Artesunate-diphenylurea derivative ARS-DPU as well as preparation method and application thereof
A technology of diphenylurea and artesunate, which is applied in the field of tumor treatment, can solve problems such as artesunate-diphenylurea derivatives that have not yet been seen, and achieve simple post-processing, simple preparation and synthesis methods, and high reaction rate. The effect of mild conditions
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Embodiment 1
[0048] Synthesis of intermediate (2) and product characterization:
[0049] The synthesis of intermediate (2) is shown in formula (3), comprises the following steps:
[0050]
[0051] Under nitrogen protection, 50 mL of 3.84 g of artesunate in dichloromethane, 1.83 g of 3-aminobenzylamine, 1.89 g of N,N'-diisopropylcarbodiimide DIC and 4- Dimethylaminopyridine DMAP1.03g, after dissolving, stir at room temperature for 2h, add 30ml of saturated saline after the reaction, extract with organic solvent, keep the organic phase, remove the solvent under reduced pressure to obtain a solid, then add petroleum Ether, filtration, the filter residue was alternately washed with petroleum ether and methanol, and then vacuum-dried at a temperature lower than 35°C to obtain 4.21g of a high-purity white solid product, namely intermediate (2), with a yield of 86.2%. The original map as figure 1 , figure 2 , image 3 As shown, the product is characterized as:
[0052] m.p.170.6–171.8°C....
Embodiment 2
[0054] Synthesis and product characterization of artesunate-diphenylurea derivative ARS-DPU(I):
[0055] The synthesis of artesunate base-diphenylurea derivative ARS-DPU (I) is shown in formula (4), comprising the following steps:
[0056]
[0057] Under nitrogen protection, 2.44 g of the intermediate (2) prepared in Example 1 was dissolved in 20 mL of DMF solution, 3 mL of triethylamine was added, and a DMF solution of 1.33 g of 4-chloro-3-trifluoromethylphenyl isocyanate was slowly added dropwise 10 mL, stirred at room temperature for 2 h, removed the low-boiling point solvent and triethylamine under reduced pressure, added 15 mL of distilled water, extracted 3 times with dichloromethane, 45 mL each time, combined the organic phases, washed with saturated saline, dried over anhydrous magnesium sulfate, and reduced The solvent was removed under pressure to obtain the crude product, which was separated by silica gel column chromatography to obtain a white solid, i.e. the pr...
Embodiment 3
[0060] Preliminary studies have found that the bladder cancer cell line T24 is resistant to two marketed drugs, Regorafenib (Reg) and Sorafenib (Sor), and the method of in vitro low-concentration gradient escalation combined with high-dose intermittent pulse method , to establish two drug-resistant cell lines: T24 / Reg and T24 / Sor, the specific scheme is as follows: Among them, the chemical structural formulas of Regorafenib and Sorafenib are as follows:
[0061]
[0062] T24 cells in the logarithmic growth phase were divided into 5×10 cells per well 3 Cells were seeded in a 96-well plate at a density of 100 μL per well, placed at 37°C, 5% CO 2 Cultivate overnight in the incubator; the final concentrations of sorafenib or regorafenib are 0, 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, 80, 90, 100 μM, and the medication is continued 48 hours, and observe the growth of cells in the culture medium containing different drug concentrations and the change of cell morphology under an inver...
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