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Amphotericin B methyl ester peptide derivative and preparation method thereof

A technology of derivatives and methyl groups, applied in the field of amphotericin B methyl esterified peptide derivatives and their synthesis and preparation, can solve the problems of liposome instability, increased therapeutic dose, and high cost

Pending Publication Date: 2021-07-16
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 methyl ester peptide derivative and preparation method thereof
  • Amphotericin B methyl ester peptide derivative and preparation method thereof
  • Amphotericin B methyl ester peptide derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] Example 1: Preparation and purification of DMR005-JZH

[0182] Hydrophilic peptide structure: Fmoc-AEEAc-AEEAc-AEEAc-AEEAc–AEEAc-OH

[0183] DMR005-JZH structure:

[0184]

[0185] (1) Materials and reagents

[0186] 2-CTC resin, substitution value 0.945mmol / g.

[0187] The amino acid is: Fmoc-AEEAc-OH

[0188] Synthetic reagents: HATU, DMF, DCM, DIEA, piperidine, methyl iodide.

[0189] (2) Instrument

[0190] CS-BIO peptide synthesizer, Waters600 semi-preparative high performance liquid chromatography, Beckman centrifuge, Buchi rotary evaporator.

[0191] (3) Operation steps (take 1g resin as an example)

[0192] a. Solid-phase chemical synthesis of peptides

[0193] Weigh 1.00g of 2-CTC resin, put it in the reactor of polypeptide synthesizer, add 10mL DCM, soak for 1h, weigh 2-3 times the amount of Fmoc-AEEAc-OH and absorb 4-6 times the amount of DIEA and add 10mL DCM to dissolve it , put it into the reactor, and carry out the reaction. The reaction temper...

Embodiment 2

[0218] Example 2: Preparation and purification of DMR078-JZH

[0219] Hydrophilic peptide structure: Fmoc-AEEAc-Gly-AEEAc-Gly–AEEAc-OH

[0220] DMR078-JZH structure:

[0221]

[0222] (1) Materials and reagents

[0223] 2-CTC resin, substitution value 0.945mmol / g.

[0224] The amino acids are: Fmoc-AEEAc-OH and Fmoc-Gly-OH

[0225] Synthetic reagents: HATU, DMF, DCM, DIE, piperidine, methyl iodide.

[0226] (2) Instrument

[0227] CS-BIO peptide synthesizer, Waters600 semi-preparative high performance liquid chromatography, Beckman centrifuge, Buchi rotary evaporator.

[0228] (3) Operation steps (take 1g resin as an example)

[0229] a. Solid-phase chemical synthesis of peptides

[0230] Weigh 1.00g of 2-CTC resin, put it in the reactor of polypeptide synthesizer, add 10mL DCM, soak for 1h, weigh 2-3 times the amount of Fmoc-AEEAc-OH and absorb 4-6 times the amount of DIEA and add 10mL DCM to dissolve it , put it into the reactor, and carry out the reaction. The re...

Embodiment 3

[0256] Example 3: Preparation and purification of DMR086

[0257] Hydrophilic peptide structure: Fmoc-AEEAc-AEEAc-OH

[0258] DMR086 structure:

[0259]

[0260] (1) Materials and reagents

[0261] 2-CTC resin, substitution value 0.945mmol / g.

[0262] Amino acid: Fmoc-AEEAc-OH,

[0263] Synthetic reagents: HATU, DMF, DCM, DIEA, piperidine, methyl iodide.

[0264] (2) Instrument

[0265] CS-BIO peptide synthesizer, Waters600 semi-preparative high performance liquid chromatography, Beckman centrifuge, Buchi rotary evaporator.

[0266] (3) Operation steps (take 1g resin as an example)

[0267] a. Solid-phase chemical synthesis of peptides

[0268]Weigh 1.00g of 2-CTC resin, place it in a polypeptide synthesizer reactor, add 10mL DCM, soak for 1h, weigh 2-3 times the amount of Fmoc-AEEA-OH and absorb 4-6 times the amount of DIEA and add 10mL DCM After dissolving, put it into the reactor and carry out the reaction. The reaction temperature is room temperature (25°C and a...

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Abstract

The invention belongs to the field of medicines, and particularly relates to an amphotericin B methyl ester peptide derivative and a preparation method thereof. The amphotericin B peptide derivative disclosed by the invention has a broad-spectrum and efficient bactericidal effect on drug-resistant bacteria and fungi.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to the modification of amphotericin B methyl esterified peptide derivatives and its preparation method and application, specifically to a series of amphotericin with high solubility, low toxicity and good antibacterial activity Peptide derivatives of methylated peptide B and their synthesis, preparation and application. Background technique [0002] Amphotericin B (AMB) is a polyene broad-spectrum antifungal drug, suitable for the treatment of the following fungal infections: Candidiasis, Cryptococcosis, Blastomycosis ), Coccidioidomycosis, mucormycosis caused by Mucor, Sporotrichosis caused by Sporothrix, caused by most Aspergillus ) caused by aspergillosis (aspergillosis), etc. [0003] Amphotericin B has attracted much attention since its isolation in 1955 from a Streptomyces metabolite. On the one hand, amphotericin B is the gold standard in the clinical treatment of deep fungal infecti...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00A61K31/7048A61P31/10
CPCA61P31/10C07H1/00C07H17/08Y02P20/55
Inventor 冯军东圆珍张喜全张金华赵文杰徐宏江
Owner SHANGHAI INST OF PHARMA IND
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