| From examination of crystal structures of various aminoglycosides bound to the model A-site sequence, a pattern of RNA contacts was observed between the members of 4,6 and 4,5 substituted classes of compounds. In addition to RNA contacts common to both classes, RNA contacts unique to each class were also identified. A new aminoglycoside was designed as a combination of both 4,6 and 4,5 classes. This 5-ring, novel aminoglycoside would maintain all binding contacts exhibited by both classes of aminoglycosides and would therefore be characterized by superior RNA binding affinities. Molecular dynamics confirmed the proposed binding mode. Two glycosylation-based approaches to the new compound were explored---glycosylation of the 4,6 scaffold at the 5 position, and glycosylation of the 4,5 scaffold at the 6 position. Neither approach led to the final desired compound, likely for reasons of steric hindrance.;Perfluoroalkyl-tailed, saccharide-based surfactants were prepared and explored for use as stabilizers of aqueous emulsions of sevoflurane, a volatile, highly fluorinated anesthetic. Two kinds of compounds were synthesized---fluoroalkyl and alkyl mannosides (single-headed), as well as di- and tri-glucose orthoesters of a perfluoroalkyl diol and triol (multi-headed).;Introduction of the fluoroalkyl tail was accomplished by glycosylation and Cu-catalyzed azide alkyl cycloaddition. Despite having dramatically higher solubility in its free form over other like sugars, mannose-based head groups did not provide sufficient aqueous solubility for mannosides coupled to longer fluoroalkyl tails. Shorter fluoroalkyl tails failed to stabilize sevoflurane emulsions as the sole surfactants. Di and tri-headed fluoroalkyl saccharides were then prepared. The increased number of sugar groups was expected to provide higher water solubility. Interestingly, the synthetic route followed to make these molecules yielded glycosyl orthoesters rather than the expected di- and tri-alcohol glycosides. Increased solubility and ability for emulsion formation was indeed observed with the di-glucose compound. Nevertheless, the physical properties and microscopic nature of the emulsion aggregates precluded their use in intravenous sevoflurane formulations. The tri-glucose compound proved to be extraordinarily prone to self-assembly and led to gelation of the emulsion mixture. TEM imaging of an aqueous preparation of the tri-glucose material alone revealed well-defined, left-handed, helical nano-fibers with several distinct morphologies. |
