Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications
<p>This thesis reports on investigations into fluoroborate compounds with a view to their application in 18F-PET tracer design. The principle aim was to understand how advances could be made to the functionalisation of fluoroborate compounds for bioconjugation, in addition to improving their h...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2022
|
| Subjects: |
| _version_ | 1826311238519357440 |
|---|---|
| author | Booth, AC |
| author2 | Aldridge, S |
| author_facet | Aldridge, S Booth, AC |
| author_sort | Booth, AC |
| collection | OXFORD |
| description | <p>This thesis reports on investigations into fluoroborate compounds with a view to their application in 18F-PET tracer design. The principle aim was to understand how advances could be made to the functionalisation of fluoroborate compounds for bioconjugation, in addition to improving their hydrolytic stability and optimising synthesis via efficient fluoride uptake routes.</p>
<p>Chapter 3 reports on investigations into the synthesis and fluoride binding capabilities of 1,8-bis(boryl)-naphthalene scaffolds featuring boronic acid and ester functional groups. These bidentate “ligands” were investigated for potential thermodynamic enhancement that may be attained by chelating fluoride in such a structure, and the opportunity this offered for hydrolytically robust fluoride complexes. The diboronic acid system is established to be incompatible for this application due to the formation of an exceptionally robust intramolecular anhydride that effectively blocks the binding pocket. An unsymmetrical framework featuring a single boronic ester group is demonstrated to be suitable for chelation, although fluoride binding was subsequently compromised by a thermodynamically driven, functional group rearrangement that positions fluoride in a more labile terminal position, with a B–O–B bridge again being generated.</p>
<p>Chapter 4 explores how highly robust N-heterocyclic carbene boron trifluoride adducts may be diversified to facilitate a range of methods for bioconjugation. The modular design of N-heterocyclic carbenes is exploited in this endeavour. Thus, a series of adducts has been synthesised featuring systematic variation of the carbene backbone, and the impact on their hydrolytic stability assessed. The preparation of a N-alkyne appended NHC-BF3 derivatives is also described, and their bioconjugation to a folic acid derivative detailed.</p>
<p>Chapter 5 describes the investigation of carbene stabilised boron complexes and their fluoride binding reactions. Three-coordinate carbene-stabilised catecholato-boreniums have been investigated together with related series of four-coordinate complexes featuring either an additional anionic or neutral donor group. Systematic variation of the carbene donor and the leaving group substituent have been used to tune the rate of fluoride binding by these complexes, in addition to their hydrolytic stability. Neutral and cationic boron complexes are thus explored, with the four-coordinate boronium cations being determined to offer the greatest scope for optimising reactivity and stability. Careful choice of the secondary donor (based on pKa) offers a workable compromise between the kinetics of fluoride uptake at 60 °C and the stability of the boronium precursor to hydrolysis. Thus, systematic optimisation allows rapid, promoter-free fluoride binding to be achieved with a bench-stable boronium complex.</p> |
| first_indexed | 2024-03-07T08:05:22Z |
| format | Thesis |
| id | oxford-uuid:960e4771-7f3a-4e29-a3f8-eed782e76bba |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:05:22Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:960e4771-7f3a-4e29-a3f8-eed782e76bba2023-10-30T06:51:20ZDeveloping kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applicationsThesishttp://purl.org/coar/resource_type/c_db06uuid:960e4771-7f3a-4e29-a3f8-eed782e76bbaChemistry, InorganicRadiolabelingEnglishHyrax Deposit2022Booth, ACAldridge, SFaulkner, SCornelissen, B<p>This thesis reports on investigations into fluoroborate compounds with a view to their application in 18F-PET tracer design. The principle aim was to understand how advances could be made to the functionalisation of fluoroborate compounds for bioconjugation, in addition to improving their hydrolytic stability and optimising synthesis via efficient fluoride uptake routes.</p> <p>Chapter 3 reports on investigations into the synthesis and fluoride binding capabilities of 1,8-bis(boryl)-naphthalene scaffolds featuring boronic acid and ester functional groups. These bidentate “ligands” were investigated for potential thermodynamic enhancement that may be attained by chelating fluoride in such a structure, and the opportunity this offered for hydrolytically robust fluoride complexes. The diboronic acid system is established to be incompatible for this application due to the formation of an exceptionally robust intramolecular anhydride that effectively blocks the binding pocket. An unsymmetrical framework featuring a single boronic ester group is demonstrated to be suitable for chelation, although fluoride binding was subsequently compromised by a thermodynamically driven, functional group rearrangement that positions fluoride in a more labile terminal position, with a B–O–B bridge again being generated.</p> <p>Chapter 4 explores how highly robust N-heterocyclic carbene boron trifluoride adducts may be diversified to facilitate a range of methods for bioconjugation. The modular design of N-heterocyclic carbenes is exploited in this endeavour. Thus, a series of adducts has been synthesised featuring systematic variation of the carbene backbone, and the impact on their hydrolytic stability assessed. The preparation of a N-alkyne appended NHC-BF3 derivatives is also described, and their bioconjugation to a folic acid derivative detailed.</p> <p>Chapter 5 describes the investigation of carbene stabilised boron complexes and their fluoride binding reactions. Three-coordinate carbene-stabilised catecholato-boreniums have been investigated together with related series of four-coordinate complexes featuring either an additional anionic or neutral donor group. Systematic variation of the carbene donor and the leaving group substituent have been used to tune the rate of fluoride binding by these complexes, in addition to their hydrolytic stability. Neutral and cationic boron complexes are thus explored, with the four-coordinate boronium cations being determined to offer the greatest scope for optimising reactivity and stability. Careful choice of the secondary donor (based on pKa) offers a workable compromise between the kinetics of fluoride uptake at 60 °C and the stability of the boronium precursor to hydrolysis. Thus, systematic optimisation allows rapid, promoter-free fluoride binding to be achieved with a bench-stable boronium complex.</p> |
| spellingShingle | Chemistry, Inorganic Radiolabeling Booth, AC Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications |
| title | Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications |
| title_full | Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications |
| title_fullStr | Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications |
| title_full_unstemmed | Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications |
| title_short | Developing kinetically facile routes to robust B-F containing compounds for bioconjugation and imaging applications |
| title_sort | developing kinetically facile routes to robust b f containing compounds for bioconjugation and imaging applications |
| topic | Chemistry, Inorganic Radiolabeling |
| work_keys_str_mv | AT boothac developingkineticallyfacileroutestorobustbfcontainingcompoundsforbioconjugationandimagingapplications |