Acetaminophen-cyclophosphamide anti-tumor drug and preparation method thereof

A technology of paracetamol and antitumor drugs, applied in the field of medicine, can solve the problems of affecting clinical use, poor selectivity, etc., and achieve the effects of good analgesic effect, good cross-linking effect and simple synthesis method

Inactive Publication Date: 2012-07-04
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Nitrogen mustard is a non-specific drug for the cell cycle. It has poor selectivity when used as an antitumor drug and has serious side effects, which affect the clinical use.

Method used

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  • Acetaminophen-cyclophosphamide anti-tumor drug and preparation method thereof
  • Acetaminophen-cyclophosphamide anti-tumor drug and preparation method thereof
  • Acetaminophen-cyclophosphamide anti-tumor drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1: the synthesis of compound 5

[0022] Step 1: Preparation of Compound 3

[0023] Bisdichloroethylamine hydrochloride (1) (20g, 0.112mol) and 52mL (0.60mol) of freshly distilled POCl 3 (2) Place in a 200mL round bottom flask, reflux at 110°C for 20h until the solid bisdichloroethylamine hydrochloride disappears. Excess POCl was removed under reduced pressure 3 , the resulting solid residue was dissolved in ethyl acetate, filtered to remove insoluble matter, concentrated ethyl acetate filtrate, and the filtrate was recrystallized with acetone:petroleum ether (v / v=1:5) to obtain colorless crystals, namely phosphoryl nitrogen A total of 18.0 g of mustard dichloride 3 was obtained, and the yield was 61%. The structure of the product was determined by melting point, IR, NMR, MS and elemental analysis.

[0024] Step 2: Preparation of Compound 5

[0025] Paracetamol (4) (151 mg, 1 mmol) was dissolved in 20 mL of methanol, and triethylamine (185 mL, 1.34 mmol) w...

Embodiment 2

[0026] Embodiment 2: Anti-tumor experiment in vitro

[0027] The compound 5 of the present invention was selected to test its cytotoxicity to cell lines HepG-2, A549 and HL-60 by MTT method.

[0028] 1. Compound 5 was formulated into different concentrations in RPMI-1640 culture medium and stored at 4°C.

[0029] 2. Cancer cells were cultured in RPMI-1640 medium containing 10% calf serum, 100kU / L penicillin and 100mg / L streptomycin in 5% CO 2 Cultured at constant temperature in a saturated humidity cell incubator.

[0030] 3. Take the cancer cells in the logarithmic growth phase, add 5.0×10 4 cells / mL cell suspension 100 μL.

[0031] 4. Set blank and cyclophosphamide (CP), 5-fluorouracil (5-Fu) positive control blank at the same time, add the same volume of culture medium to the blank group, add 4 μmol / L to the positive control group, set eight parallel wells for each concentration .

[0032] 5. After continuing to culture for 48 hours, add MTT (5 g / L, 20 μL) to each well...

Embodiment 3

[0038] Example 3: Cross-linking of Drugs and DNA

[0039] Compound 5 of the present invention was selected to detect its in vitro cross-linking activity on plasmid pBR322DNA, using alkaline gel electrophoresis.

[0040] 1. Prepare linear pBR322DNA. Prepare a mixture of the following systems (total 200 μL): supercoiled pBR322DNA (10 μL, 10 μg), restriction enzyme EcoR I (4 μL, 40-80u), 10 times EcoR I buffer solution (20 μL), acetylated BSA ( 20μL, 1mg / mL), secondary water (146μL). The above mixture was incubated in a constant temperature water tank at 37°C for 3 hours, then sodium acetate (20 μL, 3M) and glacial ethanol (440 μL) were added, and allowed to stand overnight at -20°C. Remove the mixture, centrifuge at 16,000 rpm for 15 minutes, pour off the ethanol, and invert for several minutes to evaporate residual ethanol. Add 30 μL of secondary water for later use. The concentration is about 0.25μg / μL.

[0041] 2. Add 2 μL (0.25 μg / μL) of linearized pBR322DNA into a 0.2 ...

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Abstract

The invention provides a chlormethine compound with double activity function groups and application of the chlormethine compound serving as an anti-tumor drug. A structure of the compound is described as follows. In-vitro anti-tumor experiments prove that the compound has good inhibiting effect on liver cancer cells of the human body. In-vitro deoxyribose nucleic acid (DNA) crosslinking experiments prove that the compound has good crosslinking effects on plasmid DNA. Mouse analgesia experiments prove that the compound has good analgesia effects. The chlormethine compound is simple in synthesizing steps and good in anti-tumor effects, possibly simulates the analgesia effects of acetaminophen in vivo, is an anti-tumor drug with double functions, and has great medical value.

Description

technical field [0001] The invention relates to the field of medicine, an antitumor compound of acetaminophen-phosphoryl mustard derivative. Background technique [0002] Nitrogen mustard is the first alkylating agent antineoplastic drug used clinically and achieved outstanding curative effect, and has a highly active nature. Since the chlorine atoms in the chloroethyl group are easily removed to form carbocations, further intramolecular ring formation reactions occur to form highly active ethyleneiminium ions. Nitrogen mustard can react with nucleophilic groups of other macromolecules in the body, such as carboxyl, amino, sulfhydryl of protein, amino and hydroxyl of nucleic acid, phosphate, etc., for alkylation modification. Nitrogen mustard is easy to covalently bond with the 7th nitrogen of guanine, resulting in cross-links in double strands of DNA or cross-links of different bases in the same strand of DNA. [0003] Nitrogen mustard is a non-specific drug for the cell ...

Claims

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Application Information

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IPC IPC(8): C07F9/22A61K31/664A61P35/00A61P35/02A61P29/00
Inventor 宋杨宋尔群李效尧
Owner SOUTHWEST UNIVERSITY
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