Tumor-specific stimuli-responsive hydroxyalkyl starch-doxorubicin conjugate, preparation and application thereof
A technology of hydroxyalkyl starch and hydroxyethyl starch, which is applied in the direction of antineoplastic drugs, medical preparations without active ingredients, medical preparations containing active ingredients, etc., which can solve the problem of insufficient drug release and poor tumor inhibitory activity To achieve the effect of slow tumor growth rate, strong anti-tumor effect and fast drug release rate
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Embodiment 1
[0047] The hydroxyethyl starch-doxorubicin conjugate HES-CN-SS-CM-DOX (formula (II)) with pH-sensitive amino acid ester and carbonate and redox-sensitive disulfide bond is as follows:
[0048]
[0049] like figure 1 As shown in content a, the synthesis steps include:
[0050] (1) Synthesis of 2-((2-hydroxyethyl)disulfanyl)ethyl (4-nitrophenyl)carbonate (Intermediate 1-1): The raw material 2,2′-dithio Diylbis(ethane-1-ol) (1.5 g, 10 mmol) was added to the reaction flask, 20 mL of anhydrous dichloromethane was added, and N,N-diisopropylethylamine (1.3 g, 10 mmol) was added in an ice bath. , 4-nitrophenylcarbonyl chloride (1.0 g, 5 mmol) dissolved in 10 ml of anhydrous dichloromethane was slowly added dropwise, after the dropwise addition was completed, the ice bath was removed, and the reaction was stopped by stirring at room temperature for 5 h. After-reaction treatment: after extraction twice with 50 ml of dichloromethane, washed with saturated brine, concentrated, mixed ...
Embodiment 2
[0054] The hydroxyethyl starch-doxorubicin conjugate HES-CN-CC-CM-DOX (formula (3)) with pH-sensitive amino acid ester and carbonate bonds is as follows:
[0055]
[0056] like figure 1 As shown in content b, the synthesis method is the same as that of HES-CN-SS-CM-DOX (formula 2), except that the raw material is replaced with hexanediol without disulfide bonds, and the prepared target product has its hydrogen NMR spectrum figure 2 Content b is shown.
Embodiment 3
[0058] With redox-sensitive disulfide bond, pH-sensitive carbonate bond, but doxorubicin adopts stable urea bond and hydroxyethyl starch coupled with hydroxyethyl starch-doxorubicin conjugate HES-CM-CC- UR-DOX (formula (4)) is as follows:
[0059]
[0060] like figure 1 As shown in content c, the synthesis steps include:
[0061] (1) Synthesis of tert-butyl (2-((2-aminoethyl)disulfanyl)ethyl)carbamate (Intermediate 3-1): add cystamine dihydrochloride ( 3.0 g, 13.3 mmol), di-tert-butyl dicarbonate (2.9 g, 13.3 mmol), 150 mL of anhydrous methanol, triethylamine (5.0 g, 50 mmol), stirring at room temperature, and monitoring the reaction by thin layer chromatography. Post-reaction treatment: Concentrate to remove methanol, successively add 60 mL of 1M sodium dihydrogen phosphate and 60 mL of diethyl ether to precipitate the product, adjust the pH of the aqueous layer to about 9 with about 50 mL of 1M sodium hydroxide, extract with ethyl acetate, and concentrate to obtain an o...
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