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Glycosylated derivative of cyclic peptide compounds and preparation method and application thereof

A technology of glycosylation and derivatives, which is applied in the field of glycosylation derivatives of cyclic peptide compounds and its preparation, can solve the problems of limited application due to drug resistance, large side effects, narrow antibacterial spectrum, etc., and achieve improved antifungal activity , strong inhibitory activity, broad-spectrum antibacterial effect

Inactive Publication Date: 2014-07-02
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the increasing drug resistance of fluconazole has seriously limited its application
Other antifungal drugs, such as polyene antifungal drugs, allylamines, morpholines, and fluoropyrimidines, are often toxic, have large side effects (such as amphotericin B), narrow antibacterial spectrum, and are prone to recurrence (such as 5- Flucytosine) and many other deficiencies (Owens, J. Nat. Rev. Drug. Discov. 2005, 1, 884-885.)
No similar reports have been seen so far

Method used

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  • Glycosylated derivative of cyclic peptide compounds and preparation method and application thereof
  • Glycosylated derivative of cyclic peptide compounds and preparation method and application thereof
  • Glycosylated derivative of cyclic peptide compounds and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 High-resolution mass spectrum and proton nuclear magnetic spectrum data of compounds 1a-1g of the present invention

[0030] See Table 1 and Table 2 for the high-resolution mass spectrum and proton NMR data of compounds 1a-f of the present invention.

[0031] Table 1 High resolution mass spectrum table of compound 1a-f of the present invention

[0032]

[0033] Table 2 Compounds of the present invention 1a-f The H NMR Data Sheet

[0034]

[0035]

Embodiment 2

[0036] Example 2 Compounds of the invention 1a-g preparation of

[0037] 2.1 Compounds of the present invention 1a-f The preparation can be roughly divided into two steps:

[0038] 2.1.1 Preparation of key intermediate glycosyl activated ester 5a-g , the reaction scheme is as follows:

[0039]

[0040] 2.1.2 Preparation of target compounds 1a-g , the reaction scheme is as follows:

[0041]

[0042] 2.2 Compounds of the present invention 1a - g The specific preparation method is as follows:

[0043] 2.2.1 Preparation of azide side chains

[0044] Weigh sodium azide (45 g, 0.69 mol) into a 250 mL three-neck flask, add 2-chloroethanol (32 mL, 0.58 mol), and add catalyst tetrabutylammonium bromide (TBAB, 4 g ), heated to reflux for 12 h, the reaction solution changed from a khaki suspension to a brown suspension. Lift to cool, add 60 mL of anhydrous ether, filter with suction, wash the filter cake with 30 mL of anhydrous ether, and combine the filtrates. S...

Embodiment 3

[0057] Example 3 Pharmacological experiments of the compounds of the present invention

[0058] 3.1 Experimental method: The micro liquid base dilution method recommended by the CLSI-M27A3 and M38-A2 documents of the Clinical and Laboratory Standards Institute (CLSI) was adopted.

[0059] 3.1.1 Experimental strains

[0060] In this experiment, the following 6 kinds of 7 common human pathogenic standard fungal strains were selected as the screening objects:

[0061] Two ATCC standard strains:

[0062] Candida albicans SC5314

[0063] Cryptococcus neoformans 32609

[0064] Five clinical strains:

[0065] Candida glabrata (Candida krusei) 537

[0066] Candida parapsilosis 22019

[0067] Trichophyton rubrum Cmccftla

[0068] Microsporum gypseum Cmccfmza

[0069] Candida albicans Y0109

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Abstract

The invention relates to a glycosylated derivative of cyclic peptide compounds. The chemical structural formula of the glycosylated derivative of cyclic octapeptide TunicyclinD is shown in the specification, wherein n is equal to 0, 1 or 2; Glycosyl is monosaccharide or disaccharide, the monosaccharide is glucose, galactose, xylose, rhamnose, mannose, ribose, glucosamine or n-acetylglucosamine; the disaccharide is maltose or lactose. The invention also provides a preparation method and application of the glycosylated derivative of the cyclic peptide compounds. The compounds provided by the invention have relatively strong in-vitro antifungal activity, thereby being capable of being used for preparing antifungal drugs; the preparation method provided by the invention is used for successfully introducing different glycosyls on carboxyl of TunicyclinD, and is simple in process and high in yield. The formula is shown in the specification.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, in particular to a glycosylated derivative of a cyclic peptide compound and its preparation method and use. Background technique [0002] In recent years, due to the increase in the number of patients with cancer radiotherapy, chemotherapy, organ transplantation and interventional therapy, the widespread use of broad-spectrum antifungal drugs, corticosteroids and immunosuppressants in clinical practice, and the prevalence of AIDS, the number of clinical deep fungal infection cases has increased sharply There are nearly 300,000 patients with systemic fungal infection diagnosed every year in the world, and among AIDS patients, 60% of the direct causes of death are systemic fungal infections (Markus, R. Drugs , 2004, 64, 1163-1180.). Fungal diseases seriously threaten human life and health. Among the drugs for the treatment of deep fungal infections, azole compounds are the most w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00C07K1/06C07K1/04A61K38/14A61P31/10
Inventor 赵庆杰胡宏岗邹燕吴秋业李翔卓小斌
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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