CN112159455B - Fusidic acid A-ring amino thiazole ring derivative and preparation method thereof - Google Patents
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Abstract
The invention discloses a fusidic acid A-ring amino thiazole ring derivative and a preparation method thereof. The preparation method comprises the following steps: when R is1When the hydroxyl is adopted, the preparation steps comprise: a. oxidizing 3-hydroxy group with pyridine chlorochromate; b. under the alkaline condition and the action of a catalyst, reacting the product obtained in the step a with alcohol or benzyl bromide; c.b, reacting the product obtained in the step c.b with pyridinium tribromide and thiourea in sequence to obtain the catalyst. When R is1When the group is oxo, the preparation steps comprise: a. oxidizing 3, 11-hydroxy with pyridine chlorochromate; b. under the alkaline condition and the action of a catalyst, reacting the product obtained in the step a with alcohol or benzyl bromide; c.b, reacting the product obtained in the step c.b with pyridinium tribromide and thiourea in sequence to obtain the catalyst. The fusidic acid derivative can obviously improve the sensitivity of tumor drug-resistant cells KBV which are resistant to the paclitaxel, so that the paclitaxel can still generate good anti-tumor activity to the paclitaxel at an extremely low concentration.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to fusidic acid A cycloaminothiazole ring derivatives with novel structures, a pharmaceutical composition containing the same and a preparation method thereof.
Technical Field
Malignant tumors are a serious threat to human health, and chemotherapy is currently one of the major methods for treating malignant tumors. Statistically, over 960 ten thousand tumor patients died in 2018, and studies have shown that multidrug resistance (MDR) of tumor cells to chemotherapeutic drugs is one of the major causes of chemotherapy failure. The natural products have the characteristic of various structures and become important sources for finding medicines or good lead compounds for treating serious diseases. The search and development of novel compounds with novel structure, low toxicity, safety and high MDR reversal activity from natural products is the hot content of research of tumor therapeutics and pharmacology.
Fusidic Acid (FA), a narrow spectrum highly potent antibiotic isolated from the fungus fusarium coccineum, is used in the treatment of skin infections, osteoarticular infections, burn infections, etc. caused by staphylococcus aureus and several other gram-positive bacteria. Fusidic acid has been extensively studied since its introduction in 1962, but has primarily focused on its antibacterial aspects.
Disclosure of Invention
The invention aims to provide a fusidic acid derivative with tumor drug resistance reversal activity and a novel structure and a preparation method thereof, and has important significance for developing a novel tumor drug resistance reversal agent.
The invention is realized by the following technical scheme:
a-cycloaminothiazole ring derivatives of fusidic acid shown in general formula I and pharmaceutically acceptable salts thereof,
wherein:
general formula I: r1Represents hydroxy, oxo;
R2represents OR3、
R3Represents H, halogen substituted or unsubstituted benzyl;
x represents C, N;
y represents F, Cl or Br.
Preferably, the A-ring aminothiazole ring derivatives of fusidic acid shown in the general formula I and pharmaceutically acceptable salts thereof,
wherein, the general formula I: r1Represents hydroxy, oxo;
R2represents OR3、
R3Represents H, benzyl;
x represents C, N;
y represents Cl.
Preferably, the A-ring aminothiazole ring derivatives of fusidic acid shown in the general formula I and pharmaceutically acceptable salts thereof,
wherein, the general formula I:
16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 α,10 β -cholest- (17Z) -17(20), benzyl 24-diene-21-oate;
16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-oic acid (7-azabenzotriazole-1) ester;
16 beta-acetoxyl-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-acid (6-chloro-1H-benzotriazole-1) ester;
16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 α,10 β -cholest- (17Z) -17(20), 24-diene-21-oic acid (1,2, 3-benzotriazin-4 (3H) -one-3) ester;
16 beta-acetoxyl group-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-acid (1H-benzotriazole-1) ester.
The application of fusidic acid A-ring amino thiazole ring derivatives shown in the general formula I and pharmaceutically acceptable salts thereof in preparing tumor drug resistance reversal agents and pharmaceutically acceptable carriers.
A process for the preparation of a Cycloaminothiazolo ring derivative of fusidic acid of general formula I and pharmaceutically acceptable salts thereof, when R is1When the hydroxyl is adopted, the preparation steps comprise:
a. oxidizing 3-hydroxy group with pyridine chlorochromate;
b. under the alkaline condition and the action of a catalyst, reacting the product obtained in the step a with alcohol or benzyl bromide;
c.b, reacting the product obtained in the step c.b with pyridinium tribromide and thiourea in sequence to obtain the catalyst.
When R is1When the group is oxo, the preparation steps comprise:
a. oxidizing 3, 11-hydroxy with pyridine chlorochromate;
b. under the alkaline condition and the action of a catalyst, reacting the product obtained in the step a with alcohol or benzyl bromide;
c.b, reacting the product obtained in the step c.b with pyridinium tribromide and thiourea in sequence to obtain the catalyst.
The invention relates to the use of fusidic acid derivatives of general formula I and pharmaceutically acceptable salts thereof for the preparation of tumour resistance-reversing agents and/or pharmaceutically acceptable carriers for the treatment of animals, preferably human diseases or conditions.
The effective amount of the tumor drug resistance reversal agent prepared from the fusidic acid derivative of the general formula I and the medically acceptable salt thereof is used together with clinical antitumor drugs for treating diseases or symptoms such as gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer. Preferably, the clinical antitumor drug is paclitaxel.
Fusidic acid is an antibacterial drug on the market, and has no tumor resistance reversion activity, and the fusidic acid derivative with the general formula I enables the sensitivity of tumor resistance cells KBV with drug resistance to paclitaxel to be obviously improved, so that paclitaxel can still generate good antitumor activity to the cells with very low concentration, and the pharmacological test of the specific implementation mode part can be seen.
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
16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 α,10 β -cholest- (17Z) -17(20), 24-diene-21-oic acid benzyl ester
500mL of eggplant-shaped bottle was taken, fusidic acid (10.0g, 19.4mmol) was dissolved in anhydrous dichloromethane (200mL), freshly prepared PCC (5.4g, 25.2mmol) was added, and the reaction was stirred at room temperature for 5 hours. After the reaction, the mixture was diluted with dichloromethane, washed with water, washed with saturated brine, and dried over sodium sulfateDrying, filtering, concentrating, and performing silica gel column chromatography (V)Chloroform:VMethanol100:1) to give X1 as a white solid (3.2g, 32.5%).
A250 mL eggplant-shaped bottle was taken, X1(2.5g, 4.9mmol) was dissolved in DMF (100mL), potassium carbonate (1.4g, 9.7mmol) and benzyl bromide (0.9mL, 7.3mmol) were added, and the reaction was stirred at 50 ℃ for 6 hours. After the reaction is finished, diluting with ethyl acetate, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (V)Chloroform:VMethanol100:1) to yield X2(2.2g, 74.5%) as a white solid.
A100 mL eggplant-shaped bottle was taken, X2(1.0g, 1.7mmol) was dissolved in chloroform (40mL), pyridinium tribromide (0.8g, 2.4mmol) was added, and the reaction was stirred at room temperature for 8 hours. After the reaction is finished, the solvent is evaporated, the ethyl acetate is diluted, the mixture is washed by water, the saturated salt solution is washed by water, the anhydrous sodium sulfate is dried, the mixture is filtered, the concentration is carried out, and the silica gel column chromatography (V) is carried outChloroform:VMethanol100:1) to yield X3(0.6g, 52.5%) as a white solid.
A50 mL eggplant-shaped bottle was taken, X3(100mg, 146. mu. mol) was dissolved in absolute ethanol (30mL), thiourea (54.5mg, 0.7mmol) was added, and the reaction was refluxed at 80 ℃ for 6 hours. After the reaction is finished, the solvent is evaporated and silica gel column chromatography is carried out (V)Chloroform:VMethanol90:1) to give a pale yellow solid (60.5mg, 62.8%).1H-NMR(CDCl3,400MHz)δ:7.45-7.28(m,5H,5×Ar-H),5.93(d,J＝8.40Hz,1H,16-H),5.24(d,J＝12.20Hz,1H,CHAr),5.09(t,J＝7.20Hz,1H,24-H),4.96(d,J＝12.20Hz,1H,CHAr),4.40(s,1H,11-H),3.70-3.68(m,1H,4-H),3.49-3.47(m,1H,1-H),3.25-3.21(m,1H,1-H),3.04(d,J＝11.50Hz,1H,13-H),2.49-2.42(m,2H,2×22-H),2.37-2.28(m,1H,12-H),2.26-2.00(m,4H,15-H,2×23-H and 5-H),1.95(s,3H,OCOCH3),1.93-1.76(m,2H,12-H and 7-H),1.66(s,3H,27-CH3),1.65-1.57(m,2H,6-H and 9-H),1.55(s,3H,26-CH3),1.31(s,3H,30-CH3),1.36-1.27(m,3H,15-H,6-H and 7-H),1.01(s,3H,19-CH3),0.97(s,3H,18-CH3),0.89(s 3H,28-CH3).
Example 2
16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-oic acid (7-azabenzotriazole-1) ester;
synthetic method reference example 1 gave a pale yellow solid (66.8mg, 69.0%).1H-NMR(CDCl3,400MHz)δ:8.53-8.50(m,1H,Pyr-H),8.25-8.20(m,1H,Pyr-H),7.30-7.27(m,1H,Pyr-H),5.85(d,J＝8.40Hz,1H,16-H),5.09(t,J＝7.20Hz,1H,24-H),4.38(s,1H,11-H),4.16-4.12(m,1H,4-H),4.00-3.96(m,1H,1-H),3.23-3.18(m,1H,1-H),3.03(d,J＝11.50Hz,1H,13-H),2.48-2.45(m,2H,2×22-H),2.37-2.28(m,1H,12-H),2.26-2.00(m,4H,15-H,2×23-H and 5-H),1.95(s,3H,OCOCH3),1.93-1.85(m,2H,12-H and 7-H),1.66(s,3H,27-CH3),1.63-1.60(m,2H,6-H and 9-H),1.58(s,3H,26-CH3),1.27(s,3H,30-CH3),1.23(s,3H,19-CH3),0.92(s,3H,18-CH3),0.89(s,3H,28-CH3).
Example 3
16 beta-acetoxyl-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-acid (6-chloro-1H-benzotriazole-1) ester;
synthetic method reference example 1 gave a pale yellow solid (62.9mg, 64.9%).1H-NMR(CDCl3,400MHz)δ:7.72-7.69(m,1H,Ar-H),7.60(s,1H,Ar-H),7.21(m,1H,Ar-H),5.86(d,J＝8.40Hz,1H,16-H),5.07(t,J＝7.20Hz,1H,24-H),4.33(s,1H,11-H),4.21-4.18(m,1H,4-H),4.01-3.98(m,1H,1-H),3.21-3.16(m,1H,1-H),3.02(d,J＝11.50Hz,1H,13-H),2.44-2.38(m,2H,2×22-H),2.37-2.28(m,1H,12-H),2.26-2.00(m,4H,15-H,2×23-H and 5-H),1.96(s,3H,OCOCH3),1.93-1.76(m,2H,12-H and 7-H),1.66(s,3H,27-CH3),1.65-1.59(m,2H,6-H and 9-H),1.58(s,3H,26-CH3),1.28(s,3H,30-CH3),1.24(s,3H,19-CH3),0.91(s,3H,18-CH3),0.87(s,3H,28-CH3).
Example 4
16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 α,10 β -cholest- (17Z) -17(20), 24-diene-21-oic acid (1,2, 3-benzotriazin-4 (3H) -one-3) ester;
synthetic method reference example 1 gave a pale yellow solid (60.3mg, 62.2%).1H-NMR(CDCl3,400MHz)δ:8.36-8.34(m,1H,Ar-H),8.21-8.19(m,1H,Ar-H),8.00-7.98(m,1H,Ar-H),7.84-7.80(m,1H,Ar-H),5.96(d,J＝8.40Hz,1H,16-H),5.19(t,J＝7.20Hz,1H,24-H),4.40(s,1H,11-H),3.42-3.40(m,1H,4-H),3.25-3.15(m,2H,2×1-H),3.14(d,J＝11.50Hz,1H,13-H),2.44-2.38(m,2H,2×22-H),2.37-2.28(m,1H,12-H),2.26-2.20(m,4H,15-H,2×23-H and 5-H),2.08(s,3H,OCOCH3),1.93-1.76(m,2H,12-H and 7-H),1.66(s,3H,27-CH3),1.65-1.59(m,2H,6-H and 9-H),1.42(s,3H,26-CH3),1.27(s,3H,30-CH3),1.24(s,3H,19-CH3),1.01(s,3H,18-CH3),0.95(s,3H,28-CH3).
Example 5
16 beta-acetoxyl-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-oic acid (1H-benzotriazole-1) ester
Synthetic method reference example 1 gave a pale yellow solid (68.7mg, 71.0%).1H-NMR(CDCl3,400MHz)δ:7.77-7.75(m,1H,Ar-H),7.67-7.66(m,1H,Ar-H),7.36-7.33(m,2H,Ar-H),5.86(d,J＝8.40Hz,1H,16-H),5.08(t,J＝7.20Hz,1H,24-H),4.35(s,1H,11-H),3.76-3.72(m,1H,4-H),3.50-3.40(m,1H,1-H),3.36-3.32(m,1H,1-H),3.12-3.10(m,1H,13-H),2.49-2.42(m,2H,2×22-H),2.37-2.28(m,1H,12-H),2.26-2.00(m,4H,15-H,2×23-H and 5-H),1.95(s,3H,OCOCH3),1.93-1.76(m,2H,12-H and 7-H),1.64(s,3H,27-CH3),1.65-1.59(m,2H,6-H and 9-H),1.57(s,3H,26-CH3),1.23(s,3H,30-CH3),1.11(s,3H,19-CH3),1.05(s,3H,18-CH3),0.90(s,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 1-5 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 pancreatin digestion, and lightly blowing and beating into single fineAnd (3) suspending the cells. 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, 10. 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 1-5 cell viability when administered alone and in combination is shown in Table 1.
TABLE 1 cell viability of examples 1-5 when administered alone and in combination
Examples 1-5 survival assay 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 1-5 have better tumor drug resistance reversal activity, wherein the activity is best in example 3, and the effect is better than the activity of a common antitumor drug Verapamil (Verapamil) 40.37 +/-2.62%. In examples 1 to 5, aminothiazole rings as heterocyclic amines are introduced into a structure to easily form a plurality of functions such as hydrogen bonds, hydrophobic interaction, coordination bonds and the like with targets, so that fusidic acid derivatives with novel structures are prepared, and meanwhile, the novel application of the derivatives in the field of tumor drug resistance reversal is provided, so that the method has important significance for developing novel tumor drug resistance reversal agents.
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 as follows:
16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 α,10 β -cholest- (17Z) -17(20), benzyl 24-diene-21-oate;
16 beta-acetoxy-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-oic acid (7-azabenzotriazole-1) ester;
16 beta-acetoxyl-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-acid (6-chloro-1H-benzotriazole-1) ester;
16 β -acetoxy-11 α -hydroxy-4 α,8 α,14 β -trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 α,10 β -cholest- (17Z) -17(20), 24-diene-21-oic acid (1,2, 3-benzotriazin-4 (3H) -one-3) ester;
16 beta-acetoxyl group-11 alpha-hydroxy-4 alpha, 8 alpha, 14 beta-trimethyl-2, 3-and [2,3-b ] aminothiazole-18-nor-5 alpha, 10 beta-cholest- (17Z) -17(20), 24-diene-21-acid (1H-benzotriazole-1) ester.
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| CN108794564A (en) * | 2018-08-03 | 2018-11-13 | 烟台大学 | Hederagenin A rings and pyrazines derivatives and its preparation method and application |
| CN106749494B (en) * | 2017-02-06 | 2019-03-12 | 烟台大学 | With the active α of tumor drug resistance reversal-hederagenin derivative and its preparation method and application |
| CN109608512A (en) * | 2018-11-21 | 2019-04-12 | 烟台大学 | With the active fusidic acid derivatives of tumor drug resistance reversal and its synthesis preparation method |
| CN109662969A (en) * | 2018-11-21 | 2019-04-23 | 烟台大学 | The tumor drug resistance reversal activity application of a kind of fusidic acid derivatives |
| CN111471080A (en) * | 2020-05-26 | 2020-07-31 | 烟台大学 | ocotillol type ginsengenin A-ring amino thiazole ring derivative and preparation method thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749494B (en) * | 2017-02-06 | 2019-03-12 | 烟台大学 | With the active α of tumor drug resistance reversal-hederagenin derivative and its preparation method and application |
| CN108794564A (en) * | 2018-08-03 | 2018-11-13 | 烟台大学 | Hederagenin A rings and pyrazines derivatives and its preparation method and application |
| CN109608512A (en) * | 2018-11-21 | 2019-04-12 | 烟台大学 | With the active fusidic acid derivatives of tumor drug resistance reversal and its synthesis preparation method |
| CN109662969A (en) * | 2018-11-21 | 2019-04-23 | 烟台大学 | The tumor drug resistance reversal activity application of a kind of fusidic acid derivatives |
| CN111471080A (en) * | 2020-05-26 | 2020-07-31 | 烟台大学 | ocotillol type ginsengenin A-ring amino thiazole ring derivative and preparation method thereof |
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