5-Substituted Icaritin Derivatives and Their Antitumor Applications

A technology of icariin and derivatives, applied in anti-tumor drugs, drug combinations, organic chemistry and other directions, can solve the problems of low bioavailability, poor solubility, restricted use, etc., and achieves easy operation and implementation, good Anti-tumor activity, good anti-tumor effect

Active Publication Date: 2022-01-28
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Icaritin (Icaritin, 1) is a natural allyl-substituted flavonoid extracted from the traditional Chinese medicine Epimedium, which has various pharmacological activities such as anti-tumor and anti-dementia. However, due to its solubility Poor and low bioavailability, limiting its clinical use

Method used

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  • 5-Substituted Icaritin Derivatives and Their Antitumor Applications
  • 5-Substituted Icaritin Derivatives and Their Antitumor Applications
  • 5-Substituted Icaritin Derivatives and Their Antitumor Applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 , Preparation of β-anhydroicariin 2:

[0017] A solution of Icaritin (3 g, 8.2 mmol) in formic acid (50 mL) was stirred at reflux for 20 h. The reaction solution was then poured into crushed ice. The solid was collected by filtration to give the title compound (2, 2.8 g, 93.3%) as a yellow powder. Melting point: 221-222°C (illumination temperature: 223°C, Akai et al., 1935).

[0018] 1 H NMR (400MHz, CHCl 3 )δ=11.47(s,1H,5-OH),8.17(d,J=8.7Hz,2H,Ar-H),7.03(d,J=8.7Hz,2H,Ar-H),6.64(s, 1H,3-OH),6.24(s,1H,Ar-H),3.88(s,3H,CH 3 O), 2.89(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.88(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ),1.37(s,6H,(CH 3 ) 2 ).

Embodiment 2

[0019] Example 2 , Compound 3 (R=CH 3 ) preparation:

[0020] Compound 2 (100mg, 0.27mmol) and K 2 CO 3 (75mg, 0.54mmol) in acetone (2ml) was stirred at room temperature for 10 minutes. Dimethyl sulfate (1 equ.) was added dropwise to the suspension over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was washed with MgSO 4 dry. The solvent was completely evaporated under reduced pressure to obtain compound 3 (95%).

[0021] 1 H NMR (400MHz, CDCl 3 )δ=12.36(s,1H,OH),8.08(d,J=9.1Hz,2H,Ar-H),7.00(d,J=9.1Hz,2H,Ar-H),6.21(s,1H, Ar-H), 3.85(d, J=14.6Hz, 6H, 2CH 3 O), 2.83(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.84(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ),1.34(s,6H,(CH 3 ) 2 ). 13 C NMR (101MHz, CDCl 3 )δ=178.7(C=O), 161.5(C=C), 160.0(C=C), 159.4(C=C), 155.1(C=C), 153...

Embodiment 3

[0022] Embodiment 3, compound 4a-j (R=CH 3 ) preparation:

[0023] (1) Compound 4a (R=CH 3 ) preparation

[0024]

[0025] Compound 3 (50mg, 0.136mmol) and K 2 CO 3 (38mg in acetone (2ml), 2equ.) Stirred at room temperature for 10 minutes. To the suspension was added iodomethane (2equ.) dropwise over 10 minutes. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was completely evaporated under reduced pressure. The residue was diluted in dichloromethane and water. The separated organic layer was washed with MgSO 4 dry. The solvent was completely evaporated under reduced pressure to give compound 4a (85%). 1 H NMR (400MHz, CDCl 3 )δ=8.06(d,J=9.0Hz,2H,Ar-H),6.97(d,J=9.0Hz,2H,Ar-H),6.22(s,1H,Ar-H),3.88(s, 3H,OCH 3 ),3.84(s,3H,OCH 3 ),3.83(s,3H,OCH 3 ), 2.85(t, J=6.7Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ), 1.85(t, J=6.8Hz, 2H, CH 2 -CH 2 -C(CH 3 ) 2 ),1.35(s,6H,(CH 3 ) 2 ). 13 C NMR (101MHz, CDCl 3)δ=174.3(C=O), 1...

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Abstract

The present invention provides a 5-substituted icariin derivative with the structural formula shown in 4, its preparation method and its anti-tumor application. Activity tests prove that the 5-substituted icariin derivatives designed and synthesized by the present invention as shown in 4 are suitable antitumor drug candidates, especially as anti-liver cancer, anti-colon cancer, lung cancer and anti-colon cancer drug candidates. In addition, the synthesis method of the 5-substituted icariin derivative of the present invention has a high yield of the synthetic route and is easy to operate and implement.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to a novel 5-substituted icariin derivative and its antitumor application. Background technique [0002] Icaritin (Icaritin, 1) is a natural allyl-substituted flavonoid extracted from the traditional Chinese medicine Epimedium, which has various pharmacological activities such as anti-tumor and anti-dementia. However, due to its solubility Poor and low bioavailability limit its clinical use. Icaritin is metabolized in vivo to β-anhydroicariin (compound 2). [0003] [0004] Studies have shown that icariin has a unique anti-tumor mechanism, and pharmacists hope to modify its flavone structure to obtain derivatives with better activity. In order to look for anti-cancer drug candidates with better efficacy and stronger toxicity, we designed and fully synthesized the following drug molecules. , propargyl and benzyl substituting a new class of 5-substituted i...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D493/04A61P35/00
CPCC07D493/04A61P35/00
Inventor王先恒赵长阔何芋岐崔晗琦柯希赵缘财
OwnerZUNYI MEDICAL UNIVERSITY