Thesis (PhD (Chemistry and Polymer Science))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: The use of fluorine in medicinal chemistry has increased dramatically in the last 20 years. The
addition of fluorine to a lead compound has various advantages such as the blocking of metabolic
active sites, the increase of solubility and lipophilicity of a compound, acting as conformational
probes for the active site of an enzyme, and influencing (in most cases increasing) the binding
affinity of a compound to a target protein. Their use as mechanism based inhibitors is also well
known.
In this study we set out to synthesize hydroxyl- and fluorinated-amino acid analogues as potential
inhibitors and probes towards the active site of various enzymes. The synthesis of the hydroxylamino
acid analogues would precede the fluorinated analogues to serve as precursors with
fuorination achieved via a fluoro-dehydroxylation reaction.
These aims have successfully been achieved with the synthesis of the two enantiopure isomers of
3-fluoro-aspartic acid. The fluorinated aspartic acid analogues were subsequently used in a
conformational analysis, with regards to substrate- and binding activity, which investigated the
interaction of these compounds with aspartate decarboxylase (PanD). The synthesis of the 3-
hydroxy-analogues of ornithine and diamino pimelic acid was also successfully achieved. These
syntheses were done in a stereospecific manner to provide one enantiomer of the L-amino acid
analogue. However, our efforts toward the synthesis of the other enantiomer of hydroxy analogues
as well as our attempts at the conversion of the hydroxyl group to a fluorine were unsuccessful to
date. Nevertheless, these results gave us a new direction towards the synthesis of the desired
compounds and have led us to new strategies and ideas.
Hopefully, the work done in this study will be part of the ground work towards new methodologies
for the synthesis of desired halogenated amino acid analogues as small molecule inhibitors. / AFRIKAANSE OPSOMMING:
The use of fluorine in medicinal chemistry has increased dramatically in the last 20 years. The
addition of fluorine to a lead compound has various advantages such as the blocking of metabolic
active sites, the increase of solubility and lipophilicity of a compound, acting as conformational
probes for the active site of an enzyme, and influencing (in most cases increasing) the binding
affinity of a compound to a target protein. Their use as mechanism based inhibitors is also well
known.
In this study we set out to synthesize hydroxyl- and fluorinated-amino acid analogues as potential
inhibitors and probes towards the active site of various enzymes. The synthesis of the hydroxylamino
acid analogues would precede the fluorinated analogues to serve as precursors with
fuorination achieved via a fluoro-dehydroxylation reaction.
These aims have successfully been achieved with the synthesis of the two enantiopure isomers of
3-fluoro-aspartic acid. The fluorinated aspartic acid analogues were subsequently used in a
conformational analysis, with regards to substrate- and binding activity, which investigated the
interaction of these compounds with aspartate decarboxylase (PanD). The synthesis of the 3-
hydroxy-analogues of ornithine and diamino pimelic acid was also successfully achieved. These
syntheses were done in a stereospecific manner to provide one enantiomer of the L-amino acid
analogue. However, our efforts toward the synthesis of the other enantiomer of hydroxy analogues
as well as our attempts at the conversion of the hydroxyl group to a fluorine were unsuccessful to
date. Nevertheless, these results gave us a new direction towards the synthesis of the desired
compounds and have led us to new strategies and ideas.
Hopefully, the work done in this study will be part of the ground work towards new methodologies
for the synthesis of desired halogenated amino acid analogues as small molecule inhibitors.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/4498 |
| Date | 03 1900 |
| Creators | De Villiers, Jandre |
| Contributors | Strauss, Erick, Jardien, Anwar, University of Stellenbosch. Faculty of Science. Dept. of Chemistry and Polymer Science. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Rights | University of Stellenbosch |
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