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Bola type quercetin derivative and its preparation method and application

A derivative, quercetin technology, applied in the field of chemical drug synthesis, can solve the problems of poor water solubility and fat solubility of quercetin, lack of tumor tissue targeting, and low bioavailability

Active Publication Date: 2019-08-02
CHONGQING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to improve quercetin’s poor water-solubility and fat-solubility, low bioavailability, and lack of targeting to tumor tissues, the inventors used the special structure of Bola-type molecules to prepare a Bola-type quercetin derivative thing

Method used

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  • Bola type quercetin derivative and its preparation method and application
  • Bola type quercetin derivative and its preparation method and application
  • Bola type quercetin derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of compound I-1-1

[0057] 1) Preparation of reaction intermediate VI-1

[0058]

[0059] Take 2.0g of rutin and place it in a round bottom flask, add 4.8g of cesium carbonate and 3.4g of benzyl bromide, then add 40ml of dimethylformamide and stir to dissolve. Heat to 60-90°C. After 48 hours, an aqueous acetic acid solution was added dropwise, and a solid precipitated out. After filtration, the filter cake was dissolved in ethanol solution of hydrochloric acid, heated to reflux for about 2 hours, and compound VI-1 was obtained after filtration.

[0060] VI-1: 1 H NMR (400MHz, CDCl 3 ):δ7.88(s,1H),7.76(d,1H,J=4Hz),7.32-7.61(m,20H),7.03(d,1H,J=4Hz),6.58(s,1H),6.48 (s,1H),5.24-5.26(m,6H),5.12(s,2H).

[0061] 2) Preparation of compound I-1-1

[0062]

[0063] Take compound VI-1 (according to 1.0eq), add 3.0eq cesium carbonate and 3.0eq 1,12-dibromododecane, use dimethylformamide as solvent, and stir for 8 hours. Compound I-1-1a was obtained by colu...

Embodiment 2

[0066] Preparation of compound I-1-2

[0067]

[0068] According to the method similar to Example 1, except that the 1,12-dibromododecane in the reaction was changed into 1,8-dibromooctane, the compound I-1-2 was obtained.

[0069] I-1-2: 1 H NMR (400MHz, DMSO-d 6 ): δ7.49(s,2H),7.40(s,2H),6.85(d,2H,J=4Hz),6.35(d,2H,J=4Hz),6.16(s,2H),3.89(t ,4H, J=8Hz), 1.60(t, 4H, J=8Hz), 1.19-1.28(m, 8H); 13 C NMR (100MHz, DMSO-d 6 ): δ178.42, 164.60, 61.71, 156.77, 156.37, 149.03, 145.58, 137.17, 121.37, 121.13, 115.97, 104.57, 98.95, 93.97, 72.42, 36.21, 31.25, 29.85, 25.8 [M+H] + .

Embodiment 3

[0071] Preparation of Compound 1-2

[0072]

[0073] Take compound VI-1 (according to 1.0eq), add 3.0eq cesium carbonate and 3.0eq 1,8-dibromooctane, use dimethylformamide as solvent, and stir for 8 hours. Compound VIII-1 was obtained by column chromatography. Compound VIII-1 was dissolved in methanol, stirred for 2 hours under the condition of palladium carbon / hydrogen, filtered, and the solvent was spin-dried to obtain compound IX-1. Dissolve compound IX-1 in acetonitrile, add potassium thioacetate, stir for 5 hours, and then separate by column chromatography to obtain compound X-1. Dissolve compound X-1 in methanol, add potassium phosphate, stir in air for 5 hours, then add 1 mol / L hydrochloric acid dropwise, then filter and separate by column chromatography to obtain compound I-2.

[0074] I-2: 1 H NMR (400MHz, DMSO-d 6 ): δ7.52(s,2H),7.43(d,2H,J=4Hz),6.90(d,2H,J=4Hz),6.44(s,2H),6.20(s,1H),3.90(s ,4H),2.66(d,4H,J=4Hz),1.60(s,8H),1.23-1.30(m,16H); 13 C-NMR (100MHz,...

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Abstract

The invention relates to bola type quercetin derivatives and a preparation method thereof. A bola type amphiphilic molecule is formed by connecting two polar head groups by using a hydrophobic chain; and unique natures such as better stability and compatibility in a plasma membrane are given to the bola type amphiphilic molecule through the special structure. The bola type quercetin derivatives shown as general formulas I-V are developed by utilizing bola type characteristics to increase the water solubility and the bioavailability of the derivatives; meanwhile, proved by research results, compared with non-bola type quercetin lipid derivatives, the bola type quercetin derivatives are capable of better inhibiting the growth activity of tumor cells; the bola type quercetin derivatives are transformed into nanometer drugs through micromolecule self-assembly on the basis of the structure to improve the physicochemical property of compounds; the ability of targeting focal tissues is enhanced and the damage of the drugs to normal tissues and cells is reduced; and R and n in the general formulas are defined as the claim.

Description

technical field [0001] The invention belongs to the field of chemical drug synthesis, and relates to Bola-type quercetin derivatives and their preparation methods and applications. Background technique [0002] Quercetin is a flavonol compound extracted from natural plants, which has various biological activities such as antioxidant, anticancer, antibacterial and anti-inflammatory. A large number of studies have shown that quercetin can target multiple cancer-related signal transduction pathways, and inhibiting the expression of various protein kinases in these pathways is an important reason for its anti-cancer activity. Recent studies have shown that quercetin can not only effectively inhibit the expression of heat shock proteins HSP27 and HSP70, but also inhibit the expression of heat shock factor HSF1. The inhibition of heat shock proteins and heat shock factors by quercetin broadens the target spectrum of the drug and also provides a new mechanism of action for its ant...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/30A61K31/352A61P35/00A61K9/14
CPCA61K9/14C07D311/30
Inventor 夏熠索亚雄周峥巍陈迷谜罗碧瑶
Owner CHONGQING UNIV
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