Anti-tumor target-activated polypeptide doxorubicin and preparation method and application thereof
A technology of polypeptide doxorubicin and peptide doxorubicin, which is applied in the field of anti-tumor targeted activated polypeptide doxorubicin. It can solve the problems of dose limitation, toxic and side effects, etc., and achieve improved drug efficacy, reduced toxicity, and good The effect of applying the foreground
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[0029] The present invention provides a method for preparing the activated polypeptide doxorubicin targeting the tumor microenvironment, comprising the following steps: first, using known chemical, biological or recombinant techniques to couple amino acid residues, and isolating the formed polypeptide R3 -Arg-R4-R5-R6; secondly, the nitrogen segment of the formed polypeptide is reacted with the carboxyl or acyl group of R7 or succinic anhydride that can bind to albumin by known chemical or biological methods to form a covalent conjugate R3 -Arg-R4-R5-R6(NH)-R, wherein R is R7 or succinyl; then the carboxyl group of R3 of R3-Arg-R4-R5-R6-R is passed through known chemical or biological The method is to covalently combine with the amino group of doxorubicin or its salt or doxorubicin derivative and its salt (ie compound A) to form a doxorubicin analogue with a short peptide and a group that can bind to serum albumin , Compound A—R3-Arg-R4-R5-R6-R. The reaction scheme is as foll...
Embodiment 1
[0034] Example 1: Synthesis of activated polypeptide doxorubicin S1 targeting tumor microenvironment
[0035] The synthetic route of S1 is as follows:
[0036]
[0037] 1. Synthesis of Cbz-L-Leu-L-Thr-L-Pro-L-Arg(Pmc)-L-Leu-OtBu Pentapeptide
[0038] 1) Cbz-L-Arg(Pmc)-L-Leu-O t Synthesis of Bu(I)
[0039]
[0040]N-benzyloxycarbonyl-N'-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-arginine (0.1mol), Dissolve N-methylmorpholine (0.1mol) in N,N-dimethylformamide (1000mL), cool to -15°C, add isobutyl chloroformate (0.1mol) dropwise under stirring, and stir for 30 minutes Finally, add a mixed solution of L-leucine tert-butyl hydrochloride (0.1mol) and triethylamine (0.1mol) in N,N-dimethylformamide (500mL) cooled in an ice bath, and then Stir at 0°C for 1 hour, rise to 15°C and stir for 3 hours, evaporate the solvent under reduced pressure, add 1 mol / L citric acid solution to the residue, collect the precipitate by filtration, wash with water and dry in vacuum, the crude pro...
Embodiment 2
[0074] Example 2 Synthesis method of the activated peptide doxorubicin S2 targeting the tumor microenvironment and capable of binding to serum albumin
[0075] ε-maleimidocaproic acid (EMC) synthesis reference Synthesis, 2008(8), 1316-1318.
[0076]
[0077] The synthetic route of S2 is as follows:
[0078]
[0079] 1. Synthesis of EMC-L-Leu-L-Thr-L-Pro-L-Arg-L-Leu-OH (XIV)
[0080] 1) EMC-L-Leu-L-Thr-L-Pro-L-Arg (Pmc)-L-Leu-O t Synthesis of Bu(XII)
[0081]
[0082] Dissolve compound 8 in anhydrous N,N-dimethylformamide (800 mL), add 6-maleimidocaproic acid (0.1 mol), 1-hydroxybenzotriazole (0.3 mol) and N , N-diisopropylethylamine (0.3mol), ice bath to below 0 ℃, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.3mol) , the reaction solution was stirred overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, water and ethyl acetate were added to separate the layers, the aqueous phase w...
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