control system was 2.0.

[0078] Use macroporous adsorption resin X-5 to desalt the resulting mixed solution, and put the desalted clear liquid on CM-SephadexC-25[NH 4 + ] chromatography column with 0.1M NH 4 Get it by repeated elution with Cl-HCl solution, measure the osmotic pressure of the eluent, and adjust the osmotic pressure to 250-350mOsm / kg·H 2 O range is available.

Embodiment 3

[0080] A kind of injection, containing 1mg / dose of embodiment 1 in the injection 111 Chelates of indium-bleomycin derivatives.

[0081] After testing, the injection 111 The radioactivity of indium is 5mCi / dose.

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Abstract

The invention relates to a bleomycin derivative or pharmaceutically acceptable salt. The derivative has a structure as shown in the specification, wherein R=-NH-(CH=CH)n-C(NH2)=NH; and n is 0, 1, 2, 3 or 4. The bleomycin derivative is a Group B derivative of bleomycin and has an anti-tumor effect. Especially the terminal R group and bithiazole can generate conjugative effect, which is helpful for chelation between the derivative and 111 indium to form a chelate. As tumor cells are easier to absorb the bleomycin derivative than normal cells, 111 indium can be carried into tumor cells with small use amount of the bleomycin derivative after the bleomycin derivative and 111 indium are chelated to form the chelate; and 111 indium has short half-life and moderate radioactive activity and can generate a good in vitro-in vivo anti-tumor effect and especially has a good effect on head and neck neoplasms.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a bleomycin derivative, a preparation method and an application. Background technique [0002] Bleomycin is a class of glycopeptide antitumor antibiotics discovered in the 1960s. It was first isolated from the fermentation product of Streptomyces verticillus by Umezawa Bino and others in Japan. It has been clinically used for more than 40 years. It is a first-line treatment drug with strong anticancer activity. Bleomycin is a mixture composed of more than 10 components, and their structures differ only in the terminal amine groups. They are divided into group A and group B according to the Rf value of paper chromatography. The main components of bleomycin are bleomycin A2 (55%-70%) and bleomycin B2 (25%-32%), which are isolated from the fermentation medium of naturally occurring Streptomyces verticillium. A1, A2, A3, A4, A5, A6 and B1, B2, B3, B4, B5, B6, etc. [0003] Bl...

Claims

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Application Information

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IPC IPC(8): C07K9/00C12P21/02A61K38/14A61P35/00
CPCA61K38/00C07K9/003C12P21/02
Inventor 汤承祁高正伦刘荷中
Owner 国科戎安生物科技(北京)有限公司
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