Document Type

Theses, Ph.D

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

1.6 BIOLOGICAL SCIENCES, Cell biology,, Biochemistry and molecular biology

Publication Details

Thesis sucessfully submitted to the Technological University Dublin in fulfilment of the requirements for PhD examination, June 2019.

Abstract

The folate receptor (FR) was identified in 1986 and has been established as a ‘molecular Trojan Horse’ target for the uptake of folate-conjugated organic molecules into cells. The FR is overexpressed in many malignancies, including those of the ovary, uterus, breast, cervix, and prostate, yet it is reportedly under-expressed in normal healthy cells. This difference in expression and the high affinity/specificity of folate towards the folate receptor presents a promising drug delivery system. The aim of this research was to utilise folic acid as a targeting moiety and generate simple metal folate and novel folate-phenanthroline complexes with cytotoxic properties. A challenging set of chemical objectives were set and resulted in the successful generation of simple metal-folate and metal-folate-phen complexes (metal = Cu2+, Mn2+, Fe3+ and Zn2+). In contrast to reports in the literature, NMR and IR evidence indicates that the folate ligand coordinates the metal centre via a tridentate ONO {α-COO-, γ-COO-, and Namide} binding mode. A challenging six-stage synthetic route yielded the novel folate-ethylenediamine-imidazole-phen (FIMP-et) ligand and the novel complexes [Cu(FIMP-et)2(H2O)2].(ClO4)2.4.5H2O and [Mn(FIMP-et)3].(ClO4)2.9H2O were subsequently isolated in high yield and purity. The complexes generated were then utilised in a series of biological studies using cellular models expressing the folate receptor. Our results suggest that the effects mediated by these complexes are not dependent on folate receptor expression. Western blot analysis and live cell analysis identified that [Cu(fol)(phen)(H2O)].3H2O, with or without the inclusion of folic acid, induced expression of proteins associated with proteasomal inhibition and apoptosis. In contrast, [Mn(fol)(phen)(H2O)].4H2O was ineffective in inducing proteasomal inhibition. Interestingly [Mn(fol)(phen)(H2O)].4H2O induces cell death through a mechanism independent of proteasomal inhibition, which may involve ROS-induced autophagy. This work advances the field of medicinal inorganic chemistry and has identified novel mechanisms of action for metal folate targeted inorganic complexes as potential chemotherapeutic agents, through proteasomal inhibition and ROS-induced autophagy.

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