A New Approach to Drug Delivery: Non- Peptidic, High Load Macrocyclic Alternatives to Cell Penetrating Peptides

Calixarenes are versatile macrocycles formed from the condensation of para-tertbutyl- phenol and formaldehyde. Chapter 1 describes the synthesis of these molecules and how conformational control and selective functionalisation can give an array of molecules with customised properties; this allows for various applications including those of biological relevance. The copper catalysed alkyne-azide cycloaddition (CuAAC) reaction is also introduced as a tool for functionalising calixarenes. The phenomenon of cell penetration is of interest where a molecule has an intracellular target, for example gene therapy, delivery of cytotoxic agents or cellular imaging. Chapter 2 introduces the mechanisms of cell uptake and the design and applications of cell penetrating peptides. Calixarenes are presented as alternatives to cell penetrating peptides and the work published to date on intracellular delivery of calixarenes is summarised. A synthetic route for calixarenes with variable fluorescent dyes and different functionalities on the upper rim via a common intermediate is presented. Synthesis of an analogue featuring guanidinium groups on the upper rim was achieved using carboxybenzyl (Cbz) protecting groups as a less labile alternative to butoxycarbonyl (Boc) groups. The syntheses of analogues with varied linkers for attachment of the dye are also presented. Biological evaluation revealed that the dynamics of cellular uptake and the intracellular localisation were sensitive to the upper-rim functionalisation and the dye molecule. The linker attaching the dye had less impact. Chapter 3 describes the suitability of calixarenes as scaffolds to form glycoconjugates. These can be used to target Pseudomonas aeruginosa; research towards development of novel treatments of infections from this pathogen is summarised. A route that has been developed towards bifunctional calixarenes featuring a fluorescent tag and points of attachment for sugars via CuAAC reactions is presented. The use of alkyne protecting groups to maintain the integrity of the scaffold during transformations was found to be particularly important.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2013

Author dc:creator

• Karthauser, Zoe

Language dc:language

en