1. Design of osmium arene anticancer complexes
- Author
-
Peacock, Anna F. A.
- Subjects
615 - Abstract
In this thesis the biological activity and aqueous solution chemistry of half-sandwich Os
11 arene complexes of the type [(η6 -arene)Os(XY)C1] is explored, and it is demonstrated that these properties can be tuned by careful choice of XY chelating ligand (N,N-, O,O- and N,O-chelates) to achieve cancer cytotoxicity comparable to carboplatin. The osmium complexes containing N,N-chelates hydrolyse more slowly than 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 O,O-chelate. This was successful in that hydrolysis is more rapid 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. Attempts to tune the stability of complexes containing XY = O,O-chelate, by replacing the 6-membered O,O-chelate with 5-membered analogues, was partially successful for the development of active complexes, but was unsuccessful in preventing hydroxo-bridged dimer formation. Within the class of N,N- and N,O-chelated complexes the choice of donor group is important. Replacing amine N-donor groups with the Π-acceptor pyridine, reduced both the rate of hydrolysis and pKa or coordinated water, and increased the overall stability of the complex. This was especially the case for complexes containing N,O-chelates, which displayed aqueous chemistry in between that of the parent compounds containing neutral N,N-or anionic O,O-chelates. Within this group of osmium arene complexes, [(η6 -arene)Os(N,O)C1], 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 [(η6 -arene)Os(XY)C1]n+ by careful choice of the XY chelating ligand, and this knowledge has allowed complexes with cancer cell cytotoxicity to be designed.- Published
- 2006