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Adriamycin derivative and its preparing method and use

A technology of doxorubicin and its derivatives, which is applied in the field of doxorubicin derivatives, can solve the problems of no practical application value, unstable amino protecting group, and inability to make injections, so as to improve bioavailability and clearly target The effect of tropism and not easy to hydrolyze

Inactive Publication Date: 2006-06-07
成都南山药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because there is antitumor activity only after being decomposed by endoasparaginase in cancer cells in cancer cells, many researches are carried out by utilizing endoasparaginase (legumain) contained in cancer cells; A large number of structural modifications of alzyme, the better effect is a compound in Cancer Research (63, 2957-2964, June 1, 2003) by Liucheng et al., which uses a large amount of and specific asparagine contained in cancer cells Dicer (legumain), design a targeting compound, connect the amino group of doxorubicin with a tetrapeptide containing asparagine, this compound can greatly reduce the toxicity of doxorubicin, but this compound is insoluble in aqueous solution , cannot be made into injections, and the amino protecting group is very unstable, it is easily hydrolyzed in normal cell tissue, and has no practical application value; therefore, it is necessary to design new compounds for the defect of unstable amino protecting group, this The compound is stable in normal cells and tissues, not easily hydrolyzed, non-toxic, and has targeting properties. After reaching cancer cells, the amino protecting group is cut off by asparagine to exert the anti-tumor activity of doxorubicin

Method used

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  • Adriamycin derivative and its preparing method and use
  • Adriamycin derivative and its preparing method and use
  • Adriamycin derivative and its preparing method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Synthesis of SUC-L-ALA-L-ALA-L-ASN-LEU-DOX (SD-1)

[0029] (Succinyl L-alanyl L-alanyl L-asparaginyl L-leucyl doxorubicin) (SD-1)

[0030] 1. Synthesis of BOC-L-ALA-L-ALA-L-ASN-L-LEU-OH

[0031] (tert-butoxycarbonyl)-L-alanyl-L-alanyl-L-asparaginyl-L-leucine)

[0032] a. Preparation of Boc-L-ASN-LEU-OBZL

[0033] Boc-L-ASN (tert-butoxycarbonyl-L-asparagine) 23.2g (100mmol), L-LEU-OBZL (L-leucine benzyl ester) 24.3g (110mmol), HOBT (1-hydroxybenzo Triazole) 14.8g (110mmol), THF (tetrahydrofuran) 300ml, dissolve together, cool down in ice water, add DCC (N,N`-dicyclohexylcarbodiimide) 22.7g (110mmol), react for 4hr, filter to remove DCU (N,N'-dicyclohexyl urea), THF was distilled off under reduced pressure, 200ml of ethyl acetate was added, impurities were washed with acid, dried and concentrated, 39g of the product recrystallized in ethyl acetate, yield 90%. The structure of the product was confirmed by mass spectrometry. + 436.1 was directly used in the n...

Embodiment 2

[0053] Embodiment 2, the synthesis of SUC-β-ALA-L-ALA-L-ASN-LEU-DOX (SD-2)

[0054] (Succinyl β-alanyl L-alanyl L-asparaginyl L-leucyl doxorubicin) (SD-2)

[0055] 1. Synthesis of BOC-β-ALA-L-ALA-L-ASN-L-LEU-OH

[0056] a. Preparation of Boc-L-ASN-LEU-OBZL

[0057] Boc-L-ASN23.2g (100mmol), L-LEU-OBZL24.3g (110mmol), HOBT14.8g (110mmol), THF300ml, dissolve together, cool down in ice water, add DCC22.7g (110mmol), react for 4hrs, filter DCU was removed, THF was distilled off under reduced pressure, 200 ml of ethyl acetate was added, impurities were washed with acid, dried and concentrated, 39 g of the product recrystallized in ethyl acetate, yield 90%. The structure of the product was confirmed by mass spectrometry. + 436.1 was directly used in the next reaction without further purification.

[0058] b. Preparation of Boc-L-ALA-L-ASN-LEU-OBZL

[0059] Weigh the product Boc-L-ASN-LEU-OBZL 34.8g (80mmol) from the previous step, dissolve it in 200ml of 1NHCL ethyl acetate, re...

Embodiment 3

[0077] Example 3 Synthesis of other derivatives of β-ALA-L-ALA-L-ASN-LEU-DOX

[0078] Based on β-ALA-L-ALA-L-ASN-LEU-DOX, it can easily pass through the reaction of acid chlorides and amino groups of various acids, the condensation reaction of amino groups and various acids, and the reaction of acid anhydrides and amino groups, The reaction of active esters and amino groups, etc., to synthesize various derivatives of β-ALA-L-ALA-L-ASN-LEU-DOX, including various natural and non-natural derivatives, various carboxylic acids, sulfonic acids, phosphoric acids Class derivatives, these reactions are easy to realize for synthetic workers, and are simply stated in the present invention.

[0079] Weigh β-ALA-L-ALA-L-ASN-LEU-DOX 0.912g (1mmol), BocGlu (obut) (tert-butyloxycarbonylglutamic acid tert-butyl ester) 0.33g (1.1mmol), if in the reaction bottle, After adding 5ml of DMF, cooling in ice water, assuming HBTU0.42g (1.1mmol), reacted for 2 hours, poured into water to precipitate, f...

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Abstract

The present invention provides one kind of adriamycin derivative in the structure as shown. The modified adriamycin derivative, pharmacological experiment shows, has obvious antitumor activity, as well as cytotoxicity lower than that of adriamycin, obvious targeting property, stable quality and high controllability.

Description

technical field [0001] The present invention relates to a derivative of doxorubicin. technical background [0002] Doxorubicin has a strong anti-tumor effect, because its structure contains both fat-soluble anthracycline and water-soluble daunosamine; it also has acidic phenolic hydroxyl groups and basic amino groups. As a cycle non-specific anticancer chemotherapy drug, doxorubicin has effects on cells in all phases, but it is most sensitive to the early stage of S phase, followed by M phase, and to G phase. 1 , S and G 2 period has a delaying effect. Its mechanism of action is that it can directly act on DNA, insert into the double helix strand of DNA, untie the latter, change the template properties of DNA, and inhibit DNA polymerase, thereby inhibiting both DNA and RNA synthesis. In addition, doxorubicin has the function of forming superoxide radicals, and has a special effect of destroying the structure and function of cell membranes. [0003] However, doxorubicin h...

Claims

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Application Information

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IPC IPC(8): C07K5/10A61K38/07A61P35/00C07H15/252
Inventor 闫光华米军
Owner 成都南山药业有限公司
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