A dimer prodrug with tumor microenvironment response and a light-regulated nano-drug and its application
A tumor microenvironment and dimer technology, which is applied in the direction of anti-tumor drugs, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problem of changing the hydrophilicity and hydrophobicity of polymers, the influence of nano-medicine structure size, etc. problems, achieve ultra-high drug loading, achieve synergistic anti-tumor therapy, and good stability
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Embodiment 1
[0111] Example 1 Synthesis of active oxygen free radical sensitive, phenylboronic acid modified camptothecin dimer prodrug BE-CPT 2
[0112] First, 4-(hydroxymethyl)phenylboronic acid pinacol ester (400 mg, 1.7 mmol) was added to dichloromethane (10 mL), then slowly added triphosgene (15 wt% in toluene, 6 mL, 8.4 mmol) and Stir at room temperature for 36 hours until completely clear. After the reaction, the solvent and unreacted triphosgene were removed by rotary evaporation, and tert-butyl-N-methyl-N-[2-methylamino-ethyl]carbamate (320 mg, 1.7 mmol). Then 10 mL of dichloromethane and triethylamine (517 μL, 3.7 mmol) were added and stirred at room temperature for 10 minutes, and finally 1 mL of methanol was added to terminate the reaction. The reaction solution was concentrated and subjected to column separation (mobile phase was n-hexane: ethyl acetate = 4:1 to 2:1), and finally Boc-BE (391 mg, yield 50%) was obtained as a colorless oil. Relevant characterizations are as ...
Embodiment 2
[0118] Example 2 Synthesis of a hypoxia-sensitive, quinone-modified camptothecin dimer prodrug hQ-CPT 2
[0119] First, hQ-NHS ester (1.39 g, 4.0 mmol), N,N-diisopropylethylamine (2 mL) were dissolved in DCM, then N,N'-dimethyl-ethylenediamine (4.30 mL , 40mmol, 10equiv), stirred at room temperature for 30 minutes. After the reaction, the solvent was removed, extracted with ethyl acetate, water, saturated Na 2 SO 4 The solution was washed 4 times (60mL×4), the organic phase was collected, and Na 2 SO 4 After drying, it was filtered and rotary evaporated to obtain a yellow solid monosubstituted and disubstituted hQ-NH mixture. Further purification is carried out in the next step. Relevant characterization data are as follows: Mass Spectrum ESI-MS (m / z): [M+H] + calculated for C 18 h 29 N 2 o 3 , 321.2; observed 321.2.
[0120] 2,6-bis (tert-butyldimethylsilyloxy) methyl) -4-methylphenol (793mg, 2mmol), triphosgene (208mg, 0.7mmol, 0.35equiv), 4-dimethylaminopyridine...
Embodiment 3
[0125] Example 3 Synthesis of sensitive camptothecin dimer prodrug Boc-CPT 2
[0126] 2,6-bis((tert-butyldimethylsilyloxy)methyl)phenol (110mg, 0.28mmol), 4-dimethylaminopyridine (85mg, 0.69mmol), triphosgene (27mg, 0.092mmol) Add dichloromethane (8 mL), and stir at room temperature for 15 minutes. Then tert-butyl-N-methyl-N-[2-methylamino-ethyl]carbamate (44 mg, 0.23 mmol) was added to the mixture and stirred at room temperature for 1 hour. The mixed solution was purified by column separation (mobile phase is n-hexane: ethyl acetate = 10:1-8:1), and a colorless oily substance Boc-OTBS was obtained 2 (85 mg, yield 60%). Relevant characterization data are as follows: Hydrogen Spectrum 1 H NMR (500MHz, CDCl 3 ): δ7.19(s,2H), 4.61(s,4H), 3.31-3.68(m,4H), 2.86-3.22(m,6H), 2.34(s,3H), 1.46(s,9H), 0.92(s,18H), 0.07(s,12H); carbon spectrum 13 C NMR (126MHz, CDCl 3 ): δ154.0, 153.8, 142.9, 135.3, 133.4, 133.3, 127.1, 60.5, 60.3, 47.6, 47.4, 35.5, 35.3, 28.5, 26.0, 21.4, 18.5, ...
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