Dendrimer gemcitabine self-assembled nanometer prodrug, and preparation method and application thereof
A technology of gemcitabine and dendrimers, which is applied in the field of dendrimer gemcitabine self-assembled nano-prodrugs and its preparation, can solve the problems of difficult regulation and optimization of drug ratios and limitations of wide application, and achieve rich surface groups and broad application prospects , the effect of high drug loading
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Embodiment 1
[0048] Example 1: Preparation of the second-generation azide-terminated dendrimer with C18 long chain as the hydrophobic part
[0049] In the first step, weigh 99.8mg (0.11mmol) of the amphiphilic dendrimers at the end of the disubstituted ester group, add 5.0mL of methanol to dissolve it, then add 1.0mL (15mmol) of ethylenediamine under stirring, and stir the reaction at 30°C After 72 hours of reaction, an appropriate amount of methanol was added, and the mixture was spin-dried under reduced pressure to obtain an oily liquid, which was settled three times with methanol / ether to obtain a dendrimer product (101.8 mg, 91%) with amino terminal modification.
[0050] In the second step, weigh 105 mg (0.6 mmol) of azidesulfonylimidazole, add 4.0 mL of a mixed solvent of methanol and acetonitrile to dissolve it, and then add 78 mg (0.075 mmol) of dendrimers at the end of the amino group, CuSO 4 ·5H 2 O (3.0mg, 5.0mol%) and K 2 CO 3 (83mg, 0.60mmol), stirred at room temperature fo...
Embodiment 2
[0052] Embodiment 2: the synthesis of the gemcitabine prodrug containing alkyne bond
[0053] In the first step, 263 mg (1.0 mmol) of gemcitabine was weighed and dissolved in 5 mL of DMF, then 603 mg (4 mmol) of TBSCl and 272 mg of imidazole were added to the reaction system overnight, and 30 mL of distilled water was added to quench the reaction, extracted with ethyl acetate, 15 mL each time, Extracted 3 times, combined extracts, dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated by silica gel column chromatography, and eluted with dichloromethane / methanol gradient to obtain 310 mg of white solid with a yield of 63.3%.
[0054] In the second step, 59.6mg (0.6mmol) of 4-pentynoic acid, 191.3mg (1.0mmol) and 135.8mg (1.0mmol) of HOBt were dissolved in 4.5mL THF, stirred in an ice bath for 30min, and the 4' prepared in the first step was added. and 250 mg (0.5 mmol) of gemcitabine protected at the 5' position, stirred at room temperature, monitor...
Embodiment 3
[0056] Example 3: Preparation of the second-generation dendrimer-gemcitabine amphiphilic prodrug with C18 long chain as the hydrophobic part
[0057] Weigh the gemcitabine prodrug containing alkyne bond (41.5mg, 0.12mmol), CuSO 4 ·5H 2 O (2.4 mg, 10 mol%) and sodium ascorbate (2.6 mg, 15 mol%), followed by addition of terminal azide-modified dendrimers, tetrahydrofuran and water under a nitrogen atmosphere, stirred at 60 ° C for 5 h, then concentrated and added CH 2 Cl 2 / Et 2 O was settled overnight, and further purified by silica gel column chromatography, gradient elution with ethyl acetate / methanol (volume ratio 2:1-1:3), to obtain 19.7 mg of white solid, with a yield of 39.4%.
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