Nitric oxide donor type tetravalent platinum derivative, preparation method and medical use thereof
A compound and pharmaceutical technology, applied in the field of pharmacy, can solve the problems of unclear direct mechanism of action, affecting DNA replication of tumor cells, etc.
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Embodiment 1
[0047]
[0048] Compound I 2 The synthesis of: prolinol (I 1 , 10g), methanol solution (5.4mol / L) of sodium methoxide (5.4mol / L) 17.8g mixed into the polytetrafluoro container, add anhydrous ether 200mL, the reaction system N 2 After the replacement, nitrogen monoxide (NO) gas was introduced to make the pressure reach 0.4-0.8 MPa, and the reaction was carried out in a sealed greenhouse for 24 hours. Post-processing, let go of unreacted excess NO gas, the pressure will be normal pressure, after opening the container, pour the reaction solution into 1L of anhydrous ether to precipitate a large amount of white solid, filter, and wash the filter cake 3 times with ether, As for drying at room temperature in a vacuum drying oven for 2 hours, the collected white product is compound I 2 . Compound I obtained 2 The next reaction was carried out directly without purification.
[0049]
[0050] Compound I 3a and I 3b The synthesis of: take 1g compound I 2 and 5mL DMF were a...
Embodiment 2
[0063]
[0064] Compound II 2 Synthesis of: Boc-piperazine (II 1 , 20mL), methanol solution (5.4mol / L) of sodium methoxide (5.4mol / L) 50.79mL mixed into the polytetrafluoro container, add anhydrous ether 200mL, the reaction system N 2 After the replacement, nitrogen monoxide (NO) gas was introduced to make the pressure reach 0.4-0.8 MPa, and the reaction was carried out in a sealed greenhouse for 24 hours. Post-treatment, let go of unreacted excess NO gas, make the pressure drop to normal pressure, open the container, pour the reaction solution into 1L of anhydrous ether to precipitate a large amount of white solid, filter, and wash the filter cake 3 times with ether, As for drying at room temperature in a vacuum drying oven for 2 hours, the white product is collected, which is compound II 2 . Compound II obtained 2 The next reaction was carried out directly without purification.
[0065]
[0066] Compound II 3 Synthesis: take 1g of compound II 2 and 5mL DMF were ...
Embodiment 3
[0081] Embodiment 3: Compound I 5a Proliferation inhibitory activity of human ovarian tumor cell A2780 and normal human ovarian cell IOSE80
[0082] Cells in logarithmic growth phase were divided into 1×10 5 cells / well were seeded in 96-well plate, placed at 37°C, 5% CO 2 Cultured under conditions until the cells were 90% confluent, then incubated with serum-free DMEM medium for 2 h to synchronize the cells. Subsequently, the supernatant was discarded, and different concentrations of CDDP, CHP, I 4a , I 5a DMEM was incubated for 72 h, and 20 μL of MTT solution (5 mg / mL) was added to each well 4 h before the end of the incubation. After the incubation, discard the supernatant of each well, add 150 μL DMSO to each well, shake on a cell shaker for 10 minutes, and measure the OD with a microplate reader after the crystals are fully dissolved. 570 . .The results are expressed as mean±SD, and then the IC is obtained by fitting through GraphPad Prism 6 according to the inhibiti...
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