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Development and photophysical investigations of maleimide chromophores for applications in photoactive bioconjugates

Malde, Roshni; (2022) Development and photophysical investigations of maleimide chromophores for applications in photoactive bioconjugates. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Bioconjugation, a technique to covalently attach molecules to biomolecules, is employed for a range of applications, e.g. studying biological systems, developing therapeutics and imaging. Bioconjugates that can undergo photochemical transformations are gaining significance as these occur with precise spatiotemporal control, only upon exposure to specific wavelengths of light. Despite this, there is slow progression of the field due to the lack of photoactive molecules that can selectively be attached to biomolecules. Next-generation maleimides have previously been shown to selectively react with cysteine residues on proteins and peptides to produce thiomaleimide conjugates. Furthermore, thiomaleimides have displayed the ability to undergo efficient exo-selective [2+2] photocycloaddition reactions. Combining these two modes of reactivity has led to the ability to photochemically rebridge protein and peptide disulfide bonds. The work conducted in this thesis has expanded the scope of this rebridging through development of an intramolecular version which reverses the stereoselectivity to produce endo products. Electronic and vibrational transient absorption spectroscopies have then been used to observe the excited states involved in the thiomaleimide [2+2] photocycloaddition, deepening current knowledge on the reaction mechanism. The determination of excited state lifetimes has shown the intramolecular version to have an accelerated triplet state decay due to faster carbon-carbon bond formation, providing evidence for the increased photoefficiency. Interestingly, dithiomaleimides were also discovered to undergo a second photochemical reaction, namely a photodecarboxylation. In this thesis, the reaction was developed further to improve the photocleavage yield upon decarboxylation and confirm the nature of the released cargo. The photoreaction was then exemplified on an antibody fragment for initial establishment of a photocleavable antibody-drug conjugate. The research in this thesis was further extended towards wavelength tunability of both the [2+2] photocycloaddition and photodecarboxylation reactions. This was achieved by studying other substituted maleimides which provides the basis for orthogonal photoreactions through wavelength-selective chromophores.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development and photophysical investigations of maleimide chromophores for applications in photoactive bioconjugates
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10153822
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