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Hydroxyl phosphate amino acid ester derivatives of Brefeldin A, preparation method thereof, and application thereof

A technology of hydroxyphosphate amino acid ester and hydroxyphosphate amino acid, applied in the field of fungal metabolites, can solve problems such as low activity

Inactive Publication Date: 2012-10-17
TIANJIN LINMEI TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2004, Shanghai Organic Institute published an article on the total synthesis of (+)-Brefeldin A, but it was only used as a research on the synthesis method
The results of biological tests showed that both alkylated and acylated (+)-Brefeldin A had certain antitumor activity, but their activity was low; while the oxidized (+)-Brefeldin A had no activity, indicating that the 4-position and 7-position The hydroxyl group on (+)-BrefeldinA plays an important role in the biological activity of

Method used

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  • Hydroxyl phosphate amino acid ester derivatives of Brefeldin A, preparation method thereof, and application thereof
  • Hydroxyl phosphate amino acid ester derivatives of Brefeldin A, preparation method thereof, and application thereof
  • Hydroxyl phosphate amino acid ester derivatives of Brefeldin A, preparation method thereof, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] In a 25mL round bottom flask, add 0.5mmol of (+)-Brefeldin A, 2mmol of phosphorylated alanine, 0.05mmol of 4-dimethylaminopyridine, add 10mL of anhydrous dichloromethane under argon protection, Add 2 mmol of dicyclohexylcarbodiimide dropwise to the reaction system under ice-water bath 2 Cl 2 After the solution was added dropwise, it was stirred overnight at room temperature, and after the completion of the reaction was monitored by thin-layer chromatography, the insoluble matter (DCU) was filtered off, and the filtrate was concentrated under reduced pressure. Using V (petroleum ether): V (ethyl acetate) = 1: 3, the pure product (D-02) was obtained with a yield of 90%. (spectral data, 31 P-NMR (CDCl 3 ):δ=5.08,4.93ppm; 1 H-NMR (400MHz, CDCl 3 ):δ7.21(dd,J=15.9,3.5Hz,1H),5.66-5.78(m,2H),5.13-5.31(m,3H),4.82-4.93(m,1H),4.53-4.66(m ,4H),3.94-4.03(m,1H),3.82-3.92(m,1H),3.20(q,J=8.7Hz,2H),2.41-2.53(m,1H),2.30-2.40(m,1H ),1.99-2.21(m,4H),1.80-1.86(m,1H),1.68-1.78(m,2H),...

Embodiment 2

[0062] Dissolve 280 mg (1 mmol) of (+)-Brefeldin A and 82 mg (1.2 mmol) of imidazole in 10 mL of dry DMF, and cool in an ice-water bath. 165 mg (1.1 mmol) of TBSCl was dissolved in 5 mL of dry DMF, and the solution was slowly added dropwise to the above-mentioned system with a syringe, stirred at room temperature for 24 h, and after the TLC plate monitored that the reaction was complete, 20 mL of an organic solvent ( II) After dilution, wash with 3 x 10 mL of water. The organic phase was concentrated under reduced pressure. Use V (petroleum ether): V (ethyl acetate) = 8: 1 to pass through the column to obtain the pure product (+)-BrefeldinA protected by TBS at position 7 (code: BFA-7TBS), with a yield of 86%. Add 0.5mmol of BFA-7TBS, 1mmol of phosphorylated alanine, and 0.05mmol of 4-dimethylaminopyridine into a 25mL round bottom flask, add 10mL of anhydrous dichloromethane under the protection of argon, and place in an ice-water bath Add 1 mmol of dicyclohexylcarbodiimide i...

Embodiment 3

[0064] Add 0.5mmol of (+)-Brefeldin A protected by TBS at position 4, 1mmol of DIPP-Ala, 0.05mmol of 4-dimethylaminopyridine into a 25mL round-bottomed flask, add 10mL of anhydrous di Chloromethane, add 1mmol of CH dicyclohexylcarbodiimide dropwise to the reaction system under ice-water bath 2 Cl 2 After the solution was added dropwise, it was stirred overnight at room temperature, and after the completion of the reaction was monitored by thin-layer chromatography, the insoluble matter (DCU) was filtered off, and the filtrate was concentrated under reduced pressure. Using petroleum ether: ethyl acetate at a ratio of 1:3 to pass through the column, the yield of pure product was 92%. In a 10 mL round bottom flask, add 0.3 mmol of (+)-Brefeldin A-7-hydroxy phosphate amino acid ester protected by TBS at position 4, add 5 mL of CH 3 OH, after the product dissolves, add 0.02mg of I to the reaction system 2 , react at 60°C for 16h, after the reaction is complete, add 1mol / L Na dro...

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Abstract

The invention relates to hydroxyl phosphate amino acid ester derivatives of Brefeldin A, a preparation method thereof, and an application thereof. The invention relates to a fungal metabolite. The derivatives comprises (+)-Brefeldin A-4,7-dihydroxyl phosphate amino acid ester, (+)-Brefeldin A-4-hydroxyl phosphate amino acid ester, and (+)-Brefeldin A-7-hydroxyl phosphate amino acid ester. According to the invention, Brefeldin A hydroxyl phosphate amino acid ester derivatives with high bioactivity, good dissolubility, and good bioavailability are synthesized. The derivatives are simple to prepare, and the cost is low. The derivatives are advantaged in novel structure, relatively stable structure, and substantial inhibitive activities against tumor cell proliferation. Compared with the original medicine (+)-Brefeldin A, the derivatives are advantaged in good dissolubility and long half-life period. The Brefeldin A hydroxyl phosphate amino acid ester derivatives can be applied in the preparations of anticancer medicines.

Description

technical field [0001] The invention relates to a fungal metabolite, in particular to a brefeldin A hydroxyphosphoric acid amino acid ester derivative and a preparation method and application thereof. Background technique [0002] (1), (+)-Brefeldin A research summary [0003] Brefeldin A (English name: (+)-Brefeldin A, referred to as BFA, Chinese name: Brefeldin A, also known as clindamycin or cyanin or ascosporine), is A macrolide fungal metabolite, first isolated from Penicillium decumben by Singleton et al. in 1958. Although the planar structure of BFA has been determined long ago, its absolute configuration was not established by Weber et al. by X-ray crystallography until 1971. Its structural formula is as follows: [0004] [0005] (+)-BrefeldinA has a wide range of biological activities, including anti-virus, anti-fungal, anti-nematode, anti-mitosis and anti-tumor. The transfer of proteins to the Golgi complex, thereby blocking the transport of proteins from th...

Claims

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Application Information

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IPC IPC(8): C07F9/655A61K31/665A61P35/00A61P35/02
Inventor 方美娟庄荣强程宏明唐果赵玉芬
Owner TIANJIN LINMEI TECH
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