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Active photosensitizer and preparation method and application thereof

A photosensitizer and active technology, applied in the field of new drug development, can solve the problems of off-target effect and drug resistance of small molecule inhibitors, and achieve the effect of improving oxidation state and avoiding drug resistance.

Inactive Publication Date: 2021-10-15
SHENZHEN LUOHU PEOPLELS HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, off-target effects and drug resistance of small molecule inhibitors have always been a problem in the field of tumor therapy

Method used

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  • Active photosensitizer and preparation method and application thereof
  • Active photosensitizer and preparation method and application thereof
  • Active photosensitizer and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0037] This embodiment relates to a kind of quinoxalinone derivative, and its preparation method is as follows: O-phenylenediamine (0.1mol, 10.8g) is dispersed in absolute ethanol (150mL), and ethyl pyruvate (0.12 mol, 13.92g), stirred at room temperature for 12h, the reaction solution was filtered, the filter cake was washed with absolute ethanol, and dried to obtain a white powder 1, (13.6g, yield 86%); 1a (20mmol, 3.2g), K 2 CO 3 (24mmol, 3.31g) was dispersed in acetone, and then bromopropene (24mmol, 3.67g) was added dropwise under stirring, the reaction mixture was reacted overnight at 62°C, the solvent was evaporated to dryness, the residue was added to water and ethyl acetate, separated The ethyl acetate phase was separated on a silica gel column (petroleum ether: ethyl acetate = 10:1), and purified to obtain 3.0 g of compound 2 with a yield of 54%. Compound 2 (2mmol, 500mg) was suspended in acetic acid, thiophene-2-carbaldehyde (3mmol, 570mg) and a catalytic amount of...

Embodiment 2

[0040] Configure 1mg / mL SHM22487C DMSO stock solution, and then pass through different ratios of DMSO / H 2 The mixed solvent of O dilutes SHM22487C into a solution with a concentration of 5 μg / mL, and its absorption spectrum is measured by a Thermo Electron-EV300 UV-Vis spectrophotometer. The maximum absorption wavelength of SHM22487C is located at 440nm. Then, the fluorescence spectrum of SHM22487C was measured by a steady-state time-resolved fluorescence spectrophotometer, and it was found that the maximum emission wavelength of SHM22487C reached 610nm. Then, the active oxygen generation efficiency was measured by the active oxygen probe ABDA by UV-Vis spectrophotometer under light. The experimental results showed that SHM22487C had a high active oxygen generation efficiency.

Embodiment 3

[0042] Prepare a DMSO stock solution containing 1 mg / mL SHM22487C and store it at room temperature in the dark. The human breast cancer cell MCF-7 was planted in a culture dish at a density of 105 / mL. After it adhered to the wall, different concentrations of SHM22487C (0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 20 μM) were added and cultured for 6 hours. , followed by 450nm laser irradiation for 5min and continued culturing for 48h, then added 20μL MTT (5mg / mL), incubated in a 37°C incubator for 4h, removed the medium, added 150μL of dimethyl sulfoxide, and then passed through a microplate reader at 570nm Check the absorbance value.

[0043] Compound ID IC 50 on HDAC1(nM)

[0044] Table 1 shows the results of SHM22487C enzyme activity inhibition research

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Abstract

The invention provides a quinoxalinone active photosensitizer based on histone deacetylase as a target and a preparation method and application thereof. An active photosensitizer molecule is obtained by performing cyclization, nucleophilic substitution, aldol condensation, hydroxylamine hydrolysis and other reactions on o-phenylenediamine and derivatives thereof. The compound can significantly inhibit the activity of HDAC1, 6 and 8, the IC50 of the compounds is 89 + / -4.6 nM, 34 + / -2.7 nM and 852 + / -6.3 nM respectively, meanwhile, the compound generates a large number of reactive oxygen free radicals under the radiation of a 450nm laser, and the compound can be used as the potential active photosensitizer. The compound can be directly added into a culture medium to be used for photodynamic binding molecular targeted therapy of breast cancer cells (MCF-7), and also can be prepared into nano particles, then intravenous injection is performed, then laser radiation is performed, and molecular targeted therapy and photodynamic therapy are simultaneously performed in a tumor-bearing mouse body.

Description

technical field [0001] The present invention relates to the technical field of novel drug development, and more particularly relates to the preparation and anti-tumor application of a quinoxalinone active photosensitizer based on histone deacetylase as a biological target. Background technique [0002] Photodynamic therapy (PDT) is a new approach to treat diseases using light-sensitive molecules and laser activation. Irradiating the lesion with a specific wavelength can activate the photosensitizing drug selectively gathered in the lesion tissue, triggering a photochemical reaction to destroy the lesion tissue. During photodynamic therapy (PDT), photosensitizing drugs transfer energy to surrounding oxygen to generate highly reactive singlet oxygen. Singlet oxygen can oxidize with nearby biomacromolecules to produce cytotoxicity and kill tumor cells. Due to the high spatio-temporal resolution of light, photodynamic therapy has the advantage over conventional therapies that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14A61K41/00A61K31/498A61P35/00
CPCC07D409/14A61K41/0057A61K31/498A61P35/00Y02P20/55
Inventor 施雷雷张鹏匡海珠高西辉曹伟灵
Owner SHENZHEN LUOHU PEOPLELS HOSPITAL
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