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Investigating the role of metal-ligand bonding on biological activity of metallotherapeutics

University of British Columbia

Defining and understanding the structure activity relationship and mechanisms of action of pharmaceutical agents in a biological environment is vital for their faster and successful clinical development. The mode of activation is often complicated for metalloanticancer drugs due to their wide spectrum of activity and interactions with biomolecules, during and after transport to cancer cells. The research herein describes the investigation of thiolate ligand oxygenation and its potential role in the mechanism of action for a family of “half-sandwich RuII arene” anticancer complexes. X-ray absorption spectroscopy (XAS), in concert with density functional theory (DFT) calculations, has been used to describe the influence of thiolato oxygenation on the nature of the Ru-S bond with the effect on ancillary ligands modifications in the parent thiolato (M-SR) and oxidized sulfenato (M-SOR) and sulfinato (M-SO₂R) species respectively. This study suggests that the sulfenato species are most susceptible to ligand exchange, but only via activation by protonation of the terminal oxo group. Perturbations of the sulfenato and sulfinato species can be achieved via either protonation or Lewis acid interaction; however the effect is greater in the sulfenato compared to that of sulfinato. DFT calculations are in agreement with the experimental data. Further studies of the electronic structure of a broader series of OsII and RuII arene complexes have been performed using a similar combined spectroscopic and computational approach. Results from these studies provide important new insights into the chemical and biochemical properties of these complexes. Finally, these studies uncover the correlation between the electronic structure and reactivity that is important and must be considered when investigating the transition metal complexes in medicinal chemistry.

Text

2013-07-10

Attribution 3.0 Unported

http://hdl.handle.net/2429/44641

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by/3.0/