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Fusidine derivatives with tumor drug-resistance reversal activity and synthetic method thereof

A technology of fusidic acid and derivatives, applied in the field of organic synthesis and medicinal chemistry, to achieve the effect of reversing the mechanism of tumor drug resistance

Active Publication Date: 2019-04-12
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, fusidic acid is a marketed antimicrobial drug, although researchers have conducted extensive research on fusidic acid, but there has been no report that fusidic acid or its derivatives have tumor resistance reversing activity

Method used

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  • Fusidine derivatives with tumor drug-resistance reversal activity and synthetic method thereof
  • Fusidine derivatives with tumor drug-resistance reversal activity and synthetic method thereof
  • Fusidine derivatives with tumor drug-resistance reversal activity and synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Benzyl 21-fusidate

[0056] Take a 500mL eggplant-shaped bottle, dissolve fusidic acid (10.01g, 0.019mol) in acetone (200mL), stir and add potassium carbonate (5.36g, 0.039mol), benzyl bromide (2.78mL, 0.023mol), 30°C React for 5-7 hours. Suction filtration, concentration, dilution with ethyl acetate (50mL), washing with 10% hydrochloric acid until acidic, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, distilling off the solvent under reduced pressure, silica gel column chromatography (V 氯仿 :V 甲醇 =210:1-190:1), to obtain benzyl 21-fusidate (8.86 g, 75.4%) as a white solid. 1 H-NMR (CDCl 3 ,400MHz)δ:7.30-7.37(m,5H,Ar-H),5.87(d,J=8.36Hz,1H,16-H),5.20(d,J=12.20Hz,1H,CHAr),5.06( t,J=7.12Hz,1H,24-H), 4.92(d,J=12.20Hz,1H,CHAr),4.33(s,1H,11-H),3.70(d,J=2.00Hz,1H, 3-OH), 3.04(d, J=11.20Hz, 1H, 13-H), 2.37-2.50(m, 2H, 2×22-H), 2.28-2.31(m, 1H, 12-H), 2.08 -2.20(m,5H,1-H,5-H,15-H and 2×23-H),1.92(s,3H,OCOCH 3 ),1.76-1.84(...

Embodiment 2

[0058] 3-(6-Nitrooxy-hexanoyl)-21-fusidic acid benzyl ester

[0059] Take a 25mL eggplant-shaped bottle, dissolve benzyl 21-fusidate (0.12mmol) in anhydrous dichloromethane (10mL), stir and add bromohexanoic acid (0.18mmol), DMAP (0.37mmol), EDCI ( 0.38mmol), 5 drops of triethylamine, and react at room temperature for 7-10 hours. Wash with 10% hydrochloric acid until acidic, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and perform silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =50:1-20:1) to obtain benzyl 3-(6-bromohexanoyl)-21-fusidate as a white solid.

[0060] Take a 25mL eggplant-shaped bottle, dissolve 3-(6-bromohexanoyl)-21-fusidic acid benzyl ester (0.069mmol) in 8mL of anhydrous acetonitrile, stir and add silver nitrate (0.18mmol), 70°C in the dark React for 18 hours. Filter, concentrate, dissolve in ethyl acetate, wash with water successively, wash with saturated brine, dry ov...

Embodiment 3

[0062] 3,11-dicarbonyl-21-fusidic acid benzyl ester

[0063] Take a 25 mL eggplant-shaped bottle, dissolve benzyl 21-fusidate (60 mg, 0.099 mmol) in 10 mL of dichloromethane, add freshly prepared PCC (64 mg, 0.30 mmol) with stirring, and stir at room temperature for 4-8 hours. Remove the solvent under reduced pressure, dilute with ethyl acetate (10mL), wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, perform silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =10:1-6:1), a pale yellow solid (40 mg, 66.7%) was obtained. 1 H-NMR (CDCl 3 ,400MHz)δ:7.32-7.37(m,5H,5×Ar-H),5.93(d,J=8.22Hz,1H,16-H),5.21(d,J=11.95Hz,1H,CHAr), 5.04(t, J=7.18Hz, 1H, 24-H), 4.95(d, J=12.13Hz, 1H, CHAr), 2.85-2.93(m, 1H, 13-H), 2.65-2.78(m, 2H ,2×22-H),2.47-2.54(m,1H,12-H),2.33-2.42(m,3H,15-H and 2×23-H),2.14-2.26(m,2H,1- H and5-H),1.97-2.11(m,3H,2×2-H and 7-H),1.95(s,3H,OCOCH 3 ), 1.81(t, J=11.88Hz, 1H, 12-H), 1.63(s, 3...

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Abstract

The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a class of fusidine derivatives with a novel structure. The structure is as shown in a general formulaI. The invention also discloses a preparation method of the derivatives and new application of the derivatives to reversal of tumor drug-resistance.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of fusidic acid derivatives with novel structures, a pharmaceutical composition containing them, a preparation method thereof, and a new application thereof in reversing tumor drug resistance. technical background [0002] Tumors seriously threaten human health, and chemotherapy is currently one of the main methods for treating tumors. According to statistics, more than 50% of malignant tumors are resistant to traditional chemical drugs, and more than 6 million people die of malignant tumors in the world every year. Studies have shown that multidrug resistance (MDR) of tumor cells to chemotherapy drugs is the cause of chemotherapy failure. One of the main reasons. Therefore, finding and developing new compounds with new structures, low toxicity and high-efficiency MDR reversal activity is a hot topic in the research of tumor therapeutics and phar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J13/00A61P35/00
CPCA61P35/00C07J13/007
Inventor 毕毅王洪波傅风华倪敬轩曹玉成郭梦琪刘书琪魏颖杰
Owner YANTAI UNIV