Our laboratory has found that a pseudo-five coordinate gold(III) complex possessing 2,9-di-sec-butyl-1,10-phenanthroline, [(di-sec-butylphen)AuCl3], exhibits antitumor activity against in-vitro tumor cell lines, but limited activity against in-vivo tumors. The current working hypothesis proposes the limited in-vivo activity of [(di-sec-butylphen)AuCl3] is due to the fact that this neutral complex may be binding to the protein serum albumin, which subsequently impedes its delivery to the tumor. It was found that [(di-sec-butylphen)AuCl3] did indeed have significant binding to serum albumin, possibly explaining why there was limited in-vivo activity. Given these results current studies aim to determine if the serum albumin binding can be inhibited by the design of new gold(III) complexes possessing increased polar character. Previous results also indicate that the di-sec-butylphen ligand has remarkable in-vitro antitumor activity, and parallel studies have therefore aimed to determine if [(di-sec-butylphen)AuCl3] dissociates and imparts a ligand-centered cell death mechanism or kills tumor cells in a distinct manner compared to free ligand. Structural analogues of the di-sec-butylphen ligand have been synthesized, including 2,9-di-sec-butyl-4-methyl-1,10-phenanthroline (di-sec-butyl-methylphen), 2,9-di-phenyl-1,10-phenanthroline (di-phenylphen), 2-sec-butyl-1,10-phenanthroline (mono-sec-butylphen), 2-n-butyl-1,10-phenanthroline (mono-n-butylphen), and 6-sec-butyl-2,2'-bipyridine (mono-sec-butylbipy). The corresponding gold(III) complexes, (di-sec-butyl-methylphen)AuCl3], [(di-phenylphen)AuCl3], [(mono-sec-butylphen)AuCl3], [(mono-n-butylphen)AuCl3], and [(mono-sec-butylbipy)AuCl3], have also been synthesized and structurally characterized by single crystal X-ray diffraction techniques. Sulforhodamine B (SRB) assays have been performed to determine the in-vitro antitumor efficacy of the entire library of phen ligands and gold(III) complexes, and the activity of the new ligands and complexes have been compared to the original IC50 values of sec-butylphen and [(sec-butylphen)AuCl3]. The data reported here indicate the antitumor activity of the gold(III) complexes does not change as a function of the ligand IC50. This lack of correlation suggests the gold(III) complexes have a distinct mechanism of imparting tumor cell death compared to their respective ligands, and should therefore be further investigated for their potential application as metal-based chemotherapies.

Anticancer efficacy of unusual five-coordinate gold(III) complexes: Distinct mechanism of tumor cell death or expensive ligand delivery systems?

248th National Meeting (2014)

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