PtIV-diazidodihydroxido complexes are inert in the dark, but can be selectively activated by irradiation with light and become potently cytotoxic towards cancer cells. By site-specific irradiation to tumour tissue, the side-effects to healthy tissue associated with conventional chemotherapeutics, such as cisplatin, can be circumvented. This thesis aims to develop design photoactivatable platinum(IV) diazidodihydroxido complexes to achieve higher photocytotoxicity, lower crossresistance and longer wavelength of activation. A series of PtIV diazidodihydroxido complexes with trans azido, trans hydryxido groups and mixed trans aliphatic/aromatic amines, was designed, synthesized and characterized. Trans, trans, trans-[Pt(N3)2(OH)2(MA)(Py)] (5) and trans, trans, trans-[Pt(N3)2(OH)2(MA)(Tz)] (8) are potently cytotoxic towards A2780, OE19 and HaCaT cell lines upon irradiation with UVA. Remarkably, they also showed potent cytotoxic effects towards A2780cis (cisplatin-resistant ovarian cancer cell subline). Also, the photocytotoxicity towards the A2780, A2780cis, OE19 and HaCaT cell lines upon irradiation with blue light (λmax = 420 nm) is still potent compared to that upon irradiation with UVA. These complexes are highly inert in the absence of light and have almost no dark toxicity. Upon irradiation with UVA/blue light, the complex 5 was observed to release free azide anions N3−, azidyl radicals N3•, nitrogen gas N2 and form nitrene intermediates. It was of importance to discover that singlet oxygen (1O2) is generated from photoreactions in the absence of an exogenous source of oxygen, whereas hydrogen peroxide (H2O2) and hydroxyl radical intermediates did not appear to be formed. Mono-functional and bi-functional Pt adducts were captured from the photoinduced binding of complexes 5 and 8 to 5'-GMP and a DNA oligonucleotide. It was discovered for the first time that the oxidation of 5'-GMP can occur during the photoreaction of complex 5 upon irradiation with UVA. Singlet oxygen and nitrene intermediate generated from this photoreaction are likely to be the cause of the oxidative damage to guanine. 4-Nitropyridine, 2,2'-bipyridine, and terpyridines were used as ligands in novel photoactivable PtIV (di)azido complexes and two were activated by green light. A new two-photon-activatable PtII complex, cis-[PtCl2(MOPEP)2](42), was also designed, synthesized and characterized. It was observed that this complex was sensitive to one-photon excitation below 500 nm and the ligand MOPEP underwent rapid solvent (acetonitrile) substitution upon irradiation. The same photoreaction was also triggered by two-photon excitation with fs-pulses laser light between 600 – 700 nm.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:564428 |
| Date | January 2012 |
| Creators | Zhao, Yao |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/52700/ |
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