Corresponding-kaurane type diterpene derivative and application in preparation of antitumor drugs thereof

A technology of kaurane diterpene derivatives, which is applied in the field of corresponding-kaurene diterpene derivatives and their application in the preparation of antitumor drugs, and can solve the problem of narrow anticancer spectrum

Inactive Publication Date: 2018-05-18
TIANJIN PEOPLE HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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 has a...

Method used

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  • Corresponding-kaurane type diterpene derivative and application in preparation of antitumor drugs thereof
  • Corresponding-kaurane type diterpene derivative and application in preparation of antitumor drugs thereof
  • Corresponding-kaurane type diterpene derivative and application in preparation of antitumor drugs thereof

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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 acetyl chloride dropwise at 0°C to 5°C while keeping warm, and raise the temperature of the reaction solution to 20°C after dropping ~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...

Embodiment 2

[0039] Pharmacological Example 2 The Inhibitory Effect of Formula (I) Compounds on Different Types of Solid Tumor Cells

[0040] 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:

[0041] Lung cancer: human normal lung epithelial cells HBEC, human lung cancer cells A549, SK-MES-1

[0042] Gastric cancer: human normal gastric mucosal epithelial cells RGM-1, human gastric cancer cells MGC-803, SGC-7901

[0043] Breast cancer: human normal breast epithelial cells MCF10A, human breast cancer cells MCF7, MDA-MB-231

[0044] Colorectal ca...

Embodiment 3

[0054] Pharmacological Example 3, Comparative Test on the Survival Period of Tumor-bearing Mice

[0055] 1. Materials

[0056] a) Cell line: colorectal cancer cell Caco-2, which can stably express luciferase, was purchased from the Cell Bank of the Type Culture Collection Committee of the Chinese Academy of Sciences.

[0057] b) Animals: 30 BALB / c nude mice, body weight (13±2g), male.

[0058] c) Drug: Iso A (drug 1), formula (I) compound (drug 2)

[0059] 2. Experimental method

[0060] a) Production of colorectal cancer tumor-bearing mouse model: colorectal cancer cells Caco-2 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).

[0061] b) Grouping and administration of experimental animals: After two weeks of feeding, the tumor-bearing situation in th...

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Abstract

Disclosed are a corresponding-kaurane type diterpene derivative and application in preparation of antitumor drugs thereof. The structure of the corresponding-kaurane type diterpene derivative is as shown in formula (I); a preparation method of the compound shown in the formula (I) comprises the following steps that 1, Isoforretin A and DMAP are dissolved in dichloromethane, triethylamine is added,the temperature is maintained between 0 DEC G-5 DEC G and acetyl chloride is added dropwisely, and the temperature of reaction liquid is increased to 20 DEC G-25 DEC G and stirring reaction is conducted after the dropwise adding is completed; 2, saturated sodium bicarbonate aqueous solution is added into the reaction liquid to quench the reaction after it is detected by TLC that the reaction is conducted completely, a water layer is extracted by the dichloromethane for three times, an organic layer is combined, the organic layer is washed by dilute hydrochloric acid for three times, and threelayers are washed by saturated saline solution. The organic layer is collected, dried by magnesium sulfate anhydrous, filtered and concentrated to obtain crude products. The crude products are purified by flash silica gel column chromatography to obtain target products in the formula (I) as pure products.

Description

Technical field: [0001] The invention relates to a novel diterpene compound and its application in the preparation of antitumor drugs. Background technique: [0002] Thioredoxin-1 ((thioredoxin-1, referred to as Trx-1) is abnormally highly expressed in many tumor cells and tumor tissues. Overexpressed Trx1 can promote tumor cell proliferation and help tumors by combining with ASK1, PTEN and other proteins. Cell escape, Trx1 can promote angiogenesis by increasing the expression of HIFα and enhancing the function of VEGF. In addition, clinical studies have shown that the higher the expression of Trx1, the worse the prognosis of tumor patients. In addition to tumors, many diseases are mediated by the above-mentioned thioredoxin system Event No. | The abnormal cell response is related. Therefore, screening new Trx1 selective inhibitors is an important demand for pharmaceutical research and development, and they may be extremely effective drugs for the treatment of tumors and oth...

Claims

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Application Information

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IPC IPC(8): C07C67/14C07C69/21A61K31/22A61P35/00
CPCC07B2200/07C07C67/14C07C69/21
Inventor 张春泽张锡朋秦海
Owner TIANJIN PEOPLE HOSPITAL
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