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Antitumor prodrug, activator, composition, and application thereof

An activator, anti-tumor technology, applied in the field of medicine, can solve the problems of drug toxicity not being well controlled, normal cell toxicity, human injury and other problems

Inactive Publication Date: 2015-05-20
SHANGHAI WEIKE BIOPHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, there are still many related problems that have not been resolved, such as the toxicity of the drug has not been well controlled, and it is also toxic to normal cells, which is very harmful to the human body.

Method used

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  • Antitumor prodrug, activator, composition, and application thereof
  • Antitumor prodrug, activator, composition, and application thereof
  • Antitumor prodrug, activator, composition, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0222] Preparation of HK-1:

[0223]

[0224] 1. Add ethyl formate and ethyl sarcosinate hydrochloride (m / v=1 / 3, m is the mass of ethyl sarcosine hydrochloride) into the reaction flask at room temperature

[0225] 2. Add TEA into the bottle;

[0226] 3. Heat up to 50-55°C for reflux reaction for 8-10 hours;

[0227] 4. TLC central control: DCM / MeOH=10 / 1, PE / EA=2 / 1, iodine display, ninhydrin color development, UV;

[0228] 5. Cool to room temperature, filter out the solid, stir the filter cake with EA, combine the washings, and concentrate to dryness under reduced pressure at 40-50°C;

[0229] 6. After cooling, filter out the solid again, and weigh the filtrate to obtain yellow liquid HK-1 with a yield of ≥90%.

[0230] 1) Preparation of YS-1:

[0231]

[0232]

[0233] Step 1: Under nitrogen protection, add 590 g (4.5 mol) of HK-1 and 6 L of ethyl formate into a 10-liter four-necked flask, and add 200 grams of sodium hydride while stirring. After the addition was...

Embodiment 2

[0381] Embodiment 2: Activity experiment and result

[0382] Materials and Methods:

[0383] 1. Compound and preparation method: The present invention is numbered YS-6, YS-9, TH302, and the 5% DMSO+5% Tween-80 solution is prepared to the required concentration.

[0384] 2. Animals: nude mice (Balb / C nu / nu), 4-6 weeks old, purchased from Beijing Huafukang Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2009-0004.

[0385] 3. Tumor cell line: Human lung adenocarcinoma cell line NCI-H460 (H460) is from the State Key Laboratory of Biotherapy, Sichuan University.

[0386] 4. Cell culture: H460 cells were cultured in RPMI 1640 medium (HyClone), which contained 10% fetal bovine serum (Hohhot Grassland Luye Bioengineering Materials Co., Ltd.) and 100U / ml penicillin and streptomycin. Take cells in the logarithmic growth phase, digest and count with 0.25% trypsin, and dilute the single cell suspension to 6×10 7 cells / ml for later use.

[0387] 5. Transplantation ...

Embodiment 3

[0419] Materials and Methods:

[0420] 1. Compounds and preparation methods: No. TH-302, YS-13, YS-14, YS-15, YS-16, 5% DMSO+5% Tween-80 solution prepared to the required concentration.

[0421] 2. Animals: nude mice (Balb / C nu / nu), 4-6 weeks old, purchased from Beijing Huafukang Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2009-0004.

[0422] 3. Tumor cell line: Human lung adenocarcinoma cell line NCI-H460 (H460) is from the State Key Laboratory of Biotherapy, Sichuan University.

[0423] 4. Cell culture: H460 cells were cultured in RPMI 1640 medium (HyClone), which contained 10% fetal bovine serum (Hohhot Grassland Green Field Bioengineering Materials Co., Ltd.) and 100U / ml penicillin and streptomycin ( HyClone). Take cells in the logarithmic growth phase, digest and count with 0.25% trypsin, and dilute the single cell suspension to 6×10 7 cells / ml for later use.

[0424] 5. Transplantation and drug treatment:

[0425] Inoculation, grouping and tr...

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Abstract

The present invention provides an antitumor prodrug, activator thereof, composition thereof and use thereof, the activator being shown as formula (I). The antitumor prodrug in the present invention has unexpectedly high selectivity in the treatment of tumor, and greatly reduces the harm of released cytotoxic drug on the human body.

Description

technical field [0001] The invention belongs to the field of medicine and relates to compounds for treating tumors, in particular to hypoxia-selective anti-tumor prodrugs and their activators, compositions and applications which have a specific killing effect on tumor cells. Background technique [0002] The vast majority of antineoplastic drugs currently used clinically are a class of chemotherapeutic drugs that can directly kill tumor cells or inhibit tumor cell growth and proliferation. Tube system, inhibition of topoisomerase, etc. Cytotoxic antineoplastic drugs are currently one of the main means of treating malignant tumors. While killing or inhibiting tumor cells, these drugs will also affect normal cells in the body (especially cells with vigorous metabolism): they are not selective, and while killing tumor cells, they also kill a large number of proliferative cells. Normal cells, such as bone marrow, visceral epithelial cells, etc., will cause adverse reactions an...

Claims

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Application Information

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IPC IPC(8): C07F9/6506C07F9/6558C07F9/6584A61K31/675A61P35/00A61P35/02
CPCA61K31/675A61K45/06A61P35/00A61P35/02C07F9/6506C07F9/65583C07F9/65848
Inventor 迈克·F·阙
Owner SHANGHAI WEIKE BIOPHARML
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