Organometallic Approaches for Selective Bioconjugation Using Boronic Acids
| dc.contributor.advisor | Ball, Zachary T | en_US |
| dc.creator | Miller, Mary K | en_US |
| dc.date.accessioned | 2021-04-13T22:07:11Z | en_US |
| dc.date.available | 2021-11-01T05:01:11Z | en_US |
| dc.date.created | 2021-05 | en_US |
| dc.date.issued | 2021-03-30 | en_US |
| dc.date.submitted | May 2021 | en_US |
| dc.date.updated | 2021-04-13T22:07:11Z | en_US |
| dc.description.abstract | Peptide and protein bioconjugates are important for the development of chemical tools and biopharmaceuticals. Due to the vast number of applications of bioconjugate structures, a need has arisen for diverse methodologies to create different bioconjugate structures. Organometallic methodologies have risen in prominence to meet this need due to the varying reaction types and residue selectivities that can be accessed using these strategies. The first two chapters review developments in transition metal chemistry in aqueous environments, which is important to understand when developing novel organometallic bioconjugation strategies. The first chapter details copper-mediated bioconjugation strategies with a focus on the mechanisms of the reactions described. The second chapter discusses methods for arylation of amines in aqueous conditions, including small molecule alkyl, aryl, and aromatic amines as well as larger biomolecules such as peptides and DNA. The development of selective protein/peptide bioconjugation strategies using boronic acids will be covered in chapter 3–5, focusing on the diversity of bioconjugate structures that can be accessed by judicious choice of metal mediator and boronic acid substrate. Copper(II) salts and ortho sulfonamide boronic acids were shown to arylate the N-terminus of naturally occurring peptides. This method allowed us to achieve excellent selectivity for the N-terminus over lysine side chains. Utilizing rhodium(III), tyrosine was selectively arylated in a unique three-component organometallic bioconjugation strategy wherein an η 6 -organometallic complex was formed. This method showed a very different substrate scope, with 2-carboxamideboronic acids showing increased reactivity, likely due to the chelation to the rhodium(III) center. Utilizing nickel(II), cysteine residues and pyroglutamate-histidine dipeptide sequences were found to be arylated with boronic acids π-deficient electron withdrawing groups, which is complementary to previously reported approaches. It was discovered that certain bioconjutation strategies could perhaps be used orthogonally with one another, which will be discussed in chapter 6. While nickel(II) is reactive with boronic acids with π-deficient electron withdrawing groups, copper(II) is reactive with vinyl boronic acids and arylboronic acids lacking ortho substitution. Furthermore, nickel(II) does not react with boronic acids that lack π-deficient electron withdrawing groups. By employing sequential reactions using diboronic acid reagents, protein heterodimer structures could be accessed using transition metal mediated methodologies developed in the Ball lab. | en_US |
| dc.embargo.terms | 2021-11-01 | en_US |
| dc.format.mimetype | application/pdf | en_US |
| dc.identifier.citation | Miller, Mary K. "Organometallic Approaches for Selective Bioconjugation Using Boronic Acids." (2021) Diss., Rice University. <a href="https://hdl.handle.net/1911/110269">https://hdl.handle.net/1911/110269</a>. | en_US |
| dc.identifier.uri | https://hdl.handle.net/1911/110269 | en_US |
| dc.language.iso | eng | en_US |
| dc.rights | Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder. | en_US |
| dc.subject | bioconjugation | en_US |
| dc.subject | boronic acids | en_US |
| dc.subject | selective | en_US |
| dc.subject | transition metals | en_US |
| dc.subject | cross-coupling | en_US |
| dc.title | Organometallic Approaches for Selective Bioconjugation Using Boronic Acids | en_US |
| dc.type | Thesis | en_US |
| dc.type.material | Text | en_US |
| thesis.degree.department | Chemistry | en_US |
| thesis.degree.discipline | Natural Sciences | en_US |
| thesis.degree.grantor | Rice University | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy | en_US |
Files
Original bundle
1 - 1 of 1