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Title: Ruthenium (II) complexes as potential chemotherapeutic agents
Author: Morris, Robert
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Five aminophosphine complexes of Ru(II) have been prepared as potential chemotherapeutic agents and characterised by NMR and X-ray crystallography. The chelate ring-opening process of the bidentate aminophosphine ligand in the complex cis, trans-[Ru(H2NCH2CH2PPh2-N,P)2Cl2 has been investigated by 2D NMR methods. The complex undergoes a ring-opening reaction in coordinating solvents via the cleaving of the Ru-N bond. This exposes a potential binding site on the metal, and leads to the possibility of in vivo reactivity. A range of water-soluble Ru(II)arene complexes of the type [(h6-arene)RuIIX(L-L)]- [(h6-arene)RuIIX(L)2]- and [(h6-arene)RuIIX2L], arene = benzene, p-cymene, alkylbenzoate, biphenyl, L-L = ethylenediamine, L = acetonitrile, isonicotinamide, X=Cl, Br, I, have been synthesised with an aim to produce anticancer active agents. They have been characterised by NMR and X-ray crystallography. The hydrolysis of [(h6-p-cymene)RuIICl(en)]+ and [(h6-biphenyl)RuIICl(en)]+ has been followed by HPLC and ESI-MS and an HPLC assay developed for use in studies relating to biological testing. The reactions of a range of Ru(II)arene complexes with the nucleotides 5'GMP, 5'CMP, 5'AMP and 5'TMP have been investigated by NMR. The complex [(h6-p-cymene)RuIICl(en)]+ binds to 5'GMP at the N7 of the guanine moiety. On reaction with a 14mer duplex oligonucleotide of known sequence it was found to lower the melting temperature of the duplex significantly to a level comparable to cisplatin. The complex forms mono and bis adducts with the oligonucleotide in a guanine specific manner, as elucidated by HPLC separation, ESI mass spectrometry and enzymatic digestion. Cytotoxic studies on Ru(II) compounds revealed a significant effect against the ovarian cancer cell line A2780. Cross resistance studies indicate that the complex [(h6-p-cymene)RuIICl(en)]+ is influenced by the protein p53, but ([h6-biphenyl)RuIICl(en)]+ possibly functions as an inhibitor of topoisomerases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available