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Title: Reaction of photoactive platinum anticancer complexes with biomolecules
Author: Phillips, Hazel I. A.
ISNI:       0000 0004 2724 4347
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2011
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Photoactive platinum compounds have the potential to reduce some of the debilitating side-effects associated with conventional chemotherapeutics, such as cisplatin. Stable platinum(IV) complexes which are reduced to active platinum(II) species only on irradiation, could provide a site-specific treatment. The photodegradation pathways of the photoactive platinum(IV) diazido complex cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] have been extensively studied. Various photoisomerisation, trans-labilisation and photoreduction pathways were observed, with several unexpected photoproducts including ammonia, oxygen and free azide. The photoreactions of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] in the presence of two amino acid derivatives, N-acetyl-L-histidine and N-acetyl-L-methionine, and the nitrogen-heterocycle 1-methylimidazole, have also been investigated. In the presence of 1-methylimidazole, surprisingly the major photoproduct was the tetra-substituted PtII complex [PtII(1-MeIm-N3)4]2+, even at a Pt/1-MeIm molar ratio of 1:1. Reactions with the amino acid derivatives identified some unusual di- and tri-substituted platinum(II) photoproducts. This work has involved using a variety of techniques including multinuclear NMR spectroscopy, DFT/TD-DFT calculations and electrospray ionisation-mass spectrometry (ESI-MS). The reaction of cisplatin (cis-[PtCl2(NH3)2]) with the protein ubiquitin was investigated using ion mobility-mass spectrometry (IM-MS), revealing multiple induced protein conformations upon platination. The preferred binding site of cisplatin on the amino acid Met1 was also directly identified for the first time. The primary platination site of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] and trans,trans,trans-[Pt(N3)2(OH)2(NH3)2] on ubiquitin was also investigated, and found to be Met1. The ESI-MS studies highlight the rapid generation and diverse nature of the photoinduced reactive platinum(II) species after short UVA irradiation times. Insights into the reaction of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] with cytochrome c are also reported. The antiviral properties of cisplatin (cis-[PtCl2(NH3)2] and the photoinduced activity of cis,trans,cis-[Pt(N3)2(OH)2(NH3)2] and trans,trans,trans-[Pt(N3)2(OH)-2(NH3)2] were assessed against the bacterial virus bacteriophage P1. This work has highlighted the complex and novel speciation of such platinum(IV) complexes upon irradiation, which may lead to new cytotoxic mechanisms in cancer cells.
Supervisor: Not available Sponsor: Engineering and Physical Sciences Research Council (EPSRC) ; University of Edinburgh ; University of Warwick
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry