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Preparation and application of molecular site-directed targeted and activated short peptide adriamycin

A compound and pharmaceutical technology, which is applied in the field of dual-target activated doxorubicin derivatives and its preparation, can solve the problems of dosage limitation, toxic and side effects of doxorubicin hydrochloride, and achieve broad-spectrum improvement, chemotherapy toxicity reduction, The effect of good application prospects

Active Publication Date: 2017-01-25
YAFEI (SHANGHAI) BIOLOG MEDICINE SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this anthracycline is known to have severe toxic side effects, including myelotoxicity, gastrointestinal disorders, stomatitis, alopecia, extravasation, acute and cumulative cardiotoxicity
Therefore, the dosage of doxorubicin hydrochloride is limited in clinical application

Method used

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  • Preparation and application of molecular site-directed targeted and activated short peptide adriamycin
  • Preparation and application of molecular site-directed targeted and activated short peptide adriamycin
  • Preparation and application of molecular site-directed targeted and activated short peptide adriamycin

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Experimental program
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Effect test

Embodiment 1

[0070] The inventor’s research found that the molecularly targeted and activated dual-targeted molecular receptors of the short peptide doxorubicin have the same distribution on the surface of tumor cells (see figure 1 ). In the immunofluorescence staining of MDA-MB231 breast cancer tumor cells, it was found that the site distribution of sialoglycoprotein receptor and aspartate endopeptidase were the same. Confocal fluorescence microscope was used to detect the corresponding antibody-labeled sialoglycoprotein receptor and aspartate endopeptidase, and DAPI was used for nuclear staining. The co-distribution of dual targeting molecule receptors can make the drug accumulate and stay near the target molecule, and improve the local concentration and activation efficiency of the drug.

Embodiment 2

[0071] Example 2: Screening of compound conformational effect and its influence on drug activation

[0072] The molecular targeted and activated short peptide doxorubicin / doxorubicin derivatives provided by the present invention, the experimental idea comes from relying on our unique synthesis technology, through the synthesis of a large number of complex compounds that are difficult to synthesize, and then connect the complex compounds to Doxorubicin or its derivatives are then screened by the size of tumor tissue activation efficiency, and the obtained compounds are screened sequentially for different short peptides, different groups, and different toxicants for tumor activation and promotion of menstruation. The specific activation site of tumor tissue is a short peptide, because the enzymatic center of aspartate endopeptidase is located at the bottom of the balloon-like invagination, and the cleavage site needs to be close to the enzymatic center. At this time, complex compoun...

Embodiment 3

[0078] Example 3: Molecular targeted and activated short peptide Adriamycin has special tissue distribution characteristics than single-point targeting

[0079] S1, S2, S3, S4, S5, and S6 compounds can target sialoglycoprotein receptors and aspartate endopeptidase, which Succinyl-AANL-DOX did not have in previous studies of the present invention. Since DOX, Succinyl-AANL-DOX and S1, S2, S3, S4, S5, S6 have autofluorescence, fluorescence microscopy can be used to detect their distribution in tumor tissues. Succinyl-AANL-DOX and S1, S2, S3, S4, S5, S6 were injected intravenously at 10umol / kg. After 12 hours, the drug distribution image of tumor tissue sections and the fluorescence intensity of tumor tissue homogenate were detected. DAPI was used for nuclear staining. Compared with Succinyl-AANL-DOX, S1 has more tumor tissue distribution and penetration after intravenous injection, indicating that S1 molecular targeted targeting makes them have a stronger tumor site retention effec...

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PUM

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Abstract

The invention relates to preparation and application of molecular site-directed targeted and activated short peptide adriamycin, in particular to a compound of the following formula I or pharmaceutically acceptable salt of the compound, a medicine composition of the compound and application of the compound in preparation of a medicine for treating or preventing cancers or cancer transferring. In the formula I, X is polar and nonpolar amino acids without charges, such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, methionine, asparaginate, glutamine and threonine; Z is adriamycin, pharmorubicin or pirarubicin; Z is connected with the lactose-XANL in the formula I through the amino of Z.

Description

Technical field [0001] The present invention relates to medicinal chemistry, in particular to doxorubicin antitumor drugs, in particular to dual-target activated doxorubicin derivatives and their preparation and use. Background technique [0002] Doxorubicin hydrochloride (Doxorubicin, DOX) is a traditional chemotherapeutic drug that has been marketed. Its structural formula is as follows: [0003] [0004] Doxorubicin hydrochloride has a broad anti-tumor spectrum and has a killing effect on a variety of tumor cells. It is suitable for acute leukemia (lymphocytic and granulocytic), malignant lymphoma, breast cancer, bronchial lung cancer (undifferentiated small cell (Sexual and non-small cell), ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck squamous cell carcinoma, testis Cancer, stomach cancer, liver cancer, etc. [0005] The mechanism of action of doxoru...

Claims

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Application Information

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IPC IPC(8): A61K47/65A61K47/54A61K31/704A61P35/00A61P35/02A61P37/02
Inventor 刘辰刘源
Owner YAFEI (SHANGHAI) BIOLOG MEDICINE SCI & TECH CO LTD
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