Antitumor properties of five-coordinate gold(III) complexes bearing substituted polypyridyl ligands

• Two unusual five-coordinate gold(III) coordination complexes have been synthesized.
• [(sec-butylphen)AuCl3] was found to have lower in vitro IC50 values than cisplatin.
• [(sec-butylphen)AuCl3] was found to have limited in vivo antitumor activity.
• Binding studies indicate that [(sec-butylphen)AuCl3] binds to serum albumin protein.
• Binding of [(sec-butylphen)AuCl3]} to BSA is stronger than observed with cisplatin.

In an on-going effort to discover metallotherapeutic alternatives to the chemotherapy drug cisplatin, neutral distorted square pyramidal gold(III) coordination complexes possessing 2,9-disubstituted-1,10-phenanthroline ligands {[(Rphen)AuCl3]; R = n-butyl, sec-butyl} have been previously synthesized and characterized. A structurally analogous gold(III) complex bearing a 6,6′-di-methylbipyridine ligand ([(methylbipy)AuCl3]) has been synthesized and fully characterized to probe the effect of differing aromatic character of the ligand on solution stability and tumor cell cytotoxicity. The two compounds [(sec-butylphen)AuCl3] and [(methylbipy)AuCl3]) were subsequently assessed for their stability against the biological reductant glutathione, and it was found that the [(sec-butylphen)AuCl3] complex exhibits slightly enhanced stability compared to the [(methylbipy)AuCl3] complex and significantly higher stability than previously reported square planar gold(III) complex ions. Furthermore, these complexes were tested for cytotoxic effects against existing lung and head and neck cancer cell lines in vitro. The [(sec-butylphen)AuCl3] complex was found to be more cytotoxic than cisplatin against five different tumor cell lines, whereas [(methylbipy)AuCl3] had more limited in vitro antitumor activity. Given that [(sec-butylphen)AuCl3] had significantly higher antitumor activity, it was tested against an in vivo tumor model. It was found that this complex did not significantly reduce the growth of xenograft tumors in mice and initial model binding studies with bovine serum albumin indicate that interactions with serum albumin proteins may be the cause for the limited in vivo activity of this potential metallotherapeutic.

A neutral five-coordinate gold(III) complex possessing the 2,9-di-sec-butyl-1,10-phenanthroline ligand [(sec-butylphen)AuCl3], exhibited impressive in vitro antitumor activity but limited in vivo efficacy. It was found that [(sec-butylphen)AuCl3] has significant binding to a model serum albumin protein. This provides a possible explanation for the limited in vivo activity of this gold-based chemotherapy.Figure optionsDownload as PowerPoint slide