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

Karthauser, Zoe (2013) A New Approach to Drug Delivery: Non- Peptidic, High Load Macrocyclic Alternatives to Cell Penetrating Peptides. Doctoral thesis, University of East Anglia.

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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.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Users 2259 not found.
Date Deposited: 12 Mar 2014 17:14
Last Modified: 12 Mar 2014 17:14
URI: https://ueaeprints.uea.ac.uk/id/eprint/48136


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