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 inhibito

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

Example Embodiment

[0034] Example 1 In vitro generation of boron Dino leucine ester inhibiting activity test:

[0035] APN enzyme source was prepared using a method (Patent Application Number: 201810629864.8) substituting boron for boron substituting leucine and isoleucine esters Dino Evaluation of inhibitory activity of aminopeptidase N and in a positive control ubenimex 1 bortezomib 2 as a positive control.

[0036] The test procedure is as follows:

[0037] (1) K562-APN cells after sonication crushed cell homogenate, seeded in 96 well plates;

[0038] (2) different concentrations of compounds were added to the wells;

[0039] After (3) 5min APN substrate was added to 1.6mM, incubated IH;

[0040] (4) Measurement of absorbance at 405nm, using Origin software to calculate IC50.

[0041] Note: The test compound used is boron substituting leucine, leucine Dino substituting boron esters, or ubenimex bortezomib.

[0042] The results show that boron substituting leucine APN inhibition activity IC50 valu...

Example Embodiment

[0044] Example 2 Boron-leucine and boron monuerine Dior ester inhibited HUVEC cells two-dimensional tube production experiment

[0045] Tumor tissue new blood vessels provide convenience for tumor cell metastasis, using HUVEC cells to carry out two-dimensional tube production test, reflecting the ability of compounds to inhibit neovascularization of tumor tissues, and investigating boron-leucine and boron The ester inhibits the ability of HUVEC cells to be generated, followed by a DMSO solvent as a blank control (recorded Ctrl), as a positive control as a positive boron.

[0046] The test steps are as follows:

[0047] (1) M199 medium 1: 1 diluted MATRIGEL glue 50 μL into a 96-well plate, incubation in the culture box;

[0048] (2) 100 μl of compound was added after 30min, and 50 μl of cells were added to the hole, and the compound concentration to the working concentration;

[0049] (3) Treatment of cells, count, 20000 Cell / 50 μl / hole per well;

[0050] (4) After 6 h, take a ...

Example Embodiment

[0053] Example 3 Boron-leucine and boronine derogate inhibited breast cancer cell migration test

[0054] Scratch tests can reflect the migration capabilities of breast cancer cells, and investigate the ability of boron-leucine and boronine derogate to inhibit breast cancer cells, and use DMSO solvent as a blank control (recorded as ctrl), boron It is a positive control.

[0055] The test steps are as follows:

[0056] (1) Breast cancer MDA-MB-231 cells into 6-well plates, add 10 μM compound treatment for 2 days;

[0057] (2) Use the pipette to assist, white gun headlines, make the painting line thickness;

[0058] (3) Take a photo at 0, 36h, and the computer is migrated.

[0059] Note: The compounds used in the test are boron leucine, boron monuerine Dior ester, DMSO solvent or boron.

[0060] The results show that such as Figure 3 ~ 4 As shown, the boron-leucine and boronine derotries can significantly inhibit breast cancer cell migration compared to blank control and positive c...

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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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