Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative

A technology of benzopyran and multidrug resistance, which is applied in the field of medicine, can solve the problems of chemical and biological metabolism instability, low antitumor multidrug resistance activity, etc., and achieve good antitumor multidrug resistance activity, good selective effect

Inactive Publication Date: 2011-08-17
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the disadvantages of catechin compounds in the prior art, such as low anti-tumor multi-drug resistance activity and unstable chemical and biological metabolism, the present invention provides a benzopyran-3-ol esterified derivative and Its preparation method, the benzopyran-3-ol esterified derivatives have the same skeleton structure as epigallocatechin gallate, but the benzopyran-3-ol esterified derivatives are low-toxic and Has good anti-tumor multidrug resistance activity

Method used

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  • Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative
  • Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative
  • Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of 5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-chromen-3-ol, 3,4, 5-trimethoxybenzoate (shown in 3 in the synthetic route structure diagram).

[0034] Add 2.0 g, 2.5 mmol of peracetylated epigallocatechin gallate to 50 mL of saturated hydrogen chloride in methanol, the solid slowly dissolves, and the solution appears pale yellow. The reaction was stirred at room temperature for 12 h, the color of the solution gradually deepened, and finally turned into wine red, and the reaction was complete as detected by TLC. The reaction solution was rotary evaporated to remove methanol to obtain epigallocatechin gallate (EGCG). EGCG was not further purified, and 100 mL of ethylene glycol dimethyl ether-acetone mixed solvent was added to dissolve it completely, and then 7.5 g of potassium carbonate and 10 mL of dimethyl sulfate were added. Heated to reflux for 48 h and evaporated to dryness. Wash with saturated sodium carbonate solution 3 times, and...

Embodiment 2

[0036] Example 2: Preparation of 5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-chromene-3-ol (synthetic route structure diagram shown in 4).

[0037] The 5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-chromene-3-ol prepared in Example 1, 3,4 , 5-trimethoxybenzoate (0.50 g, 0.86 mmol) was dissolved in a mixed solvent of 10 mL methanol and 10 mL ethylene glycol dimethyl ether, and then 0.2 g K 2 CO 3 , the reaction was stirred at room temperature, and the progress of the reaction was detected by TLC. After 1 h, the starting material disappeared. Evaporate to dryness to obtain a white solid, add 20 mL of ethyl acetate, filter off the insoluble matter, concentrate by rotary evaporation, and separate by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 4) to obtain 0.28 g of product, yield: 87% .

[0038] 1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 6.70 (s, 2 H), 6.31 ( d, J =8.0 Hz, 1 H), 6.13 ( d, J =8.0 Hz, 1 H), 6.59-6.57 (m, 1 H), 5.03-5.01 (m, ...

Embodiment 3

[0039] Example 3: Preparation of 5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-chromen-3-ol, 4-methoxy Base benzoate (shown in 5 in the synthetic route structure diagram).

[0040] Take 4-methoxybenzoic acid (0.18 g, 1.18 mmol) and 5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-benzo Pyran-3-ol (200mg, 0.53mmol), then add p-dimethylaminopyridine (0.26 g, 2.15 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g, 2.15 mmol), under nitrogen protection, dissolved in 20 ml of anhydrous dichloromethane, stirred at room temperature for 24 h to complete the reaction. Washed three times with saturated sodium bicarbonate solution, collected the organic phase, dried over anhydrous magnesium sulfate for 4 h, and spin-dried to obtain the crude product, which was separated by column (petroleum ether / ethyl acetate=3 / 1 v / v) to obtain 0.18 g of pure product , yield 68%.

[0041] 1 H NMR (CDCl 3 , 500 MHz) δ (ppm): 7.56-7.55 (m, 1 H), 7.54 (s, 1 H), 7...

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Abstract

The invention provides a benzopyranyl-3-alcohol esterified derivative and a preparation method of the benzopyranyl-3-alcohol esterified derivative. The benzopyranyl-3-alcohol esterified derivative is shown as the following formula I, wherein in the formula I, R represents one or more of hydrogen, hydroxy, alkoxy, alkyl amino, alkyl acylamino, fluorine or benzoyl; the benzoyl contains one or more of hydroxy, alkoxy, alkyl amino, alkyl acylamino or fluorinated substituents, wherein alkyl in alkoxy, alkyl amino and alkyl acylamino is C1 to C10 straight chain or branched chain alkyl; X in the formula represents hydrogen or oxygen; and Y in the formula represents oxygen or nitrogen and hydrogen. The benzopyranyl-3-alcohol esterified derivative is low-toxic, has excellent antineoplastic multidrug resistance activity and can be used for preparing a medicament for treating breast cancer, colon cancer, prostatic cancer, leukemia, myeloma, pancreatic cancer and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a benzopyran-3-ol esterified derivative, a preparation method thereof and an application as an anti-tumor multi-drug resistance inhibitor. Background technique [0002] Chemotherapy is one of the main ways to treat tumors. Multidrug resistance (MDR) of tumor cells is the main reason for tumor chemotherapy failure and tumor recurrence and metastasis, which makes chemotherapy face serious challenges. P-gp is an ATP-dependent broad-spectrum antitumor drug efflux pump. [0003] Roughly three generations of P-gp inhibitors have been developed [Ramalingam, et al: Clin Lung Cancer 2005;7:773]. The first generation itself is a P-gp substrate, which inhibits drug uptake, but its ability to inhibit P-gp efflux is poor, and its toxic and side effects are severe, which seriously limits its clinical application. Representative drugs such as verapamil, it is found earlier multi-d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/62A61K31/353A61K9/20A61K9/48A61K9/30A61K9/08A61K9/02A61P35/00A61P35/02
Inventor 万升标周铭祥江涛李学敏黄麗琼苑建张晓瑜孙东魁
Owner OCEAN UNIV OF CHINA
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