Gold(III) complexes bearing polypyridyl ligands based on the 1,10-phenanthroline (phen) have shown promising anti-cancer activity against a variety of tumor cell lines. In particular, our laboratory has found that a five-coordinate gold(III) complex possessing 2,9-di-sec-butyl-1,10-phenanthroline, [(sec-butylphen)AuCl3], was found to possess antitumor activity against in vitro tumor tumor cell lines, but limited activity against in vivo tumors in mice.  The current working hypothesis proposes that the limited in vivo activity of [(sec-butylphen)AuCl3] is due to the fact that this neutral complex may be binding to the blood protein serum albumin, which subsequently impedes its delivery to the tumor. It was found that [(sec-butylphen)AuCl3] did indeed have significant binding to bovine serum albumin which supports the hypothesis that this is the cause for limited in vivo activity. In order to test if decreasing non-polar functionality could possibly change the serum albumin binding, a 2-mono-sec-butylphen gold complex, [(mono-sec-butylphen)AuCl3], was synthesized. Serum albumin binding studies with [(sec-butylphen)AuCl3] and [(mono-sec-butylphen)AuCl3] have been completed and it was determined that there was significant binding to serum albumin. In an effort to determine if [(sec-butylphen)AuCl3] dissociates and imparts a ligand-centered cell death mechanism or kills tumor cells in a distinct manner compared to the free ligand, a series of structural analogues to the original (sec-butylphen) are currently being targeted by our labdeing targeted by our lab.omplex, a series of structural analogues to the original secbutylphenAuCl3 complex are currenlty . To date, the ligands (mono-methylphen), (mono-methyl-mono-sec-butylphen), and (di-phenyl-methylphen), and the gold(III) complexes [(mono-methyl-mono-sec-butylphen)AuCl3] and [(di-phenyl-methylphen)AuCl3] have been synthesized. For future work, sulforhodamine B (SRB) assays will be performed to determine the IC50 values of the entire library of ligands and gold(III) complexes. The IC50 values of the new ligands and complexes will be compared to the original IC50 values of sec-butylphen and [(sec-butylphen)AuCl3], respectively. If the ligands have higher IC50 values, but the gold complexes have similar IC50 values to the original  [(sec-butylphen)AuCl3] complex this will suggest the gold complexes have a distinct mechanism of imparting tumor cell death.

Anticancer activity of gold(III) complexes and ligands bearing alkyl-substituted phenanthroline ligands

247th National Meeting (2014)

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