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New application of boron-substituted leucine compound

A technique for substituting leucine and dinolate leucine, which is applied in the field of preparation of aminopeptidase N inhibitors, can solve the problem of weak proteasome inhibitory activity, insufficient tumor cell killing activity, citrate Instability and other problems, to achieve the effect of inhibiting tumor metastasis, tumor cell migration and invasion

Pending Publication Date: 2022-01-04
WEIFANG BOCHUANG INT ACAD OF BIOTECH & MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the early stage of research on small molecule APN inhibitors, it was found that the AHPA-LEU dipeptide boronic acid citrate compound with dual-target inhibitory activity of APN and proteasome has good anti-tumor activity, but citrate does not Stable, weak proteasome inhibitory activity, not strong enough to kill tumor cells

Method used

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  • New application of boron-substituted leucine compound
  • New application of boron-substituted leucine compound
  • New application of boron-substituted leucine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The in vitro enzyme inhibitory activity experiment of embodiment 1 boronated leucine dinolate:

[0035] Use the method of preparing APN enzyme source (patent application number: 201810629864.8) for the evaluation of the inhibitory activity of boronoleucine and boronoleucine dinolate on aminopeptidase N, and Ubenimex positive control 1 , bortezomib served as positive control 2.

[0036] The test steps are as follows:

[0037] (1) K562-APN cells were sonicated to prepare cell homogenate, and seeded in 96-well plates;

[0038] (2) Adding compounds with different concentration gradients to the wells;

[0039] (3) Add APN substrate to 1.6mM after 5min and incubate for 1h;

[0040] (4) Measure the absorbance value at 405nm, and use Origin software to calculate IC50.

[0041] NOTE: The compounds used in the assay were boronoleucine, boronoleucine dinolate, ubenimex, or bortezomib.

[0042] The results showed that the IC50 value of boronoleucine on APN inhibitory activity ...

Embodiment 2

[0044] Example 2 Boroleucine and boroleucine dinolate inhibit the formation of two-dimensional tubes in HUVEC cells

[0045] Angiogenesis in tumor tissue can facilitate the metastasis of tumor cells. Using HUVEC cells to carry out two-dimensional tube formation test can reflect the ability of compounds to inhibit angiogenesis in tumor tissue. Boroleucine and Boleucine Dino Esters inhibit the ability of HUVEC cells to form two-dimensional tubes, and DMSO solvent is used as a blank control (denoted as Ctrl), and bortezomib is used as a positive control.

[0046] The test steps are as follows:

[0047] (1) Spread 50 μl of Matrigel gel diluted 1:1 in M199 medium on a 96-well plate, and incubate in an incubator;

[0048] (2) Add 100 μl of compound after 30 minutes, and make the concentration of the compound reach the working concentration after adding 50 μl of cells to the well;

[0049] (3) Treat cells, count, add 20000cell / 50μl / well to each well;

[0050] (4) After culturing f...

Embodiment 3

[0053] Example 3 Boroleucine and Boroleucine Dinoester Inhibit Breast Cancer Cell Migration Experiment

[0054] Scratch test can reflect the migration ability of breast cancer cells, investigate the ability of boronated leucine and boronated leucine dinolate to inhibit the migration of breast cancer cells, and use DMSO solvent as blank control (denoted as Ctrl), and boron Tezomib was used as a positive control.

[0055] The test steps are as follows:

[0056] (1) Lay breast cancer MDA-MB-231 cells to a 6-well plate, add 10 μM compound to treat for 2 days;

[0057] (2) With the aid of a pipette, draw a line with a white tip to make the line thickness consistent;

[0058] (3) Take pictures at 0 and 36 hours, and measure the migration distance by computer.

[0059] NOTE: The compounds used in the assay were boronoleucine, boronoleucine dinolate, DMSO solvent, or bortezomib.

[0060] The results show that if Figure 3-4 As shown, compared with the blank control and the positi...

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Abstract

The invention discloses application of a boron-substituted leucine compound to preparation of an aminopeptidase N inhibitor and preparation of a medicine for inhibiting tumor growth. The boron-substituted leucine compound is boron-substituted leucine with a structure shown in a formula 1 or boron-substituted leucine Dinuozhi (derivatives of alpha-amino boric acid) with a structure shown in a formula 2; and according to the new application, the boron-substituted leucine and the boron-substituted leucine Dinuozhi are used for preparing the APN inhibitor, so that the activity of the APN can be obviously inhibited. The compound can be used as an APN inhibitor primer for new drug research and development, and can also be used for synthesizing an APN-targeted fluorescent probe for early tumor discovery.

Description

technical field [0001] The invention relates to the technical field of aminopeptidase N inhibitors, in particular to the application of boroleucine and boroleucine dinolate in the preparation of aminopeptidase N inhibitors. Background technique [0002] Aminopeptidase N (Aminopeptidase N, APN / CD13, EC 3.4.11.2) is a zinc ion-dependent transmembrane metalloprotease that localizes on the outer surface of the cell membrane in the form of a homodimer through non-covalent binding. APN is closely related to tumor occurrence, development, and metastasis, and inhibiting APN can inhibit tumor cell metastasis. In addition, APN is a biomarker of semi-quiescent HCC stem cells, and enhancing the expression of APN can promote the survival of HCC stem cells. The above suggests that targeted inhibition of APN may have a good effect on tumor therapy. [0003] Boroleucine ((S)-1-amino-3-methylbutylboronic acid) and boroleucine dinoate ((S)-1-amino-3-methylbutylboronic acid pinane di Alcoho...

Claims

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Application Information

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IPC IPC(8): A61K31/69A61P35/00A61P35/04
CPCA61K31/69A61P35/00A61P35/04
Inventor 徐文方马玉倩戴曰慧沈晓艳王学健
Owner WEIFANG BOCHUANG INT ACAD OF BIOTECH & MEDICINE
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