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Borate chemotherapy sensitizer with symmetrical structure as well as preparation method and application of borate chemotherapy sensitizer

A symmetrical structure and sensitizer technology, applied in chemical instruments and methods, active ingredients of boron compounds, medical preparations containing active ingredients, etc., can solve problems such as limited practical application, achieve easy modification or reaction, and simple preparation method Effect

Active Publication Date: 2022-08-05
ANQING NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the current phenylboronic acid pinacol esters have single-end functional groups, and their practical use is limited.

Method used

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  • Borate chemotherapy sensitizer with symmetrical structure as well as preparation method and application of borate chemotherapy sensitizer
  • Borate chemotherapy sensitizer with symmetrical structure as well as preparation method and application of borate chemotherapy sensitizer
  • Borate chemotherapy sensitizer with symmetrical structure as well as preparation method and application of borate chemotherapy sensitizer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Synthesis of chemosensitizer 2BOH with symmetrical structure:

[0035] Weigh pentaerythritol, 2-hydroxymethylphenylboronic acid, and water-binding agent in a 100-ml reaction flask at a molar ratio of 1:2.5:8, and use anhydrous tetrahydrofuran as a solvent. At room temperature, it was stirred slowly with nitrogen gas for 24 hours; after the reaction, it was filtered twice with a sand core funnel by natural dripping method, the filtrate was evaporated to dryness, and then washed with an aqueous sodium hydroxide solution with a pH of 8.0. The silica gel column was separated and purified and then frozen. After drying, a white powdery product with a symmetrical structure was obtained as a chemosensitizer named 2BOH, and the yield was 62.16%;

[0036] Its reaction equation is as follows:

[0037]

[0038] Chemosensitizer 2BOH 1 H NMR as figure 1 shown: 1 H NMR (400MHz, DMSO-d6, δ, ppm): 4.04 (s, 8H, -O-CH2-C), 5.20 (d, 4H, -CH2-Ar), 7.27-7.57 (m, 8H, -ARH ).

[0039]...

Embodiment 2

[0042] The effect of 2BOH on intracellular GSH levels:

[0043] Human lung cancer cells (A549) or human lung cancer cisplatin-resistant cells (A549 / DDP) were added to a six-well plate of cells and cultured overnight to allow cells to adhere. Then, the old medium was aspirated, and 1.8 mL of fresh medium and 200 μL of 2BOH at various concentrations were added to each well. The culture was continued for 4 h, then the cells were washed with PBS, the cell structure was disrupted with lysis buffer, and the supernatant was collected by centrifugation at 2000 rpm. Finally, the GSH content in the supernatant was determined using the GSH / GSSG kit.

[0044] The result is as Figure 4As shown, the GSH level in cisplatin-resistant human lung cancer cells is much higher than that in human lung cancer cells, that is, the GSH concentration in drug-resistant tumor cells is higher than that in drug-sensitive tumor cells; when treated with different concentrations of 2BOH, the intracellular G...

Embodiment 3

[0046] Cytotoxicity assay of 2BOH:

[0047] Human lung cancer cells (A549) or human lung cancer cisplatin-resistant cells (A549 / DDP) were seeded in a 96-well plate with about 5,000 cells per well. After overnight culture, the old medium was removed and 180 μL of fresh medium was added. , 20 μL of different concentrations of 2BOH (the concentration was set at 5-160 μg / mL), and continued to co-culture for 24 h. Finally, the medium was removed, 150 μL of DMSO was added, and after shaking for 10 min, the absorbance of crystal violet produced by living cells was detected at a wavelength of 570 nm, and the cell viability was calculated.

[0048] The result is as Figure 5 As shown, in A549 and A549 / DDP cells, cell viability was generally higher after 2BOH treatment, and only at higher 2BOH concentrations, showed weaker cytotoxicity. This is due to the massive consumption of intracellular GSH by 2BOH, resulting in a redox imbalance, which in turn triggers reactive oxygen species to...

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Abstract

The invention belongs to the related fields of pharmacology, functional molecules and the like, and particularly relates to a borate chemosensitizer with a symmetrical structure as well as a preparation method and application of the borate chemosensitizer. The chemotherapy sensitizer prepared by the invention has good biocompatibility, stimuli responsiveness and easy modification, can be used for preparing a small-molecule prodrug, and can weaken an intracellular detoxification system while triggering drug release, so that the chemotherapy sensitizer has a good application prospect in the aspect of overcoming chemotherapy drug resistance.

Description

technical field [0001] The invention belongs to the related fields of pharmacology and functional molecules, and particularly relates to a boronic ester chemotherapy sensitizer with a symmetrical structure, a preparation method and an application thereof. Background technique [0002] Small molecule drug chemotherapy has always been one of the main methods of clinical cancer treatment. So far, a wide variety of small molecule drugs have been developed for clinical use, such as doxorubicin, cisplatin, and chlorambucil. However, when chemotherapy with the same drug is used for a long time, it is often ineffective or ineffective in the later stages of treatment, mainly due to the development of tumor multidrug resistance (MDR). The mechanism of MDR is complex, mainly involving the overexpression of drug efflux transporters, the detoxification system in cells, and DNA repair. Among them, glutathione and its related enzymes (GSH / GST), as an intracellular detoxification system, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/69A61K33/243A61K31/282A61K31/704A61K31/355A61K31/196A61P35/00C07F5/02
CPCA61K31/69A61K33/243A61K31/282A61K31/704A61K31/355A61K31/196A61P35/00C07F5/02A61K2300/00
Inventor 程旭冯佩胡婷
Owner ANQING NORMAL UNIV
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