Chemotherapeutics are potent molecules capable of systematically treating cancer. As healthy tissues contain features also inherent to cancer cells, treatment often results in unwanted sideeffect. As chemotherapeutic side-effect produces significant harm and often limits optimal drug dosing, new strategies must be developed to improve treatment selectivity. A prodrug strategy provides one option to improve the selectivity of an established chemotherapeutic. By modifying a pharmaceutically active drug, interaction with biology may be functionally masked. Subsequent ‘un-masking’ the prodrug exclusively at the intended treatment site may direct treatment only to where the anticancer effect is required. This thesis progresses the novel approach of bioorthogonal organometallic (BOOM) prodrug activation. A metal catalyst and masked chemotherapeutic constitute reaction partners to provide a new strategy for intratumoural prodrug activation. Whereby the prodrug and metal catalyst are independently non-cytotoxic, in combination the prodrug undergoes catalytic activation to deliver an anticancer affect. By positioning the metal catalyst within a tumour (i.e. by microsurgery), an administered masked prodrug sensitive to catalyst-mediated activation could allow for ‘targeted’ chemotherapy localised to the tumour site. The design, synthesis and study of new BOOM prodrug candidates are reported herein. Novel protecting groups are developed to enhance drug masking to biology and subsequent catalyst-mediated activation. Prodrug screening studies are carried out in cancer cell culture models, with zebrafish and in ex vivo rodent model tumour explants. The catalyst, a palladium (Pd0) functionalised bead system, is optimised for enhanced activation, drug release and in vivo implantation. The potentially infinite generation of active chemotherapeutics exclusively in tumour would increase the efficacy of treatment whilst reducing harmful effect on healthy tissue.

Powerful tools have emerged in the past few years to allow the sensing, imaging and modulation of biological processes in living systems. Bioorthogonal organometallic reactions are transformations catalysed by transition metals, which are compatible within a biological environment. Palladium-mediated cross-coupling and decaging reactions, for example, have been successfully applied to catalyse non-natural chemical transformations within a biological milieu. Up until now, copper-catalysed cycloaddition reactions have been used extensively for the conjugation, immobilisation, and purification of biomolecules, but their further application in vivo has been limited by the inherent toxicity of copper. Herein, different transition metal catalysts were designed and applied in cellular and in vivo manipulations. Polymeric solid supports were functionalised with palladium nanoparticles and used as biocompatible, heterogeneous catalysts in selective decaging and cross-coupling reactions to activate fluorescent probes and synthesise cytotoxic anticancer drugs in situ. In order to gain tumour selectively, targeting functionalities were incorporated into the particles to allow the spatial control of the selective activation of labelling probes. The simultaneous synthesis of two different anticancer agents intracellularly, by two totally different mechanisms (in situ synthesis and decaging), is reported. The cellular toxicity of copper was addressed by entrapping copper nanoparticles on a polymeric solid support, allowing the activation of labelling probes, as well as the synthesis of an anticancer agent from two benign components through the well-known copper catalysed azide-alkyne cycloaddition. The biocompatibility of the copper catalysts in vivo was shown by implantation in zebrafish embryos.

Ce manuscrit aborde plusieurs interactions / réactions chimiques importantes se produisant dans la soluton en utilisant la calorimétrie par titrage isothermique (ITC) et la théorie de la densité fonctionnelle statique (DFT). Cette thèse porte son attention notamment sur : l'association de paires de Lewis (frustrées) ((F)LPs), la migration cis du groupe méthyle au sein du pentaméthylmanganèse induit par les phosphines, l'aminolyse de carbènes de Fischer, l'insertion d'alcynes dans des palladacycles, l'affinité de divers donneurs de Lewis à l’hexafluoroisopropanol. L'ITC s'est révélé être une technique expérimentale puissante pour obtenir des données thermochimiques fiables sur les systèmes étudiés. Les calculs statiques DFT-D ont montré une capacité d’estimation correcte des paramètres de réaction thermodynamique lorsque l’influence de la solvatation n’est pas significative. Autrement, lorsque l’influence du solvant est apparente, les calculs ne permettent pas de reproduire les résultats expérimentaux. En plus, les résultats expérimentaux et théoriques révèlent l’existence d’ensembles moléculaires plus grandes dans la solution de FLP, soulignant le rôle des interactions non covalentes. / This manuscript adressed several important chemical interactions/reactions taking place in solutuon by using Isothermal Titration Calorimetry (ITC) and static Density Functional Theory (DFT). Namely, this thesis dealt with: association of (frustrated) Lewis pairs ((F)LPs), cis-migration of methyl group within pentamethylmanganese induced by phosphines, aminolysis of Fischer carbenes, insertion of alkynes into palladacycles, affinity of various Lewis donors to hexafluoroisopropanol. The ITC proved to be powerful experimental technique for obteining reliable thermochemical data of sutudied systems. The static DFT-D calculations showed capability for proper estiamtion of thermodynamic reaction parameters when an influence of solvation is not sighnificant. Otherwise, when the influence of solvent is not innocent, the calculations moslty failed to reproduce the experimantal results. In addition, Both the experimantal and therortical results revield existance of larger molecular clusters in solution of FLPs emphasising a role of non-covalent interactions.