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A novel quinazolinone compound and its preparation method and application

A quinazolinone and compound technology, applied in the field of novel quinazolinone compounds and their preparation, can solve the problems of high onset concentration, unclear mode of action, and small quantity, and achieve DNA damage induction and normal cell toxicity Small, strong selective effects

Active Publication Date: 2021-06-01
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The currently reported BLM inhibitors, on the one hand, are small in number; on the other hand, there are problems such as high intracellular onset concentration and unclear mode of action, so there is still a lot of room for research

Method used

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  • A novel quinazolinone compound and its preparation method and application
  • A novel quinazolinone compound and its preparation method and application
  • A novel quinazolinone compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of embodiment 1 compound 1f

[0043] The preparation process of compound 1f is specifically as follows:

[0044] S1, synthesis of intermediate d1

[0045]

[0046] Add 4.2g (24.3mmol) of 2-amino-4,5-difluorobenzoic acid into a 100mL reaction flask filled with 12mL of acetic anhydride, and react at 120°C for 1.5 hours. After cooling, a large amount of white solid precipitated out. The reaction liquid was rotary-evaporated under reduced pressure. After removing most of the acetic anhydride, a large amount of white solid appeared, which was filtered by suction and washed with ethanol to obtain the white solid d1, which was directly put into the next reaction.

[0047] 1 H NMR (400MHz, DMSO) δ8.13(dd, J=9.9, 8.5Hz, 1H), 7.74(dd, J=11.1, 7.2 Hz, 1H), 2.40(s, 3H).

[0048] S2, synthesis of intermediate d2

[0049]

[0050] Take 1g of d1 (5.07mmol) and 9mL ammonia water in a 100mL reaction flask, condense and reflux at 70°C (put a balloon on the cond...

Embodiment 2

[0079] Example 2 EMSA verification experiment of helicase activity

[0080] The compound prepared in Example 1 was used as the test object to test its ability to inhibit the unwinding of BLM.

[0081] 1. Anneal double-stranded Biotin forked-DNA with a final concentration of 10 nM at 95°C for 5 minutes and slowly cool down to room temperature to form a stable double helix structure;

[0082] 2. Mix the purified BLM protein with different concentrations of compounds in the helicase working solution, and incubate at 37°C for 1 hour. The final concentration of the protein is 30nM, then mix the protein compound mixed solution with the DNA solution, and mix After homogenization, continue to incubate at 37°C for 1 hour;

[0083] 3. After the incubation, add DNA Loading buffer to the sample to end the enzyme reaction. After mixing well, load the sample to 8% Native-PAGE with a buffer of 0.5×TB, 80V ice bath for about 3 hours, until bromine The phenol blue band is close to the edge o...

Embodiment 3

[0087] Embodiment 3 MTT experiment

[0088] 1. Inoculate the HCT116 cells in the logarithmic growth phase in a 96-well cell culture plate, the number of cells is 5000 / well, and place them in a 5% CO2 incubator for 24 hours;

[0089] 2. After the cells are completely adhered to the wall, discard the old medium, add medium containing different concentrations of compounds, and culture for different times according to the requirements of different experiments;

[0090] 3. When testing, add 20 μL of MTT solution with a concentration of 2.5 mg / mL to each well of cells, and continue to incubate at 37 ° C for 4 h;

[0091] 4. After MTT incubation, discard the old culture medium, add 100 μL of DMSO to each well, and the solution in the well is purple at this time. After oscillating evenly, use a multi-functional microplate reader to detect the absorption value of each well at a wavelength of 570nm, and calculate the half inhibitory concentration IC of the compound on cell proliferation ...

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Abstract

The invention discloses a novel quinazolinone compound and its preparation method and application. The structure of the compound is shown in formula I; wherein, R 1 is hydrogen, halogen, C 1～4 Alkyl, C 1～4 Alkoxy, C 1～4 Haloalkyl, C 1～6 Amino substituted alkyl, amine or alkylamino; R 2 for hydrogen, C 1～4 Alkyl or C 1～4 Haloalkyl; R 3 is hydrogen, halogen, hydroxyl, nitro, C 1～4 Alkyl or C 1～4 One or more of haloalkyl groups. The novel quinazolinone compound of the present invention has a novel structure, has a good inhibitory effect on a variety of tumor cells, and has strong selectivity with BLM protein, strong binding ability, and can significantly induce DNA damage. Normal cells have less toxicity and have broad application space in the preparation of antitumor drugs.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, and more specifically, relates to a novel quinazolinone compound and its preparation method and application. Background technique [0002] Malignant tumors are a large class of diseases that endanger human health. According to the World Health Organization (WHO), 8 million people die of cancer every year in the world, and nearly 2 million people die of cancer every year in China. Although the drug treatment of tumors has made great progress, and has become an indispensable main measure of current clinical treatment. However, problems such as high toxicity and side effects and drug resistance are still the main obstacles to clinical tumor drug treatment. The international medical community regards the development of innovative anti-tumor drugs with new targets and targeted therapy as a new hope for changing the status quo of cancer treatment, and it is also the leading directi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/90A61P35/00A61P35/02A61K31/517
CPCA61P35/00A61P35/02C07D239/90
Inventor 黄志纾陈硕斌王晨曦涂嘉莉张子林
Owner SUN YAT SEN UNIV
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