CN111346082A

CN111346082A - Application of benzoic acid compound in preparation of medicine for treating acute leukemia

Info

Publication number: CN111346082A
Application number: CN202010192386.6A
Authority: CN
Inventors: 任玉杰; 刘飞
Original assignee: Shanghai Institute of Technology
Current assignee: Shanghai Institute of Technology
Priority date: 2020-03-18
Filing date: 2020-03-18
Publication date: 2020-06-30

Abstract

The invention relates to an application of a benzoic acid compound in preparing a medicament for treating acute leukemia, wherein the benzoic acid compound is 2- (3-tert-butylamino) benzoic acid, and the compound can be used as an AKR1C3 inhibitor to be applied to a medicament for treating acute myelocytic leukemia and T-cell acute lymphocytic leukemia. Compared with the prior art, the 2- (3-tert-butylaniline) benzoic acid has good inhibition effect on AKR1C3, has the advantages of low toxicity, good drug-forming property and the like, can effectively solve the problem of drug resistance of leukemia patients to the existing leukemia treatment agents, and has good application potential in the field of treatment of acute myelocytic leukemia and T-cell acute lymphocytic leukemia.

Description

Application of benzoic acid compound in preparation of medicine for treating acute leukemia

Technical Field

The invention belongs to the technical field of biological medicines, and relates to an application of a benzoic acid compound in preparation of a medicine for treating acute leukemia.

Background

Acute Myeloid Leukemia (AML) is a debilitating disease affecting both children and the elderly. The disease is now found to have an annual incidence of more than 19520, and is the second most common hematologic malignancy. The basic pathophysiology of AML manifests as a retardation of differentiation and clonal expansion of immature BLAST cells in the bone marrow, which can be attributed to various chromosomal translocations. Acute Lymphoblastic Leukemia (ALL) originates from malignant transformation of lymphoid precursors in the bone marrow and is estimated to affect 5960 people in the united states annually, mainly the elderly and adolescents. Approximately 25% of cases are classified as T-cell ALL (T-ALL), and inhibitors of T-lymphoblastic leukemia that affect the white blood cell line have irreplaceable important roles in the treatment of acute myeloid leukemia and T-cell acute lymphocytic leukemia, and are important guarantees of the ability of leukemia patients to recover health, and no drug on the market has been found that is reported to inhibit AKR1C 3.

Aldoketoreductase 1C3(AKR1C3) is a monomeric cytoplasmic multifunctional enzyme that reduces the content of steroids, ketoprostaglandins and lipid aldehydes, is widely distributed in human tissues, and participates in the metabolism of androgens, estrogens, progesterone prostaglandins, etc. Many research results of scientists prove that AKR1C3 is involved in local hormone synthesis in tumors, and AKR1C3 is an oxidoreductase which can catalyze carcinogens such as aldehyde ketone compounds and the like to be reduced into corresponding nontoxic or low toxic alcohols, so that cells are further protected from being damaged. However, overexpression of AKR1C3 leads to the development of leukemia, and therefore, we need to reasonably inhibit the production of AKR1C3 enzyme to some extent. At present, the medicine related to AKR1C3 inhibitor in medicine is not on the market, so, the synthesis path of the AKR1C3 inhibitor is researched, and the AKR1C3 inhibitor is developed to be an attractive treatment strategy in treating acute myelocytic leukemia and T-cell acute lymphocytic leukemia.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide an application of a benzoic acid compound in preparing a medicine for treating acute leukemia, in particular to an application of a benzoic acid compound with direct aldehyde ketone reductase 1C3(AKR1C3) inhibitory activity in treating acute leukemia, and solves the problem of drug resistance of leukemia patients.

The purpose of the invention can be realized by the following technical scheme:

the application of a benzoic acid compound in preparing a medicament for treating acute leukemia is disclosed, wherein the benzoic acid compound is 2- (3-tert-butylamino) benzoic acid, and the structural formula of the benzoic acid compound is shown as follows:

further, the 2- (3-tert-butylamino) benzoic acid is applied to the preparation of the medicine for treating acute myelocytic leukemia.

Further, the 2- (3-tert-butylanilino) benzoic acid is used as an AKR1C3 inhibitor in the preparation of medicines for treating acute myelogenous leukemia.

Further, the 2- (3-tert-butylanilino) benzoic acid is applied to a medicine for treating T cell acute lymphoblastic leukemia.

Further, the 2- (3-tert-butylanilino) benzoic acid is used as an AKR1C3 inhibitor in the preparation of drugs for treating T cell acute lymphoblastic leukemia.

Further, the 2- (3-tert-butylanilino) benzoic acid is applied to a medicine for treating T cell acute lymphoblastic leukemia as an inhibitor.

Furthermore, the half inhibition concentration of 2- (3-tert-butylanilino) benzoic acid on AKR1C3 is 88.94. mu.M.

Compared with the prior art, the invention has the following characteristics:

1) the 2- (3-tert-butylanilino) benzoic acid has good inhibition effect (the half inhibition concentration is 88.94 mu M) on AKR1C3, and has the advantages of low toxicity, good pharmacy and the like;

2) the 2- (3-tert-butylanilino) benzoic acid can be used as a brand-new AKR1C3 inhibitor with excellent performance, solves the problem of drug resistance of leukemia patients to the existing leukemia therapeutic agents, and has good application potential in the field of treatment of acute myelocytic leukemia and T-cell acute lymphocytic leukemia.

Detailed Description

The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.

Example 1:

cells and reagents:

cell growth medium 90% 1640+ 10% FBS, stored at 4 ℃ until use. Cell passage: when the cells grow 80-90% of the culture dish, the cells are collected by a centrifuge tube and centrifuged, then the cells are resuspended by using new culture medium, and the cells are passaged according to the ratio of 1: 10.

The compound 2- (3-tert-butylanilino) benzoic acid was purchased from Shanghai Bidi pharmaceutical science and technology, Inc. and the MS data are:¹HNMR(400MHz,DMSO)δ13.03(s,0.42H),9.64(s,1H),7.92(d,J＝8.0Hz,1H), 7.41(t,J＝7.5Hz,1H),7.31(t,J＝7.9Hz,1H),7.23(m,2H),7.15(d,J＝7.9Hz,1H),7.10 (d,J＝8.1Hz,1H),6.79(t,J＝7.5Hz,1H),1.31(s,9H).

the experimental steps are as follows:

(1) preparation of compound working solution concentration

According to the detection requirements (half inhibitory concentration IC)₅₀The value calculation generally needs to determine more than 5 points, and then is calculated by obtaining a function through curve fitting), the compound 2- (3-tert-butylamino) benzoic acid is diluted by DMSO according to 10 concentration standards detected by each compound, the initial concentration is 300 mu M, the concentration gradient is 5 times of proportion gradient, in order to ensure the reliability of in vitro test experiments, a positive compound STSP (staurosporine) is added in each experiment as a control, the initial concentration of the positive compound STSP is 10 mu M, and the concentration gradient is 5 times of proportion gradient dilution; then diluted again with cell growth medium at a ratio of 1:10 and added to the compound plate.

(2) Cell inoculation and drug treatment

First, 1 day before assay, cells were plated at 6000 cells/well in 96-well cell plates, 80. mu.L of cell suspension was plated in each well, and the plates were placed at 37 ℃ in 5% CO₂And incubated overnight. Thereafter, on the day of the experiment, 20. mu.L of the compound diluted in cell growth medium was added to each well and placed at 37 ℃ in 5% CO₂The incubators were incubated for 72 hours in the dark, respectively. Finally, after the incubation was completed, CCK8 was added at 10. mu.L/well and placed in37℃，5％CO₂Was incubated for 4 hours. The absorbance at a wavelength of 450nm was measured on Nivo, and the inhibition ratio was calculated.

(3) Inhibition curves of compounds

Radioactivity was measured at various concentrations as described above and inhibition curves were plotted using GraphPad Prism software to obtain the half inhibitory concentration IC₅₀The value is obtained. The result shows that the semi-inhibitory concentration of the obtained compound 2- (3-tert-butylanilino) benzoic acid is 88.94 mu M, which shows that the compound has good inhibitory effect on AKR1C3 enzyme, and has low toxicity and good drug forming property.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims

1. The application of the benzoic acid compound in preparing the medicine for treating acute leukemia is characterized in that the benzoic acid compound is 2- (3-tert-butylamino) benzoic acid, and the structural formula of the benzoic acid compound is as follows:

2. the use of a benzoic acid-based compound in the preparation of a medicament for treating acute leukemia according to claim 1, wherein the 2- (3-tert-butylaminobenzoic acid) is used in the treatment of acute myelogenous leukemia.

3. The use of a benzoic acid-based compound in the preparation of a medicament for treating acute leukemia according to claim 2, wherein the 2- (3-tert-butylanilino) benzoic acid is used as an AKR1C3 inhibitor in the treatment of acute myelogenous leukemia.

4. The use of a benzoic acid-based compound in the preparation of a medicament for treating acute leukemia according to claim 3, wherein the 2- (3-tert-butylaminobenzoic acid) is used as an AKR1C3 inhibitor in the preparation of a medicament for treating acute myelogenous leukemia.

5. The use of a benzoic acid in the preparation of a medicament for treating acute leukemia according to claim 1, wherein the 2- (3-tert-butylaminobenzoic acid) is used in the treatment of T-cell acute lymphoblastic leukemia.

6. The use of a benzoic acid-based compound in the preparation of a medicament for treating acute leukemia according to claim 5, wherein the 2- (3-tert-butylanilino) benzoic acid is used as an AKR1C3 inhibitor in the treatment of T-cell acute lymphoblastic leukemia.

7. The use of a benzoic acid-based compound in the preparation of a medicament for treating acute leukemia according to claim 6, wherein the 2- (3-tert-butylanilino) benzoic acid is used as an inhibitor in the treatment of T-cell acute lymphoblastic leukemia.

8. The use of a benzoic acid in the preparation of a medicament for the treatment of acute leukemia according to claim 4 or claim 7, wherein the semi-inhibitory concentration of 2- (3-tert-butylanilino) benzoic acid to AKR1C3 is 88.94. mu.M.