Gold Chemistry

Cisplatin, [cis-diamminedichloroplatinum-(II)], has been used since 1978 to treat a number of different cancer cell lines; however, its effectiveness has been limited due to both harmful side effects and the development of cisplatin resistant cancers. Gold-(III) is an isoelectronic and isostructural species to platinum-(II), suggesting it has potential as an anticancer agent. In particular, gold-(III) complexes bearing bidentate ligands based on 1,10-phenanthroline and 2,2′-bipyridine have exhibited significant anticancer activity against a variety of tumor cell lines. Previously, our lab found that a pseudo five-coordinate gold-(III) complex bearing the 2,9-di-sec-butyl-1,10-phenanthroline ligand,[(di-sec-butylphen)AuCl3], exhibited anticancer activity against five different lung and head-neck tumor cell lines; however, the complex was found to be less active than the free 2,9-di-sec-butyl-1,10-phenanthroline ligand. In order to determine if our class of gold-(III) complexes have a distinct mechanism of tumor cell death or if they simply release the ligand into the intracellular environment, a library of structural analogues of the original complex were synthesized using mono-alkyl and di-phenyl substituted 1,10-phenanthroline ligands, di-alkyl and di-phenyl substituted 4-methyl-1,10-phenanthroline ligands, and mono-alkyl 2,2′-bipyridine ligands. The redox stability of these distorted square pyramidal gold-(III) complexes was studied and the in vitro antitumor activity of the gold-(III) complexes and corresponding free ligands were determined. The [(di-n-butylphen)AuCl3] and [(mono-n-butylphen)AuCl3] complexes were found to not only be more effective than cisplatin at inhibiting the growth of A549 lung tumor cells, but also more active than their respective free ligands, providing evidence that this class of gold-(III) complexes has a mechanism of tumor cell death that is independent of the free ligand. Currently, our laboratory is investigating the activity of platinum-(II) complexes with the same set of ligands based on 1,10-phenanthroline and 2,2′-bipyridine in an effort to compare their activity with our gold-(III) complexes. Structural analysis, as well as GSH and SRB studies, is currently underway.