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Arene Ruthenium(II) Thiosemicarbazone complexes as anticancer agents
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Noffke, Anna Louise (2015) Arene Ruthenium(II) Thiosemicarbazone complexes as anticancer agents. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2754009~S1
Abstract
This thesis presents the synthesis and characterisation of thiosemicarbazones (TSCs) and their arene ruthenium complexes for the use as anticancer agents. Based on substituted benzaldehyde derivatives, 12 different TSCs were used as N,S-chelating ligands in 24 different ruthenium half-sandwich complexes. The variations in their general structure [(p-cymene)Ru(RTSC)Z]+[A] include the use of both chloride and iodide as monodentate Z ligand. Iodine substituents in the TSC (R = I) were used to introduce a possible tracer moiety.
Structure and reactivity elucidations by NMR, ESI-MS and X-ray absorption spectroscopy in Chapters 2 and 3 include the 15N-NMR chemical shift determination for the 12 TSCs by 1H15N-HMBC NMR in solution. The TSC imino (N1) and the hydrazinic (N2) nitrogen atoms exhibit significant 15N-NMR chemical coordination shifts of -60 ppm and +122 ppm, respectively. The latter indicates deprotonation of the NH in solution.
X-ray crystal structures of two complexes are presented, for [(p-cymene)Ru(PTSCNMe2)][PF6] and for the dinuclear complex [(p-cymene)Ru(DTSCIPh)]2[PF6]2. The crystallographic data were used as models for theoretical stting of Ru K-edge EXAFS data. The EXAFS fits to data obtained for the presented complexes strongly match the first coordination sphere found in the crystal structure of complex. Solution-state XAS on freeze-quenched aliquots of a solution of [(p-cymene)Ru(DTSCNMe2)Cl]Cl confirm its conversion into.
[(p-cymene)Ru(PTSCNMe2)I]PF6 and [(p-cymene)Ru(ITSCNMe2)I]PF6 with an iodine substituent are investigated in Chapter 4. Both have antiproliferative activity (IC50 = 2 M) against human ovarian cancer cells (A2780) , causing cell-cycle arrest in G1-phase and induction of apoptotic pathways. The strategic positional variations of iodine labels within this series combined with the simultaneous detection of 101Ru and 127I by ICPMS showed that the monodentate ligand Z does not enter the cancer cells. In contrast to this, the aromatic iodine substituent in the TSC ligand of [(p-cymene)Ru(R-TSC)I]+ enhances cellular accumulation of both ruthenium and TSC-bound iodine, but not the cytotoxicity of the complex.
| Item Type: | Thesis (PhD) | ||||
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| Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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| Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Aromatic compounds -- Therapeutic use, Ruthenium compounds -- Therapeutic use, Thiosemicarbazones -- Therapeutic use | ||||
| Official Date: | 15 January 2015 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | Department of Chemistry | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | Sadler, P. J. | ||||
| Sponsors: | Warwick Postgraduate Research Scholarship | ||||
| Extent: | viii, 226 leaves : illustrations (black and white, and colour). | ||||
| Language: | eng |
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