Isoforrensin A derivative and application thereof to preparation of anti-tumor medicine

A derivative and drug technology, applied in the field of Isoforrensin A derivatives and its application in the preparation of anti-tumor drugs, can solve the problem of narrow anti-cancer spectrum

Inactive Publication Date: 2018-06-08
TIANJIN PEOPLE HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The experimental results show that IsoA has a certain inhibitory effect on some tumor cells, and can prolong the survival of liver cancer tumor-bea

Method used

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  • Isoforrensin A derivative and application thereof to preparation of anti-tumor medicine
  • Isoforrensin A derivative and application thereof to preparation of anti-tumor medicine
  • Isoforrensin A derivative and application thereof to preparation of anti-tumor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Synthesis of embodiment 1 formula (I) compound

[0016] 1) Dissolve Isoforretin A and DMAP (4-dimethylaminopyridine) in dichloromethane, add triethylamine, add the corresponding 3-chloropropionyl chloride dropwise at 0°C to 5°C while keeping warm, and heat up the reaction solution after dropping to 20°C to 25°C and stir the reaction.

[0017] 2) After TLC detects that the reaction is complete, add saturated aqueous sodium bicarbonate solution to the reaction solution to quench the reaction, extract the aqueous layer three times with dichloromethane, combine the organic layer, wash the organic layer three times with dilute hydrochloric acid, and wash three layers with saturated saline . The collected organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product is purified by flash silica gel column chromatography to obtain pure product target product formula (I) compound;

[0018] The molar ratio of ...

Embodiment 2

[0038] Pharmacological Example 2 The Inhibitory Effect of Formula (I) Compounds on Different Types of Solid Tumor Cells

[0039] The compound of formula (I) (purity>99%) was dissolved in DMSO, and a 100uM mother solution was prepared and stored at -20°C. Select ten common malignant solid tumors (including lung cancer, gastric cancer, breast cancer, colorectal cancer, liver cancer, cervical cancer, esophageal cancer, oral cancer, prostate cancer, pancreatic cancer), and culture the tumor cell lines of the above ten tumors in vitro and among them The corresponding tissue normal cell lines of the five tumors are as follows:

[0040] Lung cancer: human normal lung epithelial cells HBEC, human lung cancer cells A549, SK-MES-1

[0041] Gastric cancer: human normal gastric mucosal epithelial cells RGM-1, human gastric cancer cells MGC-803, SGC-7901

[0042] Breast cancer: human normal breast epithelial cells MCF10A, human breast cancer cells MCF7, MDA-MB-231

[0043] Colorectal ca...

Embodiment 3

[0053] Pharmacological Example 3, Comparative Test on the Survival Period of Tumor-bearing Mice

[0054] 1. Materials

[0055]a) Cell line: Gastric cancer cell MGC-803, which can stably express luciferase, was purchased from the Cell Bank of the Type Culture Collection Committee of the Chinese Academy of Sciences.

[0056] b) Animals: 30 BALB / c nude mice, body weight (13±2g), male.

[0057] c) Drug: Iso A (drug 1), formula (I) compound (drug 2)

[0058] 2. Experimental method

[0059] a) Preparation of gastric cancer tumor-bearing mouse model: Gastric cancer cells MGC-803 in the logarithmic growth phase were taken, digested with trypsin and prepared into 1×10 7 cells / mL cell suspension, inoculate 200 μL (100 μl cells + 100 μl Matrigel) cell suspension into the right axilla of nude mice (only 200 μL Matrigel was injected in the normal group).

[0060] b) Grouping and administration of experimental animals: After two weeks of feeding, the tumor-bearing situation in the mice ...

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Abstract

The invention relates to an Isoforrensin A derivative and application thereof to preparation of an anti-tumor medicine. The structure of the Isoforrensin A derivative is as shown in a formula (I). Thepreparation method of the Isoforrensin A derivative of the formula (I) comprises the following steps: 1) dissolving Isoforrensin A and DMAP into dichloromethane, adding triethylamine, performing heatpreservation at 0 to 5 DEG C, adding 3-chloropropionyl chloride dropwise, heating the reaction liquid to 20 to 25 DEG C after adding, and performing stirring reaction; and 2) after TLC detection reaction is complete, adding a saturated sodium bicarbonate aqueous solution into the reaction liquid, performing quenching reaction, extracting a water layer by using dichloromethane for three times, combining organic layers, washing the organic layers with diluted hydrochloric acid for three times, and washing the three layers with a saturated salt solution. The organic layers are collected, are dried by anhydrous magnesium sulfate and are filtered and concentrated to obtain a crude product. The crude product is purified by a rapid silica gel column chromatography to obtain a pure product targetproduct compound of the formula (I).

Description

Technical field: [0001] The invention relates to a novel diterpene compound and its application in the preparation of antitumor drugs. Background technique: [0002] Chinese patent application CN106631804A discloses a compound extracted from a plant of the genus Camellia as follows: (Isoforresin A, referred to as Iso A), the compound is a corresponding - kaurane diterpene derivatives, the application pointed out that IsoA is a thioredoxin-1 inhibitor ((thioredoxin-1, referred to as Trx-1), Previous studies have shown that Trx-1 is abnormally highly expressed in many tumor cells and tumor tissues. Therefore, screening new Trx1 selective inhibitors is an important demand for pharmaceutical research and development. They may be extremely effective in the treatment of tumors and other Trx1-mediated diseases. Drugs for diseases. The experimental results show that IsoA has a certain inhibitory effect on some tumor cells, and can prolong the survival of liver cancer tumor-bearing...

Claims

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Application Information

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IPC IPC(8): C07C69/63C07C69/013C07C69/03C07C67/14A61K31/22A61P35/00
CPCC07C69/013C07C69/63
Inventor 张春泽张伟华刘艳迪付文政
Owner TIANJIN PEOPLE HOSPITAL
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