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Tetrandrine derivatives and preparation method and application thereof in preparation of antitumor medicine

A technology of tetrandrine and its derivatives, which is applied in the field of preparation of tetrandrine derivatives and their application in the preparation of anti-tumor drugs, which can solve the problems of low cure rate and achieve simple preparation methods, inhibition of proliferation, and strong activity Effect

Active Publication Date: 2014-07-16
SHANDONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the main therapeutic drugs are fluorouracil, doxorubicin, ifosfamide, semustine, paclitaxel, gemcitabine, cisplatin, etc., but the clinical cure rate is very low. Cancer drugs are very necessary

Method used

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  • Tetrandrine derivatives and preparation method and application thereof in preparation of antitumor medicine
  • Tetrandrine derivatives and preparation method and application thereof in preparation of antitumor medicine
  • Tetrandrine derivatives and preparation method and application thereof in preparation of antitumor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Weigh 6.06g of bisbenzylisoquinoline (in general formula II, X=H), 12.50g of sodium 2-chloroacetate and 0.40g of sodium hydroxide, add them to a 500mL three-necked flask, dissolve in 100mL propanol, heat and stir, The reaction was stirred at 83°C for 8 hours, the solvent was evaporated under reduced pressure, the temperature was reduced to room temperature, 10% HCl was neutralized to neutrality, 50 mL of water was added and the mixture was extracted 3 times with ethyl acetate (50 mL×3), and the extract was used anhydrous Na 2 SO 4 Drying for 8 hours, recovering ethyl acetate, TLC tracking the reaction and separation and purification of the product, the solid was dried at 60°C for 2 hours to obtain 6.21 g of light brown powder with a yield of 85.69% and a purity of 98.55% (HPLC). The melting point of the target product: 178-179℃, the time-of-flight mass spectrum: M / e(355.1601), the molecular formula is C 41 H 44 O 9 N 2 , 13 C NMR(75MHz, DMSO-d 6 ): δ20.63(C-4),23.22(C-4’),...

Embodiment 2

[0038] Weigh 6.22g of 7-hydroxybisbenzylisoquinoline (X=OH in general formula II), 10.00g of sodium 2-bromoacetate and 0.60g of potassium hydroxide, dissolve them in 100mL of n-butanol, add them to a 500mL three-necked flask , Heating and stirring to 118℃, and stirring at constant temperature for 6h, distilling off the solvent under reduced pressure, cooling to room temperature, 3%H 2 SO 4 Neutralize to neutral, add 50 mL of water and extract 3 times with chloroform (60 mL×3), and use anhydrous Na for the extract 2 SO 4 After drying for 8 hours, recovering chloroform, TLC followed the reaction and the separation and purification of the product, the solid was dried at 60°C for 2 hours to obtain 6.52 g of light red powder with a yield of 88.03% and a purity of 97.36% (HPLC). The melting point of the target product: 181-182℃, the time of flight mass spectrum: M / e(363.1575), the molecular formula is C 41 H 44 O 10 N 2 , 13 According to CNMR characterization, the main difference from ...

Embodiment 3

[0040] Weigh 6.40g of 7-chlorobisbenzylisoquinoline (X=Cl in the general formula II), 5.50g of sodium 2-iodoacetate, and γ-Al 2 O 3 -Na alkali 2.60g, add to a 500mL three-necked flask, add 200mL of water and stir and mix, cool to 10℃, react at a constant temperature for 48h, warm to room temperature and then filter, the filtrate is neutralized with dilute ammonia water, and the water is evaporated under reduced pressure to liquid volume Approximately 40 mL, crystallized overnight at 5°C, filtered, followed by TLC to track the reaction and separation and purification of the product. The obtained solid was dried at 60°C for 4h to obtain 3.63g of light red powder with a yield of 47.85% and purity. 98.15% (HPLC). The melting point of the target product: 176-178℃, the time of flight mass spectrum: M / e(372.1406), the molecular formula is C 41 H 43 O 9 N 2 Cl, 13 CNMR characterization, the main difference from Example 1 is 105.45 (C-7), which is compound 3 in Table 1.

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Abstract

The invention discloses a tetrandrine derivative with antitumor activity and a preparation method thereof. The structural formula of the compound is shown in the specification. The preparation method comprises the following steps: dissolving bisbenzylisoquinoline compound serving as raw material in certain solvent; adding an alkali reagent and a reactant Y, and mixing; reacting for 0.1 to 72 hours under temperature of -20 to 300 DEG C; neutralizing the reacted solution with acid, and then separating and purifying to prepare the objective product. The tetrandrine derivative prepared by the invention can well inhibit proliferation of human hepatoma cell line HepG2 and pancreatic cancer cell SW1990, and can be used for preparing antitumor medicines.

Description

Technical field [0001] The invention relates to a novel anti-tumor active tetrandrine derivative, a preparation method thereof and application in the preparation of an anti-tumor drug. Background technique [0002] Tetrandrine, also known as tetrandrine or tetrandrine, is a bisbenzyl isoquinoline compound. It is mainly used for rheumatism, arthralgia, neuralgia, and silicosis. Han muscle relaxant (dimethyltetrandrine iodide, a quaternary ammonium salt of tetrandrine) is a striated muscle relaxant that can be used clinically to relax striated muscle during surgery. Experimental studies have proved that tetrandrine has certain effects in anti-lung cancer, chronic myeloid leukemia, liver cancer, neuroblastoma, breast cancer, etc. Its mechanism is related to reversing multi-drug resistance, inducing cell apoptosis, and enhancing radiosensitivity. It is related to the inhibition of tumor blood vessel formation. Xu Meng et al. proved through in vitro experiments (Experimental study o...

Claims

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Application Information

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IPC IPC(8): C07D491/18A61K31/4748A61P35/00
CPCC07D491/18
Inventor 刘玉法张萌李得超钤小平杜华
Owner SHANDONG NORMAL UNIV
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