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Fusidic acid derivative with anti-tumor activity and synthesis and preparation method thereof

A technology of fusidic acid and derivatives, applied in the field of fusidic acid derivatives, can solve problems such as no anti-tumor activity, and achieve the effect of anti-tumor mechanism of action

Active Publication Date: 2019-02-12
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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  • Fusidic acid derivative with anti-tumor activity and synthesis and preparation method thereof
  • Fusidic acid derivative with anti-tumor activity and synthesis and preparation method thereof
  • Fusidic acid derivative with anti-tumor activity and synthesis and preparation method thereof

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 and 9-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 medicinal chemistry, in particular to a kind of fusidic acid derivative with a novel structure and a synthesis method and application thereof. The optimized derivative comprises 3beta-[(2-amino) acetoxyl]-21-fusidate benzyl ester, 3beta-[(2-amino)propionyloxy]-21-fusidate benzyl ester, 3beta-[(2-amino-4-methyl)acetoxy]-21-fusidate benzylester, 3beta- (3-aminopropionyloxy)-21-fusidate benzyl ester, 3beta-(4-aminobutyryl acyloxy)-21-fusidate benzyl ester, 3beta-(8-aminocapryloyloxy)-21-fusidate benzyl ester, 3beta(11-aminohendecanoyl)-21-fusidate benzyl ester, and 3beta-(L-lysyl oxide)- 21-fusidate benzyl ester. The fusidic acid derivative of the invention has an anti-tumor effect and a clear action mechanism, and can be applied tothe development of a novel anti-tumor medicine.

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): C07J41/00A61P35/00
CPCA61P35/00C07J41/0088
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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