CN109608512B - Fusidic acid derivatives with tumor resistance reversal activity - Google Patents
Fusidic acid derivatives with tumor resistance reversal activity Download PDFInfo
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Abstract
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to fusidic acid derivatives with novel structures, which have a general formula I, and also discloses a preparation method of the derivatives and a new application of the derivatives in tumor drug resistance reversal.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to fusidic acid derivatives with novel structures, a pharmaceutical composition containing the fusidic acid derivatives, a preparation method of the fusidic acid derivatives and a new application of the fusidic acid derivatives in tumor drug resistance reversal.
Technical Field
Tumors are a serious threat to human health, and chemotherapy is currently one of the major methods for treating tumors. Statistically, more than 50% of malignant tumors are resistant to traditional chemical drugs, and more than 600 million people die of malignant tumors every year worldwide, and studies show that multidrug resistance (MDR) of tumor cells to chemotherapeutic drugs is one of the main causes of chemotherapy failure. Therefore, the search and development of novel compounds with novel structures, low toxicity and high MDR reversal activity are the hot contents of research in tumor therapeutics and pharmacology.
Fusidic Acid (FA), a narrow spectrum bacteriostatic steroid-based antibiotic with a tetracyclic system, was first isolated in 1960 from the fungus fusarium coccineum and since 1962 was used for the treatment of skin infections, bone joint infections and burn infections caused by staphylococcus aureus and several other gram-positive bacteria. Furthermore, fusidic acid is a marketed antibacterial drug, and despite extensive studies on fusidic acid by researchers, no report has been made on the tumor resistance reversal activity of fusidic acid or its derivatives.
Disclosure of Invention
The invention aims to provide a fusidic acid derivative with a novel structure and a preparation method thereof, and simultaneously provides a new application of the derivative in the field of tumor drug resistance reversal, and the fusidic acid derivative has important significance for developing a novel tumor drug resistance reversal agent.
The fusidic acid derivative with tumor drug resistance reversing activity in the patent belongs to the initiative, and the new discovery has important significance for developing tumor drug resistance reversing agents with novel structures.
The invention is realized by the following technical scheme:
fusidic acid derivatives of general formula I and pharmaceutically acceptable salts thereof:
wherein:
R1represents oxo, OR3；
R2Represents oxo, hydroxy;
R3representative H, COR4ONO2、COR5COR6；
R4Represents a straight-chain alkane with 1-10 carbons;
R5represents straight-chain alkane with 1-4 carbons, phenyl, pyrazinyl;
R6represents
Preferably, some of the compounds of the present invention are:
21-fusidic acid benzyl ester;
3- (6-nitrooxy-hexanoyl) -21-fusidic acid benzyl ester;
11-carbonyl-3- (5-nitrooxy-pentanoyl) -21-fusidic acid benzyl ester;
benzyl 3, 11-dicarbonyl-21-fusidate;
4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (4' -amino) aniline;
4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (3' -amino) aniline;
2- (21-fusidic acid benzyl ester-3 β -oxy) -2-oxo-benzoyl (4' -amino) aniline;
2- (21-fusidic acid benzyl ester-3 β -oxy) -2-oxo-benzoyl (3' -amino) aniline;
pharmacological tests and action mechanism researches prove that the fusidic acid derivative has tumor drug resistance reversing effect and definite action mechanism, and can be applied to development of novel tumor drug resistance reversing agents.
The fusidic acid derivatives and optical isomers of the above compounds or pharmaceutically acceptable solvates thereof.
The preparation method of the derivative is as follows.
The compound of the general formula I is prepared by the following synthesis method:
when R is1Is hydroxy, R2When the hydroxyl is adopted, the preparation steps comprise:
using fusidic acid as a raw material, and protecting 21-COOH by benzyl bromide in the presence of inorganic base;
when R is1Is hydroxy, R2When the group is oxo, the preparation steps comprise:
a. using fusidic acid as a raw material, and protecting 21-COOH by benzyl bromide in the presence of inorganic base;
b. oxidizing the 11-hydroxyl group with freshly prepared pyridinium chlorochromate;
when R is1Is oxo, R2When the hydroxyl is adopted, the preparation steps comprise:
a. using fusidic acid as a raw material, and protecting 21-COOH by benzyl bromide in the presence of inorganic base;
b. oxidizing the 3-hydroxyl group with freshly prepared pyridinium chlorochromate;
when R is1Is oxo, R2When the group is oxo, the preparation steps comprise:
a. using fusidic acid as a raw material, and protecting 21-COOH by benzyl bromide in the presence of inorganic base;
b. oxidizing the 3, 11-hydroxy groups with freshly prepared pyridinium chlorochromate;
when R is2Is hydroxy, R1When not hydroxy or oxo, the preparation steps comprise:
a. using fusidic acid as a raw material, and protecting 21-COOH by benzyl bromide in the presence of inorganic base;
b. reacting with anhydride or side chain of straight chain bromo acid in the presence of organic base and condensing agent;
c. in the presence of organic alkali and condensing agent, the diamine and aromatic nitrate side chains react or the diamine and the aromatic nitrate side chains are nitrified with silver nitrate to obtain straight-chain nitrate derivatives;
when R is2Is oxo, R1When not hydroxy or oxo, the preparation steps comprise:
a. using fusidic acid as a raw material, and protecting 21-COOH by benzyl bromide in the presence of inorganic base;
b. reacting with anhydride or side chain of straight chain bromo acid in the presence of organic base and condensing agent;
c. oxidizing the 11-hydroxyl group with freshly prepared pyridinium chlorochromate;
d. in the presence of organic alkali and condensing agent, the diamine and aromatic nitrate side chain react or the straight-chain nitrate derivative is obtained by nitration with silver nitrate.
Fusidic acid is a marketed antibacterial drug, has no tumor resistance reversal activity per se, and no report has been made on the tumor resistance reversal activity of a derivative thereof. The fusidic acid derivatives provided by the invention have obvious tumor drug resistance reversing activity. Among them, the tumor resistance reversal activity of example 1 was the strongest. Further mechanism of action studies showed that example 1 inhibits the efflux of paclitaxel by P-gp by increasing the activity of P-glycoprotein (P-gp) ATPase, rendering KBV cells sensitive to paclitaxel, resulting in cell arrest in the G2/M phase and induction of apoptosis. The fusidic acid derivative has tumor drug resistance reversing activity and a clear action mechanism.
Drawings
FIG. 1 is a graph of the effect of example 1 on P-gp activity in KBV cells.
FIG. 2 is a graph showing the effect of example 1 in combination with paclitaxel on cell cycle distribution and apoptosis.
FIG. 3 is a graph showing the effect of example 1 on P-gp ATPase activity.
Detailed Description
1. The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.
Example 1
21-fusidic acid benzyl ester
500mL of eggplant-shaped bottle was taken, fusidic acid (10.01g, 0.019mol) was dissolved in acetone (200mL), potassium carbonate (5.36g, 0.039mol) and benzyl bromide (2.78mL, 0.023mol) were added with stirring, and reacted at 30 ℃ for 5 to 7 hours. Vacuum filtering, concentrating, diluting with ethyl acetate (50mL), washing with 10% hydrochloric acid, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Chloroform:V Methanol210:1-190:1) to give 21-fusidic acid benzyl ester as a white solid (8.86g, 75.4%).1H-NMR (CDCl3,400MHz)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,OCOCH3),1.76-1.84(m,2H,2-H and 12-H),1.68-1.73(m,2H,2-H,7-H),1.62(s,3H,27-CH3),1.54-1.58(m,3H,1-H,6-H and 9-H),1.50(s,3H,26-CH3),1.43-1.46(m,1H,4-H),1.36(s,3H,30-CH3), 1.25-1.29(d,J＝14.20Hz,1H,15-H),1.04-1.14(m,2H,6-H and 7-H),0.96(s,3H, 19-CH3),0.90(s,3H,18-CH3),0.89(s,3H,28-CH3).
Example 2
3- (6-Nitro-hexanoyl) -21-fusidic acid benzyl ester
A25 mL eggplant-shaped bottle was taken, benzyl 21-fusidate (0.12mmol) was dissolved in anhydrous dichloromethane (10mL), bromohexanoic acid (0.18mmol) and DMAP (0.37mmol) were added with stirring,EDCI (0.38mmol), 5 drops of triethylamine, reacted at room temperature for 7-10 hours. Washing with 10% hydrochloric acid to acidity, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Petroleum ether:VEthyl acetate1-20:1) to give benzyl 3- (6-bromohexanoyl) -21-fusidate as a white solid.
A25 mL eggplant-shaped bottle was taken, benzyl 3- (6-bromohexanoyl) -21-fusidate (0.069mmol) was dissolved in 8mL of anhydrous acetonitrile, and silver nitrate (0.18mmol) was added with stirring to react at 70 ℃ for 18 hours in the dark. Filtering, concentrating, dissolving in ethyl acetate, sequentially washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Petroleum ether:VEthyl acetate20:1-8:1) to give a white solid (32mg, 65.4%).1H-NMR(CDCl3,400MHz)δ:7.30-7.36(m,5H,Ar-H),5.89(d,J＝8.32Hz, 1H,16-H),5.21(d,J＝12.19Hz,1H,CHAr),5.06(t,J＝7.10Hz,1H,24-H),4.93 (dd,J＝4.51,7.24Hz,1H,CHAr),4.32(s,1H,11-H),3.03(d,J＝11.02Hz,1H, 13-H),2.42-2.48(m,2H,2×22-H),2.27-2.32(m,1H,12-H),2.00-2.21(m,5H,1-H, 5-H,15-H and 2×23-H),1.93(s,3H,OCOCH3),1.82-1.86(m,2H,2-H and 12-H), 1.70-1.77(m,2H,2-H,7-H),1.64(s,3H,27-CH3),1.56-1.59(m,3H,1-H,6-H and 9-H),1.53(s,3H,26-CH3),1.50-1.53(m,1H,4-H),1.39(s,3H,30-CH3),1.23-1.28 (s,3H,15-H),1.04-1.18(m,2H,6-H and 7-H),0.98(s,3H,19-CH3),0.91(s,3H, 18-CH3),0.83(d,J＝6.72Hz,3H,28-CH3).
Example 3
3, 11-dicarbonyl-21-fusidic acid benzyl ester
A25 mL eggplant-shaped bottle was taken, benzyl 21-fusidate (60mg, 0.099mmol) was dissolved in 10mL dichloromethane, and fresh PCC (64mg, 0.30mmol) was added with stirring and stirred at room temperature for 4 to 8 hours. Removing solvent under reduced pressure, diluting with ethyl acetate (10mL), washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating solvent under reduced pressure, and performing silica gel column chromatography (V)Petroleum ether:VEthyl acetate10:1-6:1) to give a pale yellow solid (40mg, 66.7%).1H-NMR(CDCl3,400MHz)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 and 5-H),1.97-2.11(m,3H,2×2-H and 7-H),1.95(s,3H,OCOCH3), 1.81(t,J＝11.88Hz,1H,12-H),1.63(s,3H,27-CH3),1.56-1.60(m,3H,1-H,6-H and 9-H),1.52(s,3H,26-CH3),1.46(s,1H,4-H),1.42(s,1H,15-H),1.22-1.26(m, 2H,6-H and 7-H),1.20(s,3H,30-CH3),1.14(s,3H,19-CH3),1.05(s,3H,18-CH3), 1.04(s,3H,28-CH3).
Example 4
11-carbonyl-3- (5-Nitropoxy-pentanoyl) -21-fusidic acid benzyl ester
A25 mL eggplant-shaped bottle was taken, benzyl 21-fusidate (0.12mmol) was dissolved in anhydrous dichloromethane (10mL), bromovaleric acid (0.18mmol), DMAP (0.37mmol), EDCI (0.38mmol) and 5 drops of triethylamine were added with stirring, and the mixture was reacted at room temperature for 7 to 10 hours. Washing with 10% hydrochloric acid to acidity, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Petroleum ether:VEthyl acetate1-20:1) to give benzyl 11-carbonyl 3- (5-bromovaleryl) -21-fusidate as a white solid.
Starting from benzyl 11-carbonyl 3- (5-bromovaleryl) -21-fusidate and silver nitrate, reference was made to the preparation of benzyl 3- (6-nitrooxy-hexanoyl) -21-fusidate to give a white solid (34mg, 78.1%).1H-NMR(CDCl3,400MHz)δ:7.31-7.37(m,5H,Ar-H),5.91(d,J＝8.25Hz,1H, 16-H),5.21(d,J＝12.14Hz,1H,CHAr),5.04(t,J＝7.19Hz,1H,24-H),4.94(d,J＝ 12.21Hz,1H,CHAr),4.47(t,J＝5.93Hz,2H,-CH2-),2.89(dd,J＝4.09,13.13Hz, 1H,13-H),2.79-2.84(m,1H,22-H),2.63-2.72(m,2H,-CH2-),2.30-2.41(m,2H, 12-H and 22-H),2.05-2.20(m,5H,1-H,5-H,15-H and 2×23-H),1.95(s,3H, OCOCH3),1.86-1.92(m,4H,2×2-H,7-H and 12-H),1.82-1.84(m,4H,2×-CH2-), 1.71-1.81(m,4H,1-H,4-H,6-H and 9-H),1.63(s,3H,27-CH3),1.52(s,3H,26-CH3), 1.39-1.42(m,3H,15-H),1.21-1.27(m,2H,6-H and 7-H),1.18(s,3H,30-CH3),1.14 (s,3H,19-CH3),1.03(s,3H,18-CH3),0.81(d,J＝6.65Hz,3H,28-CH3).
Example 5
4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (4' -amino) aniline
A50 mL eggplant-shaped bottle was taken, benzyl 21-fusidate (420mg, 0.69mmol) was dissolved in anhydrous dichloromethane (20mL), succinic anhydride (346mg, 3.46mmol) and DMAP (254mg, 2.08mmol) were added with stirring, and the mixture was reacted at room temperature for 10 hours. Washing with 10% hydrochloric acid to acidity, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Chloroform:VMethanol150:1) to give 4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyric acid as a white solid.
A25 mL eggplant-shaped flask was taken, and p-phenylenediamine (31mg, 0.28mmol) was dissolved in anhydrous dichloromethane (5mL) and stirred at room temperature. 4- (21-fusidic acid benzyl ester-3. beta. -oxy) -4-oxo-butyric acid (40mg, 0.056mmol) was dissolved in anhydrous dichloromethane (5mL), DMAP (21mg, 0.17mmol) and EDCI (32mg, 0.16mmol) were added with stirring, and after dissolution, the solution was slowly dropped into a p-phenylenediamine solution, and reacted at room temperature for 10 hours. Washing with 10% hydrochloric acid to acidity, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Chloroform:VMethanol150:1) to give a white solid (26mg, 56.7%).1H-NMR(CDCl3, 400MHz)δ:8.07(s,1H,-NH-),7.30-7.36(m,5H,5×Ar-H),7.26(d,J＝8.68Hz,2H, 2×Ar-H),6.59(d,J＝8.67Hz,2H,2×Ar-H),5.88(d,J＝8.34Hz,1H,16-H),5.20(d, J＝12.20Hz,1H,CHAr),5.06(t,J＝7.11Hz,1H,24-H),4.92-4.94(m,2H,CHAr and 11-OH),4.28(s,1H,11-H),3.01(d,J＝11.33Hz,1H,13-H),2.74(t,J＝6.97Hz, 2H,-CH2-),2.62(t,J＝6.50Hz,2H,-CH2-),2.39-2.49(m,2H,2×22-H),2.26-2.29 (m,1H,12-H),2.07-2.18(m,5H,1-H,5-H,15-H and 2×23-H),1.99(s,3H, OCOCH3),1.91-1.95(m,2H,2-H and 12-H),1.70-1.80(m,2H,2-H and 7-H),1.63(s, 3H,27-CH3),1.52(s,3H,26-CH3),1.34(s,3H,30-CH3),1.26-1.30(m,1H,15-H), 1.20-1.23(m,4H,1-H,4-H,6-H and 9-H),1.02-1.14(m,2H,6-H and 7-H),0.95(s, 3H,19-CH3),0.90(s,3H,18-CH3),0.80(d,J＝6.56Hz,3H,28-CH3).
Example 6
4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (3' -amino) aniline
Starting from 4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyric acid and m-phenylenediamine, reference was made to the procedure for the preparation of 4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (4' -amino) aniline, resulting in a white solid (27 mg, 57.6%).1H-NMR(CDCl3,400MHz)δ:8.01(s,1H,-NH-),7.31-7.36(m,5H, 5×Ar-H),7.16(s,1H,Ar-H),7.04(t,J＝7.95Hz,1H,Ar-H),6.66(d,J＝7.85Hz,1H, Ar-H),6.40(d,J＝7.36Hz,1H,Ar-H),5.89(d,J＝8.30Hz,1H,16-H),5.21(d,J＝ 12.16Hz,1H,CHAr),5.06(t,J＝7.16Hz,1H,24-H),4.91-4.94(m,2H,CHAr and 11-OH),4.29(s,1H,11-H),3.02(d,J＝11.28Hz,1H,13-H),2.75(t,J＝5.57Hz,2H, -CH2-),2.65(t,J＝6.19Hz,2H,-CH2-),2.42-2.48(m,2H,2×22-H),2.26-2.29(m, 1H,12-H),2.07-2.16(m,3H,15-H and 2×23-H),1.97-2.04(m,2H,1-H,and 5-H), 1.93(s,3H,OCOCH3),1.72-1.79(m,2H,2-H and 12-H),1.66-1.71(m,2H,2-H and 7-H),1.64(s,3H,27-CH3),1.53(s,3H,26-CH3),1.35(s,3H,30-CH3),1.27-1.31(m, 1H,15-H),1.24-1.28(m,4H,1-H,4-H,6-H and 9-H),1.02-1.16(m,2H,6-H and C7-H),0.96(s,3H,19-CH3),0.90(s,3H,18-CH3),0.81(d,J＝6.68Hz,3H,28-CH3).
Example 7
2- (21-fusidic acid benzyl ester-3 β -oxy) -2-oxo-benzoyl (4' -amino) aniline
Starting from benzyl 21-fusidate and phthalic anhydride, reference is made to the preparation of 4- (benzyl 21-fusidate-3 β -oxy) -4-oxo-butyric acid, yielding 2- (benzyl 21-fusidate-3 β -oxy) -2-oxo-benzoic acid as a white solid.
Starting from 2- (21-fusidic acid benzyl ester-3 β -oxy) -2-oxo-benzoic acid and p-phenylenediamine, reference is made to 4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (4' -amino)Preparation of Aniline to give a white solid (35mg, 60.1%).1H-NMR(CDCl3,400MHz)δ:8.28(s,1H,-NH-),7.85(t,J＝ 4.44Hz,2H,2×Ar-H),7.52-7.58(m,2H,2×Ar-H),7.47(td,J＝1.46,7.59Hz,1H, Ar-H),7.40(t,J＝8.66Hz,1H,Ar-H),7.30-7.36(m,5H,5×Ar-H),6.65(t,J＝8.60 Hz,2H,2×Ar-H),6.38(d,J＝8.51Hz,2H,-NH2),5.87(d,J＝8.32Hz,1H,16-H), 5.19-5.25(m,2H,CHAr and 11-OH),5.07(t,J＝6.95Hz,1H,24-H),4.93(d,J＝ 12.19Hz,1H,CHAr),4.24(s,1H,11-H),3.02(d,J＝11.67Hz,1H,13-H),2.39-2.52 (m,2H,2×22-H),2.26-2.30(m,1H,12-H),2.07-2.18(m,3H,15-H and 2×23-H), 1.96-1.03(m,2H,1-H and 5-H),1.92(s,3H,OCOCH3),1.77-1.83(m,2H,2-H and 12-H),1.68-1.75(m,2H,2-H and 7-H),1.64(s,3H,27-CH3),1.54(s,3H,26-CH3), 1.33(s,3H,30-CH3),1.16-1.37(m,4H,1-H,4-H,6-H,9-H and 15-H),1.01-1.12(m, 2H,6-H and 7-H),0.95(s,3H,19-CH3),0.89(s,3H,18-CH3),0.88(d,J＝6.58Hz, 3H,28-CH3).
Example 8
2- (21-fusidic acid benzyl ester-3 β -oxy) -2-oxo-benzoyl (3' -amino) aniline
Starting from 2- (21-fusidic acid benzyl ester-3 β -oxy) -2-oxo-benzoic acid and m-phenylenediamine, reference was made to the preparation of 4- (21-fusidic acid benzyl ester-3 β -oxy) -4-oxo-butyryl (4' -amino) aniline, which yielded a white solid (31mg, 55.5%).1H-NMR(CDCl3,400MHz)δ:7.85(d,J＝7.63Hz,1H,Ar-H), 7.78(s,1H,Ar-H),7.54-7.57(m,2H,2×Ar-H),7.47-7.51(m,1H,Ar-H),7.30-7.37 (m,5H,5×Ar-H),7.06(t,J＝7.94Hz,1H,Ar-H),6.70(d,J＝7.70Hz,1H,Ar-H), 6.45(d,J＝7.36Hz,1H,Ar-H),5.87(d,J＝8.27Hz,1H,16-H),5.23(d,J＝2.14Hz, 1H,11-OH),5.21(d,J＝12.23Hz,1H,CHAr),5.06(t,J＝6.96Hz,1H,24-H),4.93 (d,J＝12.20Hz,1H,CHAr),4.23(s,1H,11-H),3.04(d,J＝11.55Hz,1H,13-H), 2.38-2.52(m,2H,2×22-H),2.26-2.30(m,1H,12-H),2.07-2.18(m,3H,15-H and 2×23-H),1.96-1.04(m,2H,1-H and 5-H),1.92(s,3H,OCOCH3),1.77-1.83(m,2H, 2-H and 12-H),1.70-1.74(m,2H,2-H and 7-H),1.65(s,3H,27-CH3),1.54(s,3H, 26-CH3),1.34(s,3H,30-CH3),1.23-1.38(m,4H,1-H,4-H,6-H,9-H and 15-H), 1.00-1.12(m,2H,6-H and 7-H),0.94(s,3H,19-CH3),0.89(s,3H,18-CH3),0.83(d, J＝6.12Hz,3H,28-CH3).
2. The following are the results of pharmacological experiments with some of the compounds of the invention.
(1) The experimental method comprises the following steps: examples 1-8 detection of the survival Rate of the antitumor drug paclitaxel in KBV resistant Strain cells
Cell plating: taking KBV drug-resistant strain cells with good growth state in logarithmic phase, adding culture medium after trypsinization, and gently blowing and beating to obtain single cell suspension. After cell counting, the cell concentration was diluted to 3-4X 10 with the medium4cells/mL were seeded in a 96-well cell plate culture plate at a volume of 100. mu.L/well, and were left to stand in a carbon dioxide incubator.
Cell administration: after 24h of cell plating, 5. mu.M of each of the different compounds was added in combination with 100nM of Paclitaxel and corresponding solvent control cultures. Each set of 3 parallel wells. And (4) after the medicine is added, placing the 96-well plate in an incubator, and performing static culture for 72 hours.
MTT detection: after the cells were cultured for 72 hours after administration of the corresponding drugs, the cell viability was examined.
(2) The experimental results are as follows:
examples 1-8 cell viability when administered alone and in combination is shown in table 1.
Examples 1-8 survival analysis of antitumor drug paclitaxel in KBV resistant strain cells:
the survival rate evaluation result of KBV drug-resistant strain cells of the derivative shows that fusidic acid has no tumor drug resistance reversal activity per se, and examples 1-8 have better tumor drug resistance reversal activity, wherein the activity is the best in example 1.
TABLE 1 cell viability in examples 1-8 alone and in combination
3. The following is a study experiment of the mechanism of action of example 1.
(1) The experimental method comprises the following steps:
intracellular rhodamine 123 accumulation assay:
KBV cells were treated with or without the indicated concentration of sample for 2 hours, then 10 μ M rhodamine 123 was added and incubated for about half an hour. The cells were washed three times with PBS buffer, and the mean fluorescence intensity of 10000 cells was automatically calculated using a flow cytometer.
Cell cycle analysis:
KBV cells were cultured in 6-well plates for 24 hours, treated with a sample of a certain concentration for 24 hours, harvested and fixed in 70% ethanol solution overnight at-20 ℃, washed with phosphate buffered saline, and then treated with propidium iodide solution (phosphate buffered saline containing 20mg/mL propidium iodide and 20mg/mL RNaseA) for half an hour. Cell fluorescence values were measured and cell cycle distribution was analyzed using a flow cytometer.
Determination of ATPase Activity:
the diluted P-gp protein is placed in a well plate containing the sample or positive control and verapamil. After incubation at 37 ℃ for about 5 minutes, Mg-ATP was added and the solution was mixed and then incubated at 37 ℃ for 40 minutes. ATP detection reagent was added to stop the reaction and the solution was mixed, and then the well plate was left at room temperature for 20 minutes. Values were read by a SpectraMax M5 multifunctional microplate reader.
(2) The experimental results are as follows:
FIG. 1 is a graph of the effect of example 1 on P-gp activity in KBV cells. Rhodamine 123, as a P-gp substrate, is commonly used as a biomarker to explore the effect of compounds on P-gp efflux function. The accumulation of rhodamine 123 in KBV cells increased in the experimental group with 10 μ M addition of example 1, indicating that 10 μ M of example 1 caused KBV cells to reduce efflux of paclitaxel by acting on P-gp.
FIG. 2 is a graph showing the effect of example 1 in combination with paclitaxel on cell cycle distribution and apoptosis. As can be seen, example 1 at 5. mu.M and 10. mu.M reversed the resistance of KBV cells to paclitaxel, wherein an increase in the proportion of cells in Sub-G1 phase was observed after 24h of the combined use of example 1 and paclitaxel, and an increase in the proportion of cells in G2/M phase was observed in the 5. mu.M or 10. mu.M experimental group combined use of example 1 and paclitaxel compared to the other experimental group, indicating that it could effectively arrest KBV cells at G2/M phase and induce their apoptosis.
FIG. 3 is a graph showing the effect of example 1 on P-gp ATPase activity. As can be seen from the figure, both example 1 and verapamil significantly increased the rate of ATP consumption, indicating that example 1 enhanced the activity of P-gp ATPase.
The research result of action mechanism shows that example 1 inhibits the efflux of paclitaxel by P-gp by enhancing the activity of P-gp ATPase, so that KBV cells are sensitive to paclitaxel, thereby causing the cells to block in the G2/M phase and inducing apoptosis.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (1)
1. Fusidic acid derivatives and pharmaceutically acceptable salts thereof, characterized in that said fusidic acid derivatives are:
3- (6-nitrooxy-hexanoyl) -21-fusidic acid benzyl ester;
11-carbonyl-3- (5-nitrooxy-pentanoyl) -21-fusidic acid benzyl ester;
benzyl 3, 11-dicarbonyl-21-fusidate;
4- (21-fusidic acid benzyl ester-3)β-oxy) -4-oxo-butyryl (4' -amino) aniline;
4-(21-fusidic acid benzyl ester-3β-oxy) -4-oxo-butyryl (3' -amino) aniline;
4- [2- (21-fusidic acid benzyl ester-3 β -oxycarbonyl) benzamido ] aniline;
3- [2- (21-fusidic acid benzyl ester-3 beta-oxycarbonyl) benzamido ] aniline.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4004004A (en) * | 1974-09-12 | 1977-01-18 | Leo Pharmaceutical Products Ltd. A/S | Fusidic acid derivatives |
| CN108659091A (en) * | 2018-05-24 | 2018-10-16 | 烟台大学 | novel fusidic acid derivatives and its synthesis preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4004004A (en) * | 1974-09-12 | 1977-01-18 | Leo Pharmaceutical Products Ltd. A/S | Fusidic acid derivatives |
| CN108659091A (en) * | 2018-05-24 | 2018-10-16 | 烟台大学 | novel fusidic acid derivatives and its synthesis preparation method and application |
Non-Patent Citations (1)
| Title |
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| Discovery, synthesis of novel fusidic acid derivatives possessed aminoterminal groups at the 3-hydroxyl position with anticancer activity;Jingxuan Ni et al.;《European Journal of Medicinal Chemistry》;20181103;第162卷;122-131 * |
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