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Use of fusidic acid derivatives in preparation of antitumor drugs

An anti-tumor drug, fusidic acid technology, applied in the direction of anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problem of no anti-tumor activity, and achieve the effect of anti-tumor mechanism of action

Active Publication Date: 2018-11-30
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Publicly disclosed applications, fusidic acid is only used as an antibacterial drug clinically, without other indications, and fusidic acid derivatives reported in the literature have no antitumor activity

Method used

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  • Use of fusidic acid derivatives in preparation of antitumor drugs
  • Use of fusidic acid derivatives in preparation of antitumor drugs
  • Use of fusidic acid derivatives in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 3β-[(2-Amino)acetoxy]-21-fusidic acid benzyl ester

[0048] 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.

[0049] Take a 25mL eggplant-shaped bottle, dissolve benzyl 21-fusidate (0.10mmol) in anhydrous dichloromethane (10mL), stir and add Boc-protected amino acid (0.22mmol), DMAP (0.31mmol), EDCI ( 0.30mmol), react at room temperature for 4-6 hours. Wash with 10% hydrochloric acid until acidic, wash with water, wash w...

Embodiment 2

[0052] 3β-[(2-amino)propionyloxy]-21-fusidic acid benzyl ester

[0053] Using X2 as raw material, referring to the preparation method of benzyl 3β-[(2-amino)acetoxy]-21-fusidate, a white solid (46 mg, 86.7%) was obtained. 1 H-NMR (CDCl 3 ,400MHz)δ:7.29-7.35(m,5H,5×Ar-H),5.88(d,J=8.27Hz,1H,16-H),5.20(d,J=12.18Hz,1H,CHAr), 5.05(t, J=7.16Hz, 1H, 24-H), 4.91(d, J=2.46Hz, 1H, 11-OH), 4.92(d, J=12.14Hz, 1H, CHAr), 4.64(d, J=24.20Hz, 2H, -NH 2 ),4.31(s,1H,11-H),3.59(q,J=6.38Hz,1H,-CH-),3.01(d,J=11.13Hz,1H,13-H),2.38-2.49(m ,2H,2×22-H),2.24-2.28(m,1H,12-H),2.05-2.19(m,5H,1-H,5-H,15-H and 2×23-H), 1.92(s,3H,OCOCH 3 ),1.67-1.89(m,4H,2×2-H,7-H and 12-H),1.62(s,3H,27-CH 3 ),1.54-1.60(m,3H,1-H,6-H and9-H),1.51(s,3H,26-CH 3 ),1.47(s,1H,4-H),1.36(s,3H,-CH 3 ),1.35(s,3H,30-CH 3 ),1.24-1.31(m,1H,15-H),1.09-1.17(m,2H,6-H and 7-H),0.97(s,3H,19-CH 3 ),0.91(s,3H,18-CH 3 ),0.83(d,J=6.69Hz,3H,28-CH 3 ).

Embodiment 3

[0055] Benzyl 3β-[(2-amino-4-methyl)pentanoyloxy]-21-fusidate

[0056] Using X3 as raw material, referring to the preparation method of benzyl 3β-[(2-amino)acetoxy]-21-fusidate, a white solid (28 mg, 79.4%) was obtained. 1 H-NMR (CDCl 3 ,400MHz)δ:7.30-7.36(m,5H,5×Ar-H),5.88(d,J=8.26Hz,1H,16-H),5.20(d,J=12.21Hz,1H,CHAr), 5.06(t, J=6.94Hz, 1H, 24-H), 4.91-4.94(m, 2H, CHAr and 11-OH), 4.64(d, J=23.61Hz, 2H, -NH 2 ), 4.31(s, 1H, 11-H), 3.49(t, J=7.43Hz, 1H, -CH-), 3.02(d, J=11.58Hz, 1H, 13-H), 2.38-2.52(m ,2H,2×22-H),2.26-2.29(m,1H,12-H),2.07-2.20(m,3H,15-H and 2×23-H),1.96-2.04(m,2H, 1-H and 5-H),1.92(s,3H,OCOCH 3 ),1.68-1.88(m,4H,2×2-H,7-H and 12-H),1.63(s,3H,27-CH 3 ),1.54-1.61(m,3H,1-H,6-H and 9-H),1.52(s,3H,26-CH 3 ),1.38-1.46(m,1H,4-H),1.36(s,3H,30-CH 3 ),1.25-1.33(m,1H,15-H),1.03-1.17(m,2H,6-H and 7-H),0.98(s,3H,19-CH 3 ),0.94(s,3H,-CH 3 ), 0.93 (d, J=1.78Hz, 3H, 18-CH 3 ),0.91(s,3H,-CH 3 ),0.83(d,J=6.66Hz,3H,28-CH 3 ).

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Abstract

The invention relates to the field of organic synthesis and pharmacochemistry, and in particular, relates to fusidic acid derivatives with a novel structure and a preparation method and an applicationthereof. Preferably, the derivatives comprise 3[beta]-[(2-amino)acetoxyl]-21-benzyl fusilate, 3[beta]-[(2-amino)propionyloxy]-21-benzyl fusilate, 3[beta]-[(2-amino-4-methyl)valeryloxy]-21-benzyl fusilate, 3[beta]-(3-aminopropionyloxy)-21-benzyl fusilate, 3[beta]-(4-aminobutyryloxy)-21-benzyl fusilate, 3[beta]-(8-aminocapryloyloxy)-21-benzyl fusilate, 3[beta]-(11-aminoundecanoyloxy)-21-benzyl fusilate, and 3[beta]-(L-lysyloxy)-21-benzyl fusilate; the fusidic acid derivatives are used for preparing antitumor drugs.

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 and a preparation method thereof. technical background [0002] Cancer is a particularly complex, widespread and deadly disease. In 2012, there were 14.1 million new cancer cases and 8.2 million deaths worldwide. The number of cancer deaths is expected to continue to increase, and it is estimated that 13.1 million people will die by 2030. Cancer has become a major disease that seriously endangers human health and life, and there is still no very satisfactory treatment method so far. Chemotherapy has become one of the most important therapeutic methods in cancer treatment. The development of structurally novel therapeutics is of paramount importance. [0003] Fusidic acid (Fusidic acid, FA) is a steroid-based narrow-spectrum antibacterial antibiotic w...

Claims

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Application Information

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IPC IPC(8): A61K31/56A61P35/00
CPCA61K31/56A61P35/00
Inventor 毕毅王洪波倪敬轩郭梦琦王炳华魏颖杰马金波张玮育
Owner YANTAI UNIV
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