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Aspartase-targeted activated adriamycin derivative as well as preparation method and application thereof

An aspartase target, adriamycin technology, applied in the field of antitumor drug compounds, can solve the problems of limited dose, toxic and side effects, and achieve the effects of improved drug efficacy, reduced toxicity, and good application prospects

Active Publication Date: 2013-04-17
上海亲合力生物医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application of this anthracycline compound is limited because of its severe toxic and side effects.

Method used

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  • Aspartase-targeted activated adriamycin derivative as well as preparation method and application thereof
  • Aspartase-targeted activated adriamycin derivative as well as preparation method and application thereof
  • Aspartase-targeted activated adriamycin derivative as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0034] The invention provides a method for preparing a polypeptide doxorubicin activated by aspartase targeting tumor microenvironment, comprising the following steps: first, using known chemical, biological or recombinant techniques to couple amino acid residues, and separating The formed polypeptide R3-Asn-R4-R5 is obtained; secondly, the nitrogen segment of the formed polypeptide is formed into a covalent bond R3- Asn-R4-R5-R6; then the carboxyl group of R3 of R3-Asn-R4-R5-R6 is combined with doxorubicin or its salt or doxorubicin derivative and its salt (ie The amino group of compound A) is covalently bonded to form a doxorubicin analog with a short peptide and a group capable of binding to serum albumin, compound A—R3-Asn-R4-R5-R6. The reaction scheme is as follows:

[0035]

[0036] Among them, the condensing agent includes known chemical reagents used for the condensation reaction of carboxylic acid and amino group to form amides, used alone or in combination, such ...

Embodiment 1

[0039] Example 1: Synthesis of activated polypeptide doxorubicin S1 and S2 targeting the tumor microenvironment

[0040] The synthetic routes of S1 and S2 are as follows:

[0041] .

[0042] 1) Synthesis of Cbz-L-Ala-L-Ala-OMe (I)

[0043]

[0044] Dissolve N-benzyloxycarbonyl-L-alanine (100g, 0.45mol) in dry N,N-dimethylformamide (3L), add 1-hydroxybenzotriazole (72.6g , 0.54mol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (103.3g, 0.54mol), after stirring for 1 hour, add dropwise in ice bath to 0°C L-alanine methyl ester (46.2g, 0.45mol) and N,N-diisopropylethylamine (173.8g, 1.34mol) in N,N-dimethylformamide (1L) solution, dropwise After completion, stir at room temperature for 10 hours, evaporate the solvent under reduced pressure, dissolve the crude product in dichloromethane (2L), wash with saturated ammonium chloride solution, water and saturated sodium chloride solution successively, and wash the organic phase with anhydrous sodium sulfate A...

Embodiment 2

[0081] Embodiment 2 obtains injection

[0082] The synthesized S1 and S2 were vacuum-dried to obtain a red powder, which was sterilized by gas for aseptic treatment and subpackaged in a sterile room. Before the animal experiment, dissolve it with water for injection containing 50% alcohol in a sterile room, and then dilute it with water for injection to the required concentration.

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Abstract

The invention discloses an aspartase-targeted activated adriamycin derivative, as well as a preparation method and an application thereof. The adriamycin derivative is prepared by condensing amino of a compound A and carboxyl of a compound B; and the structure formulae of the adriamycin derivative, the compound A and the compound B are shown in the specification: in the formulae, R3 is Leu (leucine) or empty, R4 is any one of Ala (alanine), Thr (threonine), Val (valine) and Ile (isoleucine), R5 is any one of Ala, Thr, Val and Asn (asparaginate), R6 is a functional group for prolonging drug metabolic half-life period, a selection group (n is 1-20) or a group shown in the specification, and R7 is substituted or unsubstituted C1-C20 straight or branch chain saturated or unsaturated aliphatic hydrocarbon or substituted or unsubstituted C6-C20 aromatic hydrocarbon. Compared with adriamycin, the aspartase-targeted activated adriamycin derivative has the characteristics of specific tumor targeting and high internal metabolic half-life period at the same time, has the efficient and safe anti-tumor effect, and can be used for preparing anti-tumor drugs.

Description

technical field [0001] The invention relates to an antitumor drug compound, in particular to a preparation method and use of a doxorubicin derivative with targeted activation of aspartase and high half-life of in vivo metabolism. Background technique [0002] Doxorubicin hydrochloride and epirubicin are potent antineoplastic agents currently in broad-spectrum use for the treatment of hematological and solid tumors, such as breast and ovarian cancers, sarcomas, and many other solid tumors. However, the clinical application of this anthracycline compound is limited because of its severe toxic and side effects. Doxorubicin hydrochloride has caused multiple adverse reactions, including myelotoxicity, gastrointestinal disorders, stomatitis, alopecia, extravasation, and acute and cumulative cardiotoxicity. The main limitation of doxorubicin hydrochloride is that after each course of treatment, high doses of doxorubicin hydrochloride lead to a sharp decrease in monocytes and plate...

Claims

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Application Information

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IPC IPC(8): C07K5/083C07K5/093C07K5/103C07K5/113C07K1/107A61K31/704A61K47/48A61P35/00
Inventor 刘辰刘源
Owner 上海亲合力生物医药科技股份有限公司
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