The synthesis and characterization of simple mimics of pore forming antibiotics such as amphotericin B were explored. A sub-unit approach to the synthesis was employed which allowed for construction of a set of candidate structures. The targets are assembled by joining two "wall" units via a "linkage" unit with subsequent addition of polar head groups to either end of the structure. The wall units are macrocyclic diene tetraesters derived from maleic anhydride prepared by either acid catalyzed ester formation from diols or carboxylate substitution of dihalides (compounds 14, 15, 22, 23, 24, 30, 31, 34). Either set of reaction conditions limit the range of functionality possible in the starting diol or dihalide. Macrocycles 22, 23, and 24 were linked with m-xylylene dithiol via a 2:1 Michael addition reaction to give bis-macrocyclic alkene precursors. Alternatively, macrocycles 22 and 23 reacted with 3-thio-1-propanol and the mono-alcohol products were converted to iodides which were linked with 2R,3R-(+)-tartaric acid. Three types of polar head groups--neutral (1-thio-β-D-glucose and 3-thio-1-propanol), cationic (2-aminoethanethiol), and anionic (2-thioacetic acid)--were added to the bis-macrocyclic alkene precursors via Michael addition reactions. A total of fourteen candidate structures were prepared for transport evaluation.
The activity of the fourteen mimics synthesized were determined by the pH-stat technique in which the transport of alkali metal cations across large unilamellar lipid bilayer vesicles were monitored by the collapse of a proton gradient. All the active compounds showed a zero order decay in proton gradient. Of the fourteen mimics surveyed, three had activities comparable to amphotericin B (compounds 51, 52, and 59). The other eleven compounds were not sufficiently active for further characterization. The "add back" experiments, the kinetic orders, and the alkali metal ion selectivity studies are consistent with the proposal that the mimics behave as pore formers. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/9565 |
| Date | 29 June 2018 |
| Creators | Zojaji, Mohammad |
| Contributors | Fyles, Thomas M. |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Available to the World Wide Web |
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