Doxorubicin prodrug as well as preparation method and application thereof
A doxorubicin and prodrug technology, which is applied in the field of doxorubicin prodrug and its preparation that binds serum albumin in situ and has tumor targeting ability, can solve the problem of inability to precisely control drug molecules, lack of tumor targeting, etc. question
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Embodiment 1
[0068] The present embodiment provides a kind of doxorubicin prodrug---shear type TCO axial isomer-Dox-EMCH (TCO dax -Dox-EMCH), whose structure is as follows:
[0069]
[0070] The specific reaction formula is as follows:
[0071]
[0072] (1) The shear type TCO axial isomer (TCO dax ) and 4-nitrophenol chloromethyl ester were dissolved in tetrahydrofuran, adding pyridine, wherein the molar ratio of pyridine and 4-nitrophenol chloromethyl ester was 1:1, reacted at 30°C for 24h to obtain shear type TCO axial isomerization Body p-nitrophenyl carbonate;
[0073] (2) Trans cyclooctenol p-nitrophenyl carbonate and doxorubicin in a molar ratio of 0.8:1 in dimethylformamide, add triethylamine, wherein triethylamine and trans cyclooctene The molar ratio of alcohol to nitrobenzene carbonate is 3:1, and the TCO is obtained by reacting in the dark at 25°C for 48h dax -Dox;
[0074] (3) 6-maleimidocaproyl hydrazide trifluoroacetate with a molar ratio of 0.9:1 and TCO dax -Dox...
Embodiment 2
[0080] The present embodiment provides a kind of doxorubicin prodrug---shear type TCO plane isomer-Dox-EMCH (TCO deq -Dox-EMCH), whose structure is as follows:
[0081]
[0082] The specific reaction formula is as follows:
[0083]
[0084] (1) The shear type TCO planar isomer (TCO deq ) and 4-nitrophenol chloromethyl ester were dissolved in tetrahydrofuran, and pyridine was added, wherein the molar ratio of pyridine to 4-nitrophenol chloromethyl ester was 1:1, and reacted at 30°C for 24h to obtain the shear type TCO plane isomer p-Nitrobenzene carbonate;
[0085] (2) Add N,N-diisopropylethylamine to trans-cyclooctenol p-nitrophenylcarbonate and doxorubicin at a molar ratio of 0.9:1 in dimethylformamide, where N, The molar ratio of N-diisopropylethylamine to trans-cyclooctenol-p-nitrobenzene carbonate is 2:1, react at 30°C in the dark for 36h to obtain TCO deq -Dox;
[0086] (3) 6-maleimidocaproyl hydrazide trifluoroacetate and TCO with a molar ratio of 0.8:1 deq -...
Embodiment 3
[0089] In this example, the prodrug-activated switch NapK(Tz)FYp was prepared by the following method, and its structure is as follows:
[0090]
[0091] The specific reaction formula is as follows:
[0092]
[0093] (1) Dissolve NapKFYp and Tz-NHS with a molar ratio of 1.2:1 in dimethylformamide, add N,N-diisopropylethylamine, where N,N-diisopropylethylamine and Tz -The molar ratio of NHS is 2:1, react at 25°C for 24h to obtain NapK(Tz)FYp;
[0094] (2) The obtained prodrug-activated switch NapK(Tz)FYp was purified to obtain a refined product with a yield of 85.5%.
[0095] use 1 The prepared activation switch NapK(Tz)FYp was characterized by H-NMR method and electrospray-mass spectrometry (ESI-MS) method, and the results are as follows:
[0096] 1 H-NMR characterization results are: 1 H NMR (DMSO-d 6 ,400MHz)δ(ppm):8.39(d,2H), 8.22(m,2H),8.09(t,1H),7.97(d,1H),7.88-7.77(m,3H),7.71(s,1H ),7.52(d,2H),7.50-7.41(m,2H),7.39(d,1H),7.14(m,9H),4.54(m,1H),4.41(m,1H),4.19(...
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