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Design of osmium arene anticancer complexes
| Content Provider | Semantic Scholar |
|---|---|
| Author | Peacock, Anna |
| Copyright Year | 2006 |
| Abstract | Ru11 r16-arene half-sandwich complexes, [(1 6-arene)Ru(XY)Cl] where XY = chelating ligand, show promising anticancer activity both in vitro and in vivo, including activity against cisplatin-resistant cell lines. Potential biological and medical applications of organometallic complexes are hampered by a lack of knowledge of their aqueous solution chemistry. In this thesis the biological activity and aqueous solution chemistry of half-sandwich Os " arene complexes of the type [( 6-arene)Os(XY)Cl] is explored, and it is demonstrated that these properties can be tuned by careful choice of XY chelating ligand (N,N-, 0,0and N,0-chelates) to achieve cancer cell cytotoxicity comparable to carboplatin. The osmium complexes containing N,N-chelates hydrolyse more slowly that their ,ruthenium analogues and the PKa of the resulting water is more acidic. Efforts to increase the rates of hydrolysis and the resulting pKa led to replacement of the neutral N,N-chelating ligand by an anionic 0,0-chelate. This was successful in that hydrolysis is more rapid (too fast to follow by NMR) and the pKa of the coordinated water has increased by ca. 0.8 units. However, these complexes are deactivated by formation of the inert and thermodynamically stable hydroxo-bridged dimers, [(71 6_ arene)0s(p-0H)30s(i 6-arene)], the proportion of which increases with decrease in metal concentration (predominating at micromolar concentrations), even in the presence of 0.1 M saline. Although G (guanine) and A (adenine) bases bind rapidly to 6-arene)0s(0,O)}, and more strongly to Os" than to Ru", the Os" adduct [(1 6 {(i p-cym)Os(ma1)(G)] was unstable with respect to formation of the hydroxo-bridged dimer at micromolar concentrations. Attempts to tune the stability of complexes containing XY = 0,0-chelate, by replacing the 6-membered 0,0-chelate with 5membered analogues, was partially successful for the development of active complexes, but was unsuccessful in preventing hydroxo-bridged dimer formation. Within the class of N,Nand N,O-chelated complexes the choice of donor group is important. Replacing amine N-donor groups with the it-acceptor pyridine, reduced both the rate of hydrolysis and pKa of coordinated water, and increased the overall stability of the complex. This was especially the case for complexes containing N,Ochelates, which displayed aqueous chemistry in between that of the parent compounds containing neutral N,Nor anionic 0,0-chelates. Within this group of osmium arene complexes, [(i 6-arene)Os(N,O)Cl], active cytotoxic complexes were obtained, and the first X-ray crystal structures of osmium bound to either G or A nucleobases is reported. This work shows that a wide range of reactivity can be obtained for complexes of the form [(i 6-arene)Os(XY)Cl] by careful choice of the XY chelating ligand, including control of hydrolysis rates, acidity of bound water, formation of hydroxo-bridged dimer, and this knowledge has allowed complexes with cancer cell cytotoxicity to be designed. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://www.era.lib.ed.ac.uk/bitstream/handle/1842/15612/Peacock2006.Pdf?isAllowed=y&sequence=1 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
