Platinum complexes as potential photochemotherapeutic agents
Abstract
A major challenge of platinum anticancer therapy lies in overcoming the severe
side-effects associated with treatment. Photoactivatable PtIV azido complexes,
which are stable in the dark and reduced to cytotoxic PtII species upon irradiation,
have recently emerged as a potential site-specific treatment. This thesis is
concerned with the investigation of PtII and PtIV azido complexes as potential
cytotoxic and photochemotherapeutic agents.
PtII azido complexes such as [Pt(en)(N3)2] were shown to bind to both
5'-guanosine monophosphate (5'-GMP) and glutathione, at a much reduced rate
compared with their PtII chlorido analogues. Interestingly, and unexpectedly, these
PtII azido complexes showed moderate cytotoxicity towards the A2780 cancer cell
line (IC50 21–47 μM). Binding to 5'-GMP was observed to occur more rapidly
upon irradiation with UVA light, although the extent of binding was low and the
complexes did not demonstrate phototoxicity towards HaCaT keratinocytes.
The pendant hydroxyl group of a PtII azido complex was functionalised with a
fluorescent probe; conjugation to one axial hydroxyl ligand of a PtIV azido
complex was also achieved. The latter conjugate showed a rapid increase in
fluorescence intensity upon irradiation, resulting from loss of the axial ligands
upon photoreduction. The functionalisation of quantum dots with PtII complexes
was also investigated. Water soluble CdSe-ZnS quantum dots were synthesised
and derivatised with an amine ligand to which platinum was bound. Conjugation
of apo-transferrin to quantum dots was also achieved, with subsequent platinum
binding yielding a conjugate with improved aqueous solubility and fluorescence
properties. However, the conjugate was inactive towards the A2780 cancer cell
line, likely due to surface modifications preventing cellular internalisation. PtII
chlorido and azido conjugates with a porphyrin were synthesised and found to
show differing behaviour upon irradiation with visible light; evidence of hydrogen
peroxide generation from the chlorido complex was much reduced in the case of
the azido complex; it is suggested this may result from quenching of reactive
oxygen species by the azide anion released upon irradiation.
PtII chlorido and azido complexes of highly coloured azo ligands were synthesised
in an attempt to shift the wavelength of activation into the visible region. TD-DFT
calculations allowed frontier orbital analysis and assignment of the transitions in
the absorption spectra. Irradiation of the PtII azido complexes with UVA or
broadband visible light led to their decomposition; one water-soluble complex
was found to show moderate cytotoxicity and phototoxicity; in addition, its
intense blue colour allowed for visual monitoring of this complex inside cells.