Gemcitabine ProTide anaerobic activated pro-drug and application thereof
A technology of gemcitabine and oxygen activation, applied in organic chemistry, anti-tumor drugs, drug combinations, etc., can solve the problem of limited tumor effect, achieve small cell toxicity, large cell toxicity, and good anti-tumor effect
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Embodiment 1
[0032] Embodiment 1: the synthesis of target compound 001-021:
[0033] Synthesis of Compound 001
[0034]
[0035] Synthesis of 3'-O-(tert-butoxycarbonyl)gemcitabine
[0036] Synthetic route (obtained by reference method, The Journal of Organic Chemistry, 1999, 64:8319-8322):
[0037]
[0038] Experimental operation: gemcitabine (gemcitabine, 0.60g, 2mmol), Na 2 CO3 (1.06g), 40mL dioxane, 40mL water, di-tert-butyl dicarbonate (DBDC, 0.44g, 2mmol) were stirred at room temperature for 48 hours. Add 20mL water, extract with 2×300mL ethyl acetate, Na 2 SO 4 Dry and concentrate under reduced pressure. Flash column chromatography (CH 2 Cl 2 -Ethyl acetate-EtOH 1:1:0.02) gave 3'-O-(N-tert-butoxycarbonyl)gemcitabine (0.60 g). 1 H NMR(DMSO-d6,300MHz)δ(ppm):7.64(d,1H)7.40(d,2H),6.21(t,1H),5.81(d,1H),5.25-5.12(m,2H), 4.13(t,1H)3.71-3.60(m,2H),1,45(s,9H).
[0039] Synthetic route (obtained by reference method, The Journal of Medicinal Chemistry, 2014, 57:1531-1542):
[0...
Embodiment 2
[0103] Example 2: In vitro inhibitory effect of the target compound on tumor cell proliferation under normoxic and hypoxic conditions
[0104] Take tumor cells in the logarithmic growth phase, add 0.25% trypsin to digest for 3 minutes, suspend the cells with RPMI-1640 containing 10% calf serum, count them, and adjust the cell concentration to 1×10 5 cells / mL, inoculate 100 μL / well in Top-count dedicated 96-well cell culture plate, 37°C, 5% CO 2 Incubate for 24h. Then the cells were divided into experimental group and control group, and the experimental group was added with target compound solution (0.001 μg / mL, 0.01 μg / mL, 0.1 μg / mL, 1 μg / mL, 10 μg / mL), each concentration was quadruple well , and the volume of each well was supplemented with 200 μL. Each group was cultured for 72 hours after sample addition (hypoxia group was stored in 5% CO 2 , 95%N 2 Continue to culture for 72h respectively), before the end of culture, each well was added 3 H-TdR 3×10 5 Bq, use Top-cou...
Embodiment 3
[0109] Example 3: Inhibitory effect of target compound on orthotopic xenograft tumor of human BxPC-3 nude mice
[0110] BxPC-3 human pancreatic cancer cells in the logarithmic growth phase were taken in 5×10 6 1 cell·0.2mL -1 ·Only -1 The concentration was inoculated subcutaneously on the back of nude mice to establish a nude mouse subcutaneous xenograft tumor model of human primary pancreatic cancer. After the subcutaneous xenograft tumor had grown to 1 cm, it was taken out, and the central necrotic tissue was removed under sterile conditions, and the surrounding healthy tumor tissue was selected and cut into 1mm 3 organization block.
[0111] Surgical orthotopic transplantation model preparation: intraperitoneally anesthetized nude mice with pentobarbital sodium (50 mg / Kg), made an incision next to the left upper rectus abdominis muscle, exposed the spleen and pancreatic tail, cut the pancreatic capsule, and implanted the tumor block near the splenic artery near the pancr...
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