Docetaxel target prodrug and application thereof on preventing colorectal carcinoma

A doene taxane and colon cancer technology, applied in the field of biomedicine, can solve the problems of poor selectivity of cytotoxic small molecule compounds, high systemic toxicity, and expanded application, and achieve good anti-colon cancer potential and good anti-colon cancer activity , high biocompatibility effect

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 docetaxane-like cytotoxic small molecule compounds with poor selectivity and high systemic toxicity, and to expand the application of such compounds in the treatment of colon cancer

Method used

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  • Docetaxel target prodrug and application thereof on preventing colorectal carcinoma
  • Docetaxel target prodrug and application thereof on preventing colorectal carcinoma
  • Docetaxel target prodrug and application thereof on preventing colorectal carcinoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Preparation of docetaxel or tetrafluorodcetaxel coupled with colon cancer targeting polypeptide A1-A5 prodrug via bridging group Leu-PABOH(a)

[0026] Taxane targeting prodrugs were prepared by coupling paclitaxel (DTX) or tetrafluorodcetaxel (4FDT) with colon cancer targeting polypeptides A1-A5, and the synthetic route was as follows: figure 1 shown, including the following steps:

[0027] 1) Synthesis and activation modification of bridging group Leu-PABOH

[0028]

[0029]References (Elsadek B, Graeser R, Esser N, et al. Development of a novelprodrug of paclitaxel that is cleaved by prostate-specific antigen: An invitro and in vivo evaluation study [J]. European Journal of Cancer, 2010, 46( 18): The method adopted in 3434-3444) completes the synthesis and activation modification of the bridging group Leu-PABOH through a two-step reaction. That is: in a 25mL single-necked bottle, add 1mmol of Fmoc-L-Leu (1), 2mmol of p-aminobenzyl alcohol (PABOH) and 2...

Embodiment 2

[0070] Example 2: Proliferation inhibitory activity of targeted anti-colon cancer prodrugs on human colon cancer cell lines HCT116 and SW620 in vitro and toxicity evaluation on normal colon cell line CCD18Co and kidney cell line HEK293

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Abstract

The invention belongs to the field of biomedicine, specifically relates to a docetaxel target prodrug and a pharmaceutical application thereof, and provides a novel docetaxel target prodrug represented by the formula (1) and an application thereof on preventing colorectal carcinoma. The provided compound has a pharmacology research value and can be used as an anti-cancer prodrug that targets the specific high expression of tumors of colorectal carcinoma. The prodrug can be used to treat colorectal carcinoma caused by specific high expression of one or more of matrix metalloproteinase MMP-7, cysteine cathepsin B, and fibroblast activator protein [alpha]. In the formula (1), A represents a substrate polypeptide sequence that can specifically identify and hydrolyze components that are obviously and highly expressed in tissues of colorectal carcinoma including but not limited to matrix metalloproteinase MMP-7, cysteine cathepsin B, and fibroblast activator protein [alpha]; B represents a degradable bridge connection group selected from (a to i) and is connected to the carbon end or nitrogen end of A through amido bonds; and R1 includes but not limited to a fluorine atom, a hydrogen atom, and the like.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a novel targeting prodrug of docetaxel and its anti-colon cancer medicinal application. Background technique [0002] The prior art discloses that colon cancer is one of common malignant tumors, and its morbidity and mortality rank the third among malignant tumors in developed countries in Europe and America. Five and sixth rose to fourth and fifth, and about 200,000 people die of colon cancer each year. Surgical resection is the most basic treatment, and adjuvant chemotherapy is the routine postoperative treatment for patients with stage II and III colon cancer. At present, adjuvant chemotherapy drugs for colon cancer are divided into two categories: one is chemical small molecule drugs, mainly including 5-fluorouracil, capecitabine, tegafur, irinotecan, oxaliplatin, etc., which can be used alone or Combination medication, but all inevitably produce toxic and side effect...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K31/337A61P35/00
CPCA61K31/337
Inventor 孙逊刘正玉王明亮唐美麟韩吉来
Owner FUDAN UNIV
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