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Amphotericin B peptide derivative and preparation method thereof

A technology of amphotericin and compounds, applied in the field of medicine, can solve the problems of increasing treatment dosage, high price and high cost

Active Publication Date: 2020-01-10
SHANGHAI INST OF PHARMA IND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But amphotericin B liposome preparation also has the following disadvantages: one, the antibacterial activity of liposome preparation is worse than amphotericin B, need to increase the therapeutic dose, two, liposome preparation cost is higher , the price is relatively expensive, three, the instability of liposome itself, four, liposome preparations have not fundamentally eliminated the toxic side effects such as nephrotoxicity of amphotericin B

Method used

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  • Amphotericin B peptide derivative and preparation method thereof
  • Amphotericin B peptide derivative and preparation method thereof
  • Amphotericin B peptide derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: Preparation and purification of DMR005

[0086] Hydrophilic peptide structure: Fmoc-AEEAc-AEEAc-AEEAc-AEEAc–AEEAc-OH

[0087] DMR005 structure:

[0088]

[0089] (1) Materials and reagents

[0090] 2-CTC resin, substitution value 0.945mmol / g.

[0091] Amino acid: Fmoc-AEEAc-OH

[0092] Synthetic reagents: HATU, DMF, DCM, DIEA, piperidine.

[0093] (2) Instruments

[0094] CS-BIO peptide synthesizer, Waters600 semi-preparative high performance liquid chromatograph, Beckman centrifuge, Buchi rotary steamer.

[0095] (3) Operation steps (take 1g resin as an example)

[0096] a. Solid-phase chemical synthesis of peptides

[0097] Weigh 1.00g of 2-CTC resin, put it in the peptide synthesizer reactor, add 10mLDCM, soak for 1h, weigh 2-3 times the amount of Fmoc-AEEAc-OH and draw 4-6 times the amount of DIEA, add 10mLDCM to dissolve it , Put it into the reactor and proceed with the reaction. The reaction temperature is room temperature (25°C and above, otherwise the reaction time ...

Embodiment 2

[0122] Example 2: Contain n NH 2 -AEEAc-OH Preparation and Purification of Amphotericin B Peptide Derivatives

[0123] Amino acid sequence: Fmoc-(AEEAc) n -OH; n=1-20, n is an integer, the product structure is as follows:

[0124]

[0125] Synthetic NH 2 -(AEEAc) n -Amphotericin B peptide derivative of AMB, the synthesis method refers to compound DMR005, namely ① Fmoc-(AEEAc) is synthesized by solid phase synthesis n -OH; ②Preparation of Fmoc-(AEEAc) n -Osu; ③Fmoc-(AEEAc) n -Osu modifies the amino group of amphotericin B, piperidine removes Fmoc, and finally obtains NH 2 -(AEEAc) n -Crude amphotericin B peptide derivative of AMB. The crude product was purified by RP-HPLC; according to the general structure of the compound [Ⅱ], Table 3 lists the abbreviations and relative molecular weights of the compounds:

[0126] Table 3 Compound abbreviations and relative molecular masses

[0127] namenR Relative molecular mass NH 2 -AEEAc-AMB

Embodiment 3

[0128] Example 3: Determination of the solubility of amphotericin B peptide derivatives

[0129] For the determination of the solubility of amphotericin B and amphotericin B peptide derivatives, in the patent of the present invention, the solubility in water was measured. The results are shown in Table 4:

[0130] Table 4 Solubility measurement results

[0131] Compound Solubility (mg / mL) AMB<0.001

[0132] The results show that AMB is almost insoluble in water; NH 2 -AEEAc-AMB has lower solubility, DMR005 obviously improves water solubility; with NH 2 -(AEEAc) n The increase of n in -OH significantly increases the solubility of the amphotericin B peptide derivative. But at the same time, the antibacterial activity was significantly reduced (see Table 5 for the results of antibacterial activity), and even no antibacterial activity. When n is 3-7, solubility and antibacterial activity are in a good balance.

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Abstract

The invention belongs to the field of medicines, and particularly relates to an amphotericin B peptide derivative and a preparation method thereof. The amphotericin B peptide derivative is obtained bytaking R2-AEEAc-OH as a raw material, synthesizing R2-(AEEAc) n-OH series compounds by adopting a solid-phase synthesis mode, then coupling with amphotericin B through an amido bond, finally removingan amino protecting group, and purifying the product. Compared with amphotericin B, the compound provided by the invention has the characteristics of high solubility and low toxicity, and has the good antibacterial effect.

Description

Technical field [0001] The invention belongs to the field of medicine, and relates to amphotericin B peptide derivatives and preparation methods and applications thereof, and specifically relates to a series of amphotericin B peptide derivatives with high solubility, low toxicity and good antibacterial activity And its synthetic preparation and application. Background technique [0002] Amphotericin B (Amphotericin B, AMB) is a polyene broad-spectrum antifungal drug suitable for the treatment of the following fungal infections: cryptococcosis, North American blastomycosis, disseminated candidiasis, coccidioidomycosis , Histoplasmosis, mucormycosis caused by Mucor, Koji and Absidia, etc., sporotrichosis caused by the liver function test item of Sporothrix schenckii, caused by Aspergillus fumigatus Caused by aspergillosis. [0003] Since amphotericin B was isolated from the metabolites of Streptomyces in 1955, the compound has attracted much attention. On the one hand, amphoterici...

Claims

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Application Information

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IPC IPC(8): C07H17/08A61K31/7048A61P31/10A61P31/04
CPCC07H17/08A61P31/10A61P31/04Y02P20/55
Inventor 冯军东圆珍张喜全张金华赵文杰徐宏江朱冰
Owner SHANGHAI INST OF PHARMA IND