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Bicyclic octapeptide alpha-Amanitin, the death cap mushroom toxin : the total synthesis and derivatives of the hydroxyproline residue Matinkhoo, Kaveh
Abstract
This thesis presents the first total synthesis of the death cap mushroom toxin α-amanitin and the synthesis of its derivatives containing analogues of the hydroxyproline residue. In Chapter 2, an enantioselective route to the synthesis of (2S,3R,4R)-dihydroxyisoleucine, an unnatural oxidized amino acid found in α-amanitin, is presented. This includes the synthetic challenges that needed to be overcome, previous non-enantioselective syntheses of this amino acid, my failed attempts, and eventually the route to successfully obtain the desired enantiomer of this residue. Chapter 3 describes an unprecedented method to synthesize the unique, oxidant-sensitive 6-hydroxy-L-tryptathionine linkage. First, C-6 borylation of a suitably protected L-tryptophan was performed according to recent literature. Then, fluorocyclization of 6-boronate-L-tryptophan yielded a fluoropyrrolo indoline (Fpi) moiety that was shown to engage in the Savige-Fontana reaction with trifluoroacetic acid to furnish the 6-boronate-tryptathionine crosslink. In this synthesis, a boronate was used as a latent hydroxy group that could be revealed on the fully elaborated toxin following an oxidative deborylation reaction. In Chapter 4, the first total synthesis of α-amanitin is concluded. First, incorporation of 6-boronate-Fpi yielded a 6-hydroxy-tryptathionine crosslink. Then, the synthetic (2S,3R,4R)-dihydroxyisoleucine was introduced to the peptide sequence of α-amanitin. Following a macrolactamization step and a diastereoselective sulfoxidation of the tryptathionine thioether to the corresponding (R)-sulfoxide found in the natural product, the synthetic α-amanitin was afforded. Juxtaposition of the synthetic and authentic α-amanitins and extensive comparison of their physical, chemical and biological properties validated the synthetic analogue. The analogues of trans-hydroxyproline and the method for their incorporation into α-amanitin derivatives are disclosed in Chapter 5. The hydroxyproline residue of α-amanitin has been shown to be critical for the toxicity of this toxin. However, surprisingly, there is little traction in the literature regarding the structure-activity relationships (SAR) of the hydroxyproline space and how it could affect the binding of the toxin to RNA polymerase II. Hence, a series of hydroxyproline analogues, including a photocleavable hydroxyproline derivative, were synthesized and aimed to be incorporated into amanitin via an improved solid-phase strategy.
Item Metadata
Title |
Bicyclic octapeptide alpha-Amanitin, the death cap mushroom toxin : the total synthesis and derivatives of the hydroxyproline residue
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2018
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Description |
This thesis presents the first total synthesis of the death cap mushroom toxin α-amanitin and the synthesis of its derivatives containing analogues of the hydroxyproline residue. In Chapter 2, an enantioselective route to the synthesis of (2S,3R,4R)-dihydroxyisoleucine, an unnatural oxidized amino acid found in α-amanitin, is presented. This includes the synthetic challenges that needed to be overcome, previous non-enantioselective syntheses of this amino acid, my failed attempts, and eventually the route to successfully obtain the desired enantiomer of this residue.
Chapter 3 describes an unprecedented method to synthesize the unique, oxidant-sensitive 6-hydroxy-L-tryptathionine linkage. First, C-6 borylation of a suitably protected L-tryptophan was performed according to recent literature. Then, fluorocyclization of 6-boronate-L-tryptophan yielded a fluoropyrrolo indoline (Fpi) moiety that was shown to engage in the Savige-Fontana reaction with trifluoroacetic acid to furnish the 6-boronate-tryptathionine crosslink. In this synthesis, a boronate was used as a latent hydroxy group that could be revealed on the fully elaborated toxin following an oxidative deborylation reaction.
In Chapter 4, the first total synthesis of α-amanitin is concluded. First, incorporation of 6-boronate-Fpi yielded a 6-hydroxy-tryptathionine crosslink. Then, the synthetic (2S,3R,4R)-dihydroxyisoleucine was introduced to the peptide sequence of α-amanitin. Following a macrolactamization step and a diastereoselective sulfoxidation of the tryptathionine thioether to the corresponding (R)-sulfoxide found in the natural product, the synthetic α-amanitin was afforded. Juxtaposition of the synthetic and authentic α-amanitins and extensive comparison of their physical, chemical and biological properties validated the synthetic analogue.
The analogues of trans-hydroxyproline and the method for their incorporation into α-amanitin derivatives are disclosed in Chapter 5. The hydroxyproline residue of α-amanitin has been shown to be critical for the toxicity of this toxin. However, surprisingly, there is little traction in the literature regarding the structure-activity relationships (SAR) of the hydroxyproline space and how it could affect the binding of the toxin to RNA polymerase II. Hence, a series of hydroxyproline analogues, including a photocleavable hydroxyproline derivative, were synthesized and aimed to be incorporated into amanitin via an improved solid-phase strategy.
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Genre | |
Type | |
Language |
eng
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Date Available |
2020-09-30
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0372310
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2018-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International