Ester derivative of amphotericin B and application of ester derivative

A technology for amphotericin and medicine, which is applied in the field of ester derivatives of amphotericin B and its use as an antifungal agent, and can solve the problems of poor water solubility of amphotericin B and the like

Active Publication Date: 2020-10-20
SHENZHEN CHILDRENS HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In summary, although a variety of structural modifications to amphotericin B have been reported in the literature, it is still necessary to develop new amphotericin B derivatives that can reduce its antibacterial activity while maintaining antibacterial activity. Nephrotoxicity, red blood cell hemolytic toxicity, etc., and can also solve the problem of poor water solubility of amphotericin B

Method used

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  • Ester derivative of amphotericin B and application of ester derivative
  • Ester derivative of amphotericin B and application of ester derivative
  • Ester derivative of amphotericin B and application of ester derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1) Weigh amphotericin B (1.033g, 1.12mmol), Fmoc-Osu (0.852g, 2.52mmol), add to a 250mL round bottom flask, use ultra-dry DMF (60mL) and methanol (30mL) as a mixed solvent , after stirring to dissolve, pyridine (99%, 0.85 mL) was added dropwise. Under nitrogen atmosphere, the reaction was carried out at room temperature and protected from light for 24 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, most of the solvent was distilled off under reduced pressure. Then it was added dropwise into a cold diethyl ether (200 mL) solution, and a pale yellow solid was precipitated, and the crude product was collected by centrifugation or vacuum filtration. Purified by flash column chromatography to obtain 1.05g of compound 1, yield: 81.8%; m / z: 1145.5 [M-H + ].

[0044] 2) Dissolve compound 1 (575mg, 0.5mmol) and 1,4-butanediol (360mg, 4mmol) in 10mL of anhydrous THF, add DMAP (61.0mg, 0.5mmol) and DCC (390mg, 1.5mmol) ...

Embodiment 2

[0048] Example 2 In Vitro Activity Test

[0049] Antifungal activity in vitro was determined using a serial dilution method in 96-well microplates in buffered medium RPMI 1640 pH 7.0 according to standard methods (National Committee for Clinical Laboratory Standards). At wavelength λ=531nm (A 531 ), the optical density of the cell suspension was measured using a microplate reader. On the basis of the obtained results, a graph of the relationship between the A531 value and the concentration of the test compound was made. From these graphs, read the IC50 value, which is the interpolated concentration of the test compound at which A 531 The value is exactly the A of the control sample 531 50% of the value. In addition, the MIC value, which is the lowest concentration of the test compound at which A 531 The value is the measured A of the control sample 531 A maximum of 20% of the value.

[0050] Blood toxicity assays were performed by serial dilution according to known meth...

Embodiment 3

[0053] Example 3 Cytotoxicity Test to Mammalian Cells

[0054] Cell lines used for detection: CCRF-CEM-human acute lymphoblastic leukemia; HepG2-human malignant liver cancer, LLC-PK1-pig kidney epithelial cells; all cell lines were purchased from commercial sources.

[0055] Culture CCRF-CEM cells in RPMI 1640+10% fetal bovine serum (FBS) medium, culture LLC-PK1 cells in medium 199+3% FBS medium, culture HepG2 cells in MEM+10% FBS medium . All media contained 100 μg / ml of penicillin G and streptomycin. will be 1.2×10 4 An amount of cells / well of cells was seeded in a 24-well microplate containing an appropriate medium and allowed to stand overnight. Next, test compounds were added in a volume of 10 μl (serial 2x dilutions) as a solution in dimethyl sulfoxide (DMSO). Add 10 μl of DMSO to the control wells. The microplate with the cell suspension was incubated at a temperature of 37° C. for 120 hours in an atmosphere of 95% / 5% CO 2 . After incubation, add 200 μl of 3-(4,5-...

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Abstract

The invention discloses an ester derivative of amphotericin B. The ester derivative of the amphotericin B widens the range of an existing antibacterial compound and can be used as a lead compound forcontinuous optimization. Meanwhile, the compound has good antibacterial activity, and the antibacterial activity of the compound is better than that of the amphotericin B; and compared with the amphotericin B, the compound has lower blood toxicity and cytotoxicity, and can reduce the toxic and side effects of the amphotericin on the human body while maintaining the antibacterial activity.

Description

technical field [0001] The present invention relates to an ester derivative of amphotericin B and its use as an antifungal agent. Background technique [0002] With the rapid development of social economy and the improvement of people's living standards, at the same time, human life and health are also being threatened more and more. The use of a large number of drugs, while saving human lives, has also "cultivated" some superbugs that are increasingly difficult to kill. Instead, it generally refers to those bacteria that are resistant to multiple antibiotics. Its accurate name should be "multi-drug resistant bacteria". This kind of bacteria can have a strong resistance to antibiotics and can escape the danger of being killed. Human life will therefore be greatly threatened. At present, the super bacteria that have attracted special attention mainly include: methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Streptococcus pneumoniae (MDRSP), vancomycin...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00A61P31/10A61K31/7048
CPCA61P31/10C07H1/00C07H17/08
Inventor 梁振江谭回俞玉明高明
Owner SHENZHEN CHILDRENS HOSPITAL
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