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Modification of the aglycone Josamycin using a regioselective nucleophilic substitution type SN1' and Huisgen dipolar cycloaddition

Joanna Domagalska

Abstract

The aim of the dissertation was modifications of the aglycone’s structure of 16-membered macrolide antibiotic – josamycin. 31 new type derivatives of josamycin containing introduced new triazole arm were obtained by a combination of a substitution reaction in the allyl system and the 1,3-dipolar Huisgen cycloaddition. Structures and stereochemistry of new leucomycin analogs containing new triazole functionalized arm at C(13) were determined by FT-IR, 1D and 2D NMR and molecular optimization B88 LYP (GGA) DFT method. Unexpected mechanism of substitution SN1’ within diene system was established by reaction rate analysis at different conditions. Biological tests in combination with the molecular modeling MOG PM6 indicated that the structure of new triazole arm at C(13) of the aglycone contributes leucomycins’ activity, both antimicrobial and anticancer. The most active compounds containing triazole arm substituted by saccharides also have high selectivity in cancer cells, which is important in the context of potential future applications. Additionally, demonstrated that the lack of the aldehyde in the structure of the macrolide lactone type leucomycin is not necessary to achieve a high cytotoxic and antibacterial properties by this class of novel antibiotics.
Record ID
UAMbe4cb700b08944ba85b8fb54e335bd4d
Diploma type
Doctor of Philosophy
Author
Title in Polish
Modyfikacja aglikonu josamycyny z wykorzystaniem regioselektywnej substancji nukleofilowej typu SN1' i dipolarnej cykloaddycji Huisgena
Title in English
Modification of the aglycone Josamycin using a regioselective nucleophilic substitution type SN1' and Huisgen dipolar cycloaddition
Language
pol (pl) Polish
Certifying Unit
Wydział Chemii [nowa struktura organizacyjna] (SNŚ/WC)
Scientific discipline (2.0)
6.5 chemical sciences
Status
Finished
Year of creation
2016
Defense Date
16-06-2016
Title date
16-06-2016
Supervisor
URL
http://hdl.handle.net/10593/14719 Opening in a new tab
Keywords in English
antibiotics, antibacterial activity, josamycin, spectroscopy
Abstract in English
The aim of the dissertation was modifications of the aglycone’s structure of 16-membered macrolide antibiotic – josamycin. 31 new type derivatives of josamycin containing introduced new triazole arm were obtained by a combination of a substitution reaction in the allyl system and the 1,3-dipolar Huisgen cycloaddition. Structures and stereochemistry of new leucomycin analogs containing new triazole functionalized arm at C(13) were determined by FT-IR, 1D and 2D NMR and molecular optimization B88 LYP (GGA) DFT method. Unexpected mechanism of substitution SN1’ within diene system was established by reaction rate analysis at different conditions. Biological tests in combination with the molecular modeling MOG PM6 indicated that the structure of new triazole arm at C(13) of the aglycone contributes leucomycins’ activity, both antimicrobial and anticancer. The most active compounds containing triazole arm substituted by saccharides also have high selectivity in cancer cells, which is important in the context of potential future applications. Additionally, demonstrated that the lack of the aldehyde in the structure of the macrolide lactone type leucomycin is not necessary to achieve a high cytotoxic and antibacterial properties by this class of novel antibiotics.
Thesis file
  • File: 1
    PRACA DOKTORSKA.pdf
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Uniform Resource Identifier
https://researchportal.amu.edu.pl/info/phd/UAMbe4cb700b08944ba85b8fb54e335bd4d/
URN
urn:amu-prod:UAMbe4cb700b08944ba85b8fb54e335bd4d

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