• Citer

Synthesis and studies of synthetic anion transporters using unconventional non-covalent interactions for the selective transport of chloride

par Singh, Anurag
Président du jury Bartik, Kristin
Promoteur Valkenier, Hennie
Publication Non publié, 2024-07-12

Thèse de doctorat

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

The development of synthetic anion receptors and transporters across lipid bilayer membrane is an emerging field of research within supramolecular chemistry with immense potential in various biological applications. Most synthetic anion transporters rely on hydrogen bonds (HBs) from NH groups of amides, urea, thiourea, imidazoles etc as non-covalent interaction with the anions. The use of non-covalent interactions based on sigma holes for transmembrane transport of ions has been less explored. Here in this thesis, we explore the use of halogen bonds (XB) and C–H···anion interactions with the aim to achieve chloride transport activity comparable to that obtained with more commonly used NH hydrogen bonds, but with an improved selectivity. Selectivity is a desirable property for the potential treatment of chloride channelopathies such as cystic fibrosis, where chloride transport is required but dissipation of pH gradients could lead to undesired toxic effects. Chapter 1 presents a general introduction to the field of anion transporters. Here we also present a literature overview of the synthetic transmembrane transporters involving unconventional non-covalent interaction based on sigma holes. After this discussion on synthetic anion transport and recent advances in the field, Chapter 2 introduces calix[6]arenes which are decorated with XB donor groups for anion recognition and transport. The chapter presents the design, synthesis, anion binding, and transport studies of calix[6]arenes. We also present a comparison between XB and HB donating compounds in terms of anion binding, transport activity, and selectivity, using receptors with iodotriazoles as XB donors, and squaramides or (thio)ureas as strong HB donors. This study reveals the remarkable selectivity of XB donors to transport chloride and nitrate, compared to the transport of other anions and to the dissipation of pH gradients. It also demonstrates that XB donor groups connected to a platform can achieve transport rates similar to those of powerful HB donors, while providing a superior selectivity for chloride, which opens the way to therapeutic applications of XB donors. Progressing to Chapter 3, we continued the development and evaluation of XB receptors dedicated to selective chloride ion transport. Our initial aim was to synthesize tetradentate macrocycles owing to their rigidity and structural preorganisation. However, after a setback in the synthesis of macrocycles, we shifted our focus on exploring a series of bidentate XB receptors. Some of these compounds were found to give particularly good rates of transport, but they were less chloride selective as compared to tridentate XB donor system studied in Chapter 2. They had an added advantage of deliverability to the membrane, which is a key factor when it comes to potential biological applications. Considering that a balance is required of selectivity, transport efficiency, and deliverability, we wanted to further investigate new molecules as potential chloride transporters.As an alternative strategy to obtain chloride selective transporters, Chapter 4 introduces a class of cyanostilbene-based anion transporters, which utilize C–H···anion interactions for anion recognition and transport. This chapter presents an investigation into the binding affinities and transport activities of a series of these compounds. Some demonstrated high chloride uniport activity and a marked preference for chloride over other anions. Moreover, the deliverability of the most active chloride transporter in this series makes it a candidate for testing in biological systems.Overall, this thesis explores the receptors based on unconventional non-covalent XB and C–H···anion interactions for the selective transmembrane transport of chloride. We also explored the structure activity relationship for series of receptors involving these interactions. Furthermore, the receptors also displayed good chloride transport activity along with modest deliverability making them promising candidates for in vitro studies.