Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.720801
Title: Probing ion transport mechanisms with synthetic channel-forming molecules
Author: Sharma, Kushal
Awarding Body: University of Brighton
Current Institution: University of Brighton
Date of Award: 2017
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Abstract:
Maintaining asymmetric balances of intra- and extra-cellular ion concentrations is essential for the healthy and regular functioning of a cell as the presence of specific ionic gradients are responsible for a number of cellular and physiological processes. In order to establish and maintain these ionic gradients, ion channels provide one mechanism of controlled transport of physiological ions such as sodium (Na+), potassium (K+), calcium (Ca2+) and chloride (Cl-) into and out of the cell. Natural ion channels are large and very complex proteins that are able to rapidly transport ions across the cell‟s bilayer membrane with high selectivity. In order to understand which structural characteristics are required for effective and selective ion transport, a range of macrocyclic compounds based on calix[4]arenes, oxacalix[3]arenes, pillar[5]arenes and diaza-18-crown-6 was synthesised as models for channel-forming biomolecules. Through synthetic modifications and comparisons with their monomeric equivalents, it was possible to determine relationships between their structures and their activities. Polyether-based substituents, including an extended polyether, which incorporated a trans-but-2-ene linker, were attached in order to produce membrane-spanning molecules. The key elements investigated were the effect of the macrocycles compared to their monomeric equivalents, the effect of macrocyclic cavity size on ion selectivity, the effect on ion conductance observed between a rigid macrocycle compared with a flexible macrocycle and the impact of altering polyether chain length and functionality on ion conductance and selectivity. The compounds‟ ion transport abilities were assessed on artificial planar lipid bilayers and their antimicrobial activities determined by a variation of the Kirby-Bauer disc diffusion test on the common pathogens: E. coli, S. aureus, P. aeruginosa and S. pyogenes. Planar lipid bilayer results demonstrated that a predetermined structure, the length of the polyether substituent and the fit between the size of the macrocycle to the cation were important for transmembrane ion conduction; whereas the monomeric analogues formed unregulated sized pores leading to irregular to no activity and general non-selectivity. The rigid macrocycle compared to the flexible macrocycle demonstrated key differences in conduction where it is postulated that the flexible macrocycle conducted ionophorically. Antimicrobial tests revealed that the monomeric derivatives were significantly more potent towards bacteria than their macrocyclic equivalents, presumably due to the production of surfactant-like activity whilst the macrocyclic analogues displayed limited aqueous solubility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.720801  DOI: Not available
Keywords: B000 Health Professions
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