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Docetaxel target prodrug for preventing liver cancer and pharmaceutical applications thereof

An anti-hepatic cancer, taxane technology, applied in the field of biomedicine, can solve the problems of poor selectivity and high systemic toxicity of docetaxel

Active Publication Date: 2019-03-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research and development of this kind of targeted prodrug molecules is mainly aimed at the disadvantages of docetaxel’s poor selectivity and high systemic toxicity, and to expand the application of this type of drug in the treatment of liver cancer

Method used

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  • Docetaxel target prodrug for preventing liver cancer and pharmaceutical applications thereof
  • Docetaxel target prodrug for preventing liver cancer and pharmaceutical applications thereof
  • Docetaxel target prodrug for preventing liver cancer and pharmaceutical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 Preparation of prodrugs coupled with docetaxel or tetrafluorodcetaxel via bridging group Leu-PABOH and liver cancer targeting polypeptide A1-B11

[0022] Taxane targeting prodrugs are prepared by coupling paclitaxel (DTX) or tetrafluorodcetaxel (4FDT) with liver cancer targeting polypeptides A1-B11, and the synthesis route includes the following steps:

[0023] 1) Synthesis and activation modification of bridging group Leu-PABOH

[0024]

[0025]Take a 100mL round bottom flask, add 800mg (2.27mmol) of Fmoc-L-leucine, add 300mg (2.5mmol) of aminobenzyl alcohol, add 50mL of anhydrous DCM, and stir at room temperature for 10min. Then, 610 mg (2.5 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added, and the reaction was stirred at room temperature. After 24 hours, TLC plate (dichloromethane:methanol=35:1) monitored the reaction. After the raw material Fmoc-L-leucine disappeared, water was added to stop the reaction, washed with saturated sodium c...

Embodiment 2

[0126] Example 2: (Tetrafluoro) docetaxel anti-hepatoma targeted prodrug has in vitro proliferation inhibitory activity on human liver cancer cell lines HepG2 and SMMC-7721 and toxicity to normal liver cell line HL7702 and normal kidney cell line HEK293

[0127] Experimental method: MTT method was used for in vitro cell assay. Sorafenib and 10-hydroxycamptothecin were used as positive controls, and docetaxel and tetrafluorodcetaxel were used as parent drug controls to observe the inhibition of the drug on cell growth at different concentrations, and calculate its half inhibitory rate ( IC 50 value) to evaluate its anti-hepatic tumor activity and toxicity to normal cells in vitro.

[0128] HepG2 cells and HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum, and SMMC-7721 and HL-7702 cells were cultured in 1640 medium containing 10% fetal bovine serum. When the cells are in the dividing phase, add trypsin to digest and collect the cells, and adjust the ...

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Abstract

The invention belongs to the field of biomedicine, and specifically relates to a novel docetaxel target prodrug represented by the formula (1) for preventing liver cancer and pharmaceutical applications thereof. The provided compound has a pharmacological research value and can be used an anti-cancer prodrug targeting matrix metalloproteinase (MMP-2 or MMP-9). The prodrug can be used to treat cancers caused by specific high expression of MMP-2 or MMP-9. Specifically, the prodrug can be used to treat at least one disease of liver cancer, ovarian cancer, breast cancer, non-small cell lung cancer, and colorectal carcinoma. In the formula (1), R1 represents a substrate polypeptide sequence that can specifically identify and hydrolyze MMP-2 and MMP-9 that are specifically and highly expressed in liver cancer tissues; R2 represents a methyl group or a trifluoromethyl group; and R3 represents a hydrogen atom or a fluorine atom.

Description

technical field [0001] The invention belongs to the field of biomedicine, in particular to a novel docetaxel anti-liver cancer targeting prodrug and its medicinal use. Background technique [0002] According to data, liver cancer is one of the most common malignant tumors, with more than 700,000 new cases and deaths worldwide every year. As a big country with liver disease, China's new cases account for 50.5% of the global liver cancer incidence, and the death cases account for 51.4% of the global liver cancer deaths, and the number is increasing year by year. According to the evaluation criteria such as the size and number of liver tumors, the occurrence of extrahepatic metastasis, the grade of liver function, and the presence or absence of vascular invasion, the clinical treatment options for liver cancer mainly include surgical treatment (hepatectomy, liver transplantation, local ablation, etc.). Early stage patients), hepatic artery interventional chemotherapy (the pref...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06A61K31/337A61P35/00
CPCA61K31/337C07K7/06
Inventor 孙逊郝云鹏司长梅王明亮孟志彭鹏
Owner FUDAN UNIV
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