title: Synthesis, characterization, and antitumor activity of unusual pseudo five coordinate gold(III) complexes: distinct cytotoxic mechanism or expensive ligand delivery systems?
abstract: Gold(III) complexes bearing bidentate ligands based on the 1,10-phenanthroline and 2,2'-bipyridine scaffolds have shown promising anticancer activity against a variety of tumor cell lines. In particular, our laboratory has previously found that a pseudo five coordinate gold(III) complex possessing the 2,9-di-sec-butyl-1,10-phenanthroline ligand {[((di-sec-butyl)phen)AuCl3]} exhibits antitumor activity against a panel of five different lung and head-neck tumor cell lines. However, the [((di-sec-butyl)phen)AuCl3] complex was determined to be less active than the free 2,9-di-sec-butyl-1,10-phenanthroline ligand. In order to determine if this class of gold(III) complexes has a distinct mechanism of initiating tumor cell death or if these gold complexes simply release the polypyridyl ligand in the intracellular environment, structural analogues of the [((di-sec-butyl)phen)AuCl3] complex have been synthesized and structurally characterized. These structural congeners were prepared by 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 this library of distorted square pyramidal gold(III) complexes has been studied and the in vitro antitumor activity of gold(III) complexes and corresponding polypyridyl ligands has been determined. The [((di-n-butyl)phen)AuCl3] and [((mono-n-butyl)phen)AuCl3] complexes have been found to be significantly more potent at inhibiting the growth of A549 lung tumor cells than the clinically used drug cisplatin. More importantly, these two gold(III) complexes are significantly more active than their respective free ligands, providing evidence that this class of pseudo five coordinate gold(III) complexes has a mechanism of initiating tumor cell death that is independent of the free ligand.
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Olsen
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lussier
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Brian Khoa
authors.initials: BK
authors.lastname: Le
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Angel
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Smith
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Chihyun Brian
authors.initials: CB
authors.lastname: Hwang
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Raneen
authors.initials: R
authors.lastname: Khatib
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Jenkins
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Adams
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Getcher
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA.
authors.forename: Fook
authors.initials: F
authors.lastname: Tham
authors.affiliation: Emory University Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Zhou Georgia
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA, USA.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Wilson
authors.affiliation: University of California, Riverside, Department of Chemistry, Riverside, CA 92521-0129, USA. Electronic address: jack.eichler@ucr.edu.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Eichler
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000191:economics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010618:Phenanthrolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003603:Cytotoxins; D008024:Ligands; D050607:Organogold Compounds; D010618:Phenanthrolines; D015082:2,2'-Dipyridyl; D003300:Copper; D013880:Thioredoxin-Disulfide Reductase; D002945:Cisplatin
keywords: Anticancer; Gold(III); In vitro; Polypyridyl ligands