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Benzimidazole derivative as well as preparation method and application thereof

A technology of benzimidazole and derivatives, applied in the field of benzimidazole derivatives and their preparation, can solve the problems of DNA repair defects, cell cycle arrest, p62 accumulation, etc., achieve significant proliferation and growth, inhibit H2A ubiquitination, Proliferative and growth inhibitory effects

Active Publication Date: 2022-07-22
CHONGQING UNIV OF ARTS & SCI
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

In addition, autophagy blockade leads to the accumulation of p62, which further affects the ubiquitination modification of chromatin, so that DNA repair proteins cannot be recruited to DSB sites, resulting in DNA repair defects
Finally, damaged DNA induces the accumulation of DSBs, leading to cell cycle arrest and apoptosis, suggesting that DNA repair defects caused by autophagy blockade may be new targets for cancer therapy
However, there are currently no drugs that can prevent the growth of TNBC by inhibiting autophagy and DNA repair processes

Method used

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  • Benzimidazole derivative as well as preparation method and application thereof
  • Benzimidazole derivative as well as preparation method and application thereof
  • Benzimidazole derivative as well as preparation method and application thereof

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Embodiment 1

[0043] This embodiment describes the benzimidazole derivatives and the preparation method thereof. The structural formula of the benzimidazole derivatives is as follows: figure 1 As shown, the preparation method of this benzimidazole derivative is as follows:

[0044]

[0045] Concretely, the preparation method of this benzimidazole derivative is exemplified below:

[0046] 1.56g of compound 1 acid chloride (5.0mmol) and 1.60mL of N,N-diethylaniline (10mmol) were added to 40mL of DCM to prepare a mixed suspension, and 1.04g of compound 2N-Boc was added at -78°C -1,2-phenylenediamine 2 (5.0 mmol) was mixed and incubated for 1 hour, then heated to room temperature, and after stirring for 5 hours, a yellow solid was precipitated from the solvent and filtered to obtain compound 3 in 92% yield;

[0047] At room temperature, 66 mg of compound 3 (0.1 mmol) and compound 4 (0.21 mmol) were stirred and mixed in 3 mL of DCM overnight. After the reaction was completed, the solvent was...

Embodiment 2

[0053] Example 2 Related Cell Tests

[0054] The human triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 used in this example were purchased from the American Type Culture Collection (ATCC, Virginia, USA). These cells were incubated at 37°C with 5% CO. 2 The cells were grown in high glucose DMEM (Gibco, USA) supplemented with 10% fetal bovine serum (FBS, Gibco) and 1% penicillin / streptomycin (Gibco) in a humidified incubator of

[0055] (1) Cell viability assay

[0056] The antiproliferative activity of the compounds was determined by MTT method, namely, MDA-MB-231 and MDA-MB-468 cells 24, 48 and 24 were treated with 0, 0.83, 1.56, 3.125, 6.25, 12.5, 25, 50 and 100 μmol / L test compounds. 72 hours. Next, 20 μL of MTT solution was added to each well and incubated for an additional 4 hours, then dissolved in 200 μL of DMSO. Absorbance values ​​were measured at 570 nm using a microplate reader (Bio-Tek, VT, USA) and data were analyzed by GraphPad Prism 6. All...

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Abstract

The invention relates to the technical field of compound synthesis, in particular to a benzimidazole derivative and a preparation method and application thereof.The benzimidazole derivative can remarkably inhibit proliferation and growth of triple negative breast cancer cells (TNBCs), the compound can further inhibit autophagy flow, promote accumulation of p62, induce DNA damage in the TNBC cells and inhibit DNA repair, and the compound has a good application prospect in the field of breast cancer treatment. In addition, the compound can also induce increase of cell nucleus p62 and inhibit reduction of E3 ligase RNF8, thereby causing ubiquitination of H2A. Therefore, the benzimidazole derivative disclosed by the invention has a remarkable inhibition effect on proliferation and growth of TNBC cells, and can be applied to preparation of related anti-tumor drugs.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a benzimidazole derivative and a preparation method and application thereof. Background technique [0002] Breast cancer (BC) has become the second leading cause of cancer morbidity and mortality in women worldwide. Among them, triple negative breast cancer cells (TNBC) is one of the most aggressive subtypes of breast cancer, and more than 200,000 women are diagnosed with TNBC every year, and it manifests itself in the early stages after conventional chemotherapy. Poor prognosis and high recurrence rate. Traditional treatments are largely ineffective in advanced TNBC patients due to their high tolerance to chemotherapy. Therefore, it is crucial to develop novel therapeutic agents that can inhibit TNBC cell proliferation on the one hand, and reduce side effects on the other hand. [0003] DNA damage can be caused by a variety of endogenous and exogenous factors, such...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/4184A61P35/00
CPCC07D403/04A61P35/00Y02P20/55
Inventor 杨东林张亚军李世强何刘军胡春生
Owner CHONGQING UNIV OF ARTS & SCI
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