A kind of dmxaa-pyranoxanthone hybrid compound and its preparation method and application

A technology of compounds and hybrids, applied in the field of preparation of anti-tumor drugs, can solve the problems of anti-tumor cell proliferation activity not particularly active, patients restless, visual impairment, etc., to achieve inhibition of in vitro proliferation, rapid response, and reduced toxicity Effect

Active Publication Date: 2020-02-07
广州药本君安医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the anti-tumor cell proliferation activity of DMXAA is not particularly active, and the clinically used dose is large, reaching 4.9g / m2 (Li, J.; Jameson, M.B.; Baguley, B.C.; Pili, R.; Baker, S.D. Clin. Cancer Res. 2008,14,2102-2110), which lead to DMXAA in clinical application with certain cardiotoxicity, visual disturbance, urinary incontinence and cause anxiety and restlessness in patients (Zhou, S.F.; Kestell, P.; Baguley, B.C. ; Paxton, J.W. Invest. New Drugs 2002, 20, 281-295)

Method used

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  • A kind of dmxaa-pyranoxanthone hybrid compound and its preparation method and application
  • A kind of dmxaa-pyranoxanthone hybrid compound and its preparation method and application
  • A kind of dmxaa-pyranoxanthone hybrid compound and its preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0042] Preparation of D-P hybrid compounds.

[0043] 1.1 Preparation of D-P-3 hybrid compound

[0044] Including the following 7 steps:

[0045] 1.1.1 Preparation of 2,5-dibromo-3,4-dimethylbenzoic acid

[0046] Dissolve 3,4-dimethylbenzoic acid (0.164g, 1.0mmol) in 20mL of concentrated sulfuric acid, add NBS (0.212g, 1.2mmol) in batches, and stir at room temperature for 12h; then slowly pour the reaction mixture into ice-water solution , there was a white precipitate, which was collected by filtration and washed with cold water; the crude product was recrystallized and purified with distilled water to obtain 0.303 g of white crystals, with a yield of 98.0%, M.p.: 131-134°C. 1 H NMR (400MHz, DMSO-d 6 )δ:7.68(s,1H),2.48(s,3H),2.46(s,3H); 13 CNMR (75MHz, CDCl 3 )δ: 177.1, 136.5, 135.4, 135.1, 133.7, 127.0, 123.3, 19.3, 18.9; ESI-MS (m / z): 307.9 [M+H] + . The above data confirmed that the compound was 2,5-dibromo-3,4-dimethylbenzoic acid.

[0047] 1.1.2 Preparation of 2-(...

Embodiment 2

[0082] D-P-3~D-P-6 and D / P Combined Drug Inhibitory Activity of Tumor Cell Proliferation in Vitro

[0083] Experimental method: Cells in the logarithmic growth phase were inoculated in a 96-well plate at a seeding density of 1×10 4 cells / well, cultured overnight. When the degree of fusion reaches more than 70%, drug treatment is added, and a blank group, a control group, and different concentration administration groups are set in the experiment. The D-P-n hybrid compound was serially diluted starting from 200 μM, and three replicate wells were set up for each group. After incubation for 24 h, add 10 μL of MTT solution to each well and place at 37 °C with 5% CO 2 Continue in the incubator, protect from light when MTT solution. After incubation for 4 hours, discard the solution in each well, be careful not to suck away the crystals, and finally add 100 μL of fresh DMSO solution to each well, shake it on a shaker for 15 minutes in the dark, and place it on a microplate reader...

Embodiment 3

[0093] Toxicity of D-P-6 to normal cells

[0094] Experimental method is the same as embodiment 1.

[0095] The results indicated that the compound D-P-6 showed a lower inhibitory effect on cell proliferation in vitro on the human liver cell line HL-7702 and the mouse embryonic fibroblast cell line NIH / 3T3.

[0096] Specifically, the IC of compound D-P-6 after acting on HL-7702 cells for 24 and 48 hours 50 is 452.29±41.20, 351.98±31.26μM; IC of compound D-P-6 after acting on NIH / 3T3 cells for 24 and 48h 50 are 378.03±37.22, 293.22±25.34 μM. It shows that the compound D-P-6 has strong cytotoxicity to the tested tumor cell lines, but less toxic to normal cells.

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Abstract

The invention discloses a DMXAA-Pyranoxanthone hybrid compound with anti-tumor effect, its preparation method and application. The structure of the compound is shown in Formula I. The preparation method comprises: preparing DMXAA in three steps, preparing pyranoxanthone in two steps, and combining DMXAA and pyranoxanthone into a DMXAA-Pyranoxanthone hybrid compound in two steps. The DMXAA-Pyranoxanthone hybrid compound and the DMXAA / pyranoxanthone combination drug of the present invention have excellent in vitro tumor cell proliferation inhibitory activity on breast cancer, liver cancer, and leukemia cells, and can induce tumor cell apoptosis at multiple targets. The DMXAA-Pyranoxanthone hybrid compound and the DMXAA / pyranoxanthone combination drug of the present invention can be applied to the preparation of cancer treatment drugs.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a DMXAA-Pyranoxanthone hybrid compound with anti-tumor effect and a preparation method thereof, and the application of the hybrid compound in the preparation of anti-tumor drugs Background technique [0002] As we all know, cancer has become one of the high-incidence diseases that threaten human health today. In many countries, the incidence of cancer is increasing and it has become the leading cause of death. At present, there are many methods for the treatment of tumors, many of which have certain effects, but usually cause severe systemic toxicity, cancer metastasis and recurrence, and there is still a certain distance from the cure of cancer. Therefore, the research and development of efficient, safe, and low-toxic cancer therapeutic drugs has become a hot and difficult point in current drug research. [0003] Xanthones are a class of heterocyclic compounds with a wide ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61P35/00A61P35/02
CPCC07D493/04
Inventor 陈河如刘杰王怀玲刘志军
Owner 广州药本君安医药科技股份有限公司
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