Method for preparing adriamycin-dipeptide complexes and applications

A technology of peptide complexes and doxorubicin, which is applied in medical preparations with non-active ingredients, polymer compounds with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of low reaction rate, long time consumption, and product production. To solve the problems of low efficiency and purity, achieve the effect of high reaction rate, short time consumption, high purity and yield

Inactive Publication Date: 2008-10-01
河南省健康伟业生物医药研究股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, in the prior art, the preparation method of doxorubicin-dipeptide complex generally ta

Method used

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  • Method for preparing adriamycin-dipeptide complexes and applications
  • Method for preparing adriamycin-dipeptide complexes and applications
  • Method for preparing adriamycin-dipeptide complexes and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Synthesis of benzyloxycarbonylglycylprolyl doxorubicin

[0028] (1) Activation of N-benzyloxycarbonylglycylproline:

[0029] Weigh 26.4mg (86.2μmol) of N-benzyloxycarbonylglycylproline and dissolve it in 1.5ml of N,N-dimethylformamide (DMF), add 9.8μl (86.2×1.2=103.4μmol) of chlorine Ethyl formate, stirred at room temperature for 10 minutes, added 14.5 μl (103.4 μmol) of triethylamine, stirred at room temperature for 40 minutes.

[0030] (2) Preparation of N-benzyloxycarbonylglycylprolyl doxorubicin:

[0031] Weigh 40 mg (86.2 μmol) of doxorubicin hydrochloride and dissolve it in 1.5 mL of DMF, add 12.5 μl (86.2 μmol) of triethylamine and mix well. Add the dissolved doxorubicin hydrochloride solution to the above-mentioned activated Z-GP solution, and stir at room temperature for 5 to 6 hours; the product is extracted with 30 ml of ether (5 times the volume of the reaction solution), and the precipitate is discarded by suction filtration under reduced pressu...

Embodiment 2

[0034] Example 2 In vitro cytotoxicity test of benzyloxycarbonylglycylprolyl doxorubicin (Z-GP-Dox)

[0035] K562, MOLT-4 cells were seeded in 96-well plates at a density of 10,000 / well, and free doxorubicin containing 0 μM-2 μM or Z-GP-Dox at an equimolar concentration (the solvent was DMSO) was added to the cells, Or replace the K562, MOLT-4 cell culture medium with the mEF cell culture medium incubated with the Z-GP-Dox of the above-mentioned equimolar concentration of free doxorubicin for 24 hours and 48 hours, after 24 hours and 48 hours, respectively, by The cell viability of K562 and MOLT-4 was detected by MTT method. From the results, the cytotoxicity of Z-GP-Dox was reduced by 4-7 times (K562 cells) and 9-24 times (MOLT-4 cells) respectively compared with the IC50 of Dox. However, after incubation with mEF cells, Z-GP-Dox can recover to the cytotoxicity IC50 similar to that of the parent drug, as shown in Table 1.

[0036] Table 1 Cytotoxicity comparison of Z-GP-Dox...

Embodiment 3

[0038] Example 3 Plasma stability test of benzyloxycarbonylglycylprolyl doxorubicin (Z-GP-Dox)

[0039] Containing 0.675μM Z-GP-Dox in 20% liver cancer cells, breast cancer patient serum and normal human plasma for 6 hours, 12 hours, and 24 hours respectively, the supernatant was used to act on K562 cells, and the cell survival rate was detected by MTT method. The results showed that after 24 hours, the cell survival rate still reached more than 70%, indicating that Z-GP-Dox was less cleaved into the cytotoxic parent drug doxorubicin in the serum, and it was less effective in the serum of patients with liver cancer, breast cancer patients and normal people. in is stable. See attached figure 1 shown.

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Abstract

The invention discloses a preparation method of an adriamycin-dipeptide compound. Dipeptide or polypeptide containing proline residue is connected to amino of the adriamycin by the acylation through the technique of peptide modification; the toxicity of the adriamycin can be reduced and at the same time the pro-drug can release the adriamycin under the action of tumor interstitial cells so as to ensure that the adriamycin can enrich around tumor tissue to improve the selectivity of the adriamycin to the tumor tissue. The preparation method of the invention has the advantages of fast reaction rate, short term, relatively high productive rate and purity.

Description

technical field [0001] The invention belongs to the technical field of biology and medicine, and specifically relates to a preparation method and application of a doxorubicin-dipeptide complex with anticancer activity. Background technique [0002] Due to its extensive anti-tumor effects, doxorubicin is often used as a first-line drug in the treatment of cancer in the clinical treatment of liver cancer, gastric cancer, breast cancer, lung cancer, ovarian cancer and various blood cancers. However, adverse reactions such as myelosuppression and cardiotoxicity of doxorubicin often destroy the patient's immune function, seriously affecting the therapeutic effect. Therefore, finding a modification method to reduce the toxicity of doxorubicin and improve the selectivity of doxorubicin to tumor tissue has become one of the focuses of current research. [0003] A core of prodrug technology is that the structure of many anti-tumor small molecule chemical drugs contains free amino gr...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K47/42A61K31/704A61P35/00A61K47/62
Inventor 杜军刘鹏卜宪章谢白露
Owner 河南省健康伟业生物医药研究股份有限公司
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