UBC Theses and Dissertations
Coordination chemistry of antimicrobial and anticancer agents Mjos, Katja Dralle
The World Health Organization has named the resistance of microbes to known antimicrobial drugs as an increasingly serious threat to global public health. Isolates of the ESKAPE pathogens (E. faecium, S. aureus, K. pneumonia, A. baumanii, P. aeruginosa, and Enterobacter species) are responsible for many nosocomial infections each year that require complicated, and therefore expensive, medical treatment, often leading to death in immune-compromised patients. Over the past 50 years, (fluoro-)quinolone antimicrobial agents have been widely used in the clinic as broad-spectrum antibiotics, but lately growing resistance against this drug class has been reported. Combining metal ions with known organic small-molecule drugs is one strategy to overcome such developed resistances. Previously, the antimicrobial properties of copper(II) and gallium(III) had been investigated, leading to Greek mythology comparisons for their mechanism of action: Cu²⁺ as the ”Achilles Heel”, Ga³⁺ as the ”Trojan Horse” subterfuge for Fe³⁺. In this thesis, gallium(III) and copper(II) coordination complexes of (fluoro-)quinolone antimicrobial agents, and derivatives thereof, were synthesized in an attempt to combine the antimicrobial potency of Cu²⁺ and Ga³⁺ with that of the quinolone antimicrobial agents in one molecule. The antimicrobial susceptibility of these coordination complexes was evaluated against five isolates of the ESKAPE pathogens; combinational effects between the metals and the quinolone ligands were not observed. While the combination of metal ions with small, organic drug molecules may lead to novel potent metallodrugs, the interaction of metal ions with drugs in vivo is often associated with toxic side-effects of medical treatment, for which the iron(III)-mediated cumulative-dose cardiotoxicity of doxorubicin is one example. Vosaroxin is a first-in-class anticancer quinolone derivative in clinical trials. Unlike the anthracycline anticancer drug doxorubicin, vosaroxin is minimally metabolized in vivo. Spectrophotometric titrations and further studies of the isolated tris(vosaroxino)iron(III) and -gallium(III) complexes supported a strong coordination of the metal ion suggesting that vosaroxin treatment may not result in cardiotoxicity.
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