Antitumor properties of five-coordinate gold(III) complexes bearing substituted polypyridyl ligands.
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 {[((R)phen)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 ([((methyl)bipy)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-butyl)phen)AuCl3] and [((methyl)bipy)AuCl3]) were subsequently assessed for their stability against the biological reductant glutathione, and it was found that the [((sec-butyl)phen)AuCl3] complex exhibits slightly enhanced stability compared to the [((methyl)bipy)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-butyl)phen)AuCl3] complex was found to be more cytotoxic than cisplatin against five different tumor cell lines, whereas [((methyl)bipy)AuCl3] had more limited in vitro antitumor activity. Given that [((sec-butyl)phen)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.
Emory University, Department of Chemistry, Atlanta, GA, United States.
Chinar D
CD
Sanghvi
Pauline M
PM
Olsen
Catherine
C
Elix
Shifang Bruce
SB
Peng
Dongsheng
D
Wang
Zhuo Georgia
ZG
Chen
Dong M
DM
Shin
Kenneth I
KI
Hardcastle
Cora E
CE
MacBeth
Jack F
JF
Eichler
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005978:Glutathione / Q000737:chemistry; D006046:Gold / Q000737:chemistry*; D017612:Gold Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D013053:Spectrophotometry / Q000379:methods; D047368:Tumor Burden / Q000187:drug effects; D014961:X-Ray Diffraction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D017612:Gold Compounds; D011725:Pyridines; D006046:Gold; D005978:Glutathione; C023666:pyridine
Anticancer; Gold(III); Polypyridyl; Serum albumin