Zhao, Yao, (Researcher in chemistry) (2012) Synthesis, characterization, photochemistry and anticancer activity of novel photoactivatable platinum(IV) diazidodihydroxido complexes. PhD thesis, University of Warwick.

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Abstract

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.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Antineoplastic agents, Platinum compounds -- Therapeutic use, Platinum compounds -- Synthesis, Photochemistry
Official Date:	June 2012
Dates:	Date Event June 2012 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Sadler, P. J.
Sponsors:	University of Warwick ; Overseas Research Students Awards Scheme (ORSAS)
Extent:	xxvi, 295 leaves : illustrations, charts
Language:	eng

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