Reaction of photoactive platinum anticancer complexes with biomolecules
Phillips, Hazel I. A. (2011) Reaction of photoactive platinum anticancer complexes with biomolecules. PhD thesis, University of Warwick.Full text not available from this repository.
Official URL: http://webcat.warwick.ac.uk:80/record=b2580714~S1
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.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QD Chemistry|
|Library of Congress Subject Headings (LCSH):||Antineoplastic agents, Platinum compounds -- Therapeutic use, Photodegradation|
|Official Date:||September 2011|
|Institution:||University of Warwick|
|Theses Department:||Department of Chemistry|
|Supervisor(s)/Advisor:||Sadler, P. J.|
|Sponsors:||Engineering and Physical Sciences Research Council (EPSRC) ; University of Edinburgh ; University of Warwick|
|Extent:||xix, 339 leaves : ill., charts|
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