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A Dynamic Combinatorial Approach to the Development of Anion Receptors for Transmembrane Transport

par Halgreen, Lau
Président du jury Bartik, Kristin
Promoteur Valkenier, Hennie
Publication Non publié, 2023-04-17

Thèse de doctorat

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Résumé :

Development of synthetic anion receptors capable of facilitating transmembrane transport across lipid bilayers have been an active area of research since the late 1990s. However, despite the great biological relevance of phosphates, their transmembrane transport by synthetic anion receptors remains an area in which only a few examples can be found.This thesis details the work carried out towards the development of receptors capable of facilitating the transport of organic phosphates, using dynamic covalent chemistry as an approach to the development and synthesis of these receptors. The work is divided into three overall parts describing the three approaches used in the development process. The first part of the thesis deals with the dynamic approach using acylhydrazones as the dynamic covalent functional group, detailing the design concept of the dynamic combinatorial libraries, the synthesis of the building blocks, as well as the initial attempts at carrying out exchange with the obtained building blocks. This chapter also describes the challenges involved in using acylhydrazones in transmembrane transport through a range of acylhydrazone based receptors which have been synthesized and evaluated for Cl-/NO3- antiport in liposomes using the lucigenin assay. The results of these investigations, in combination with the lessons learned from the initial dynamic combinatorial chemistry exchange experiments, led to the conclusion that acylhydrazones turned out to be a moiety with too many drawbacks when used in the design of receptors capable of facilitation of transmembrane transport.The second part of the thesis deals with alternative azomethine based moieties as replacements for acylhydrazones as the dynamic bond. Herein we show that, while imines have some precedent as transmembrane transporters and dynamic combinatorial libraries using imines can facilitate amplification in the presence of TBAH2PO4, outside of edge cases imines are too unstable within a lipidic invironment to function well as part of receptors meant to facilitate transmembrane transport. Investigations of azines, a more hydrolytically stable dynamic azomethine based bond, are also discussed in this part of the thesis. The azine bond, despite not imparting any significant negative effect on transport rates, is demonstrated to exhibit poor complementarity between the preferred conformation of the azine bond and the possible arrangement of binding moieties within azine based scaffolds.The third part of the thesis describes some of the non-dynamic receptors which were developed either as derivatives of dynamic combinatorial libraries or from building blocks developed for use in dynamic combinatorial libraries. In particular, a range of macrocycles of the same size featuring different degrees of flexibility are investigated to demonstrate the effect of structural flexibility on the anion binding ability for anions of different sizes, revealing an intermediate degree of flexibility to provide the best affinities. The non-dynamic receptors are also evaluated for transport in Cl-/NO3- antiport assays as well as Cl-/H2PO4- antiport assays but were found to be inactive, despite good anion affinities.This thesis thus shows that hydrazones, imines and azines each have their own set of drawbacks making them challenging to use for development of transmembrane transporters by a combinatorial approach, and even when high affinity receptors are obtained, their ability to facilitate transmembrane transport is still not guaranteed.