title: Inhibition of the cathepsin cysteine proteases B and K by square-planar cycloaurated gold(III) compounds and investigation of their anti-cancer activity.
abstract: Gold(III) compounds have been examined for potential anti-cancer activity. It is proposed that the molecular targets of these compounds are thiol-containing biological molecules such as the cathepsin cysteine proteases. These enzymes have been implicated in many diseases including cancer. The catalytic mechanism of the cathepsin cysteine proteases is dependent upon a cysteine at the active site which is accessible to the interaction of thiophilic metals such as gold. The synthesis and biological activity of square-planar six-membered cycloaurated Au(III) compounds with a pyridinyl-phenyl linked backbone and two monodentate or one bidentate leaving group is described. Gold(III) cycloaurated compounds were able to inhibit both cathepsins B and K. Structure/activity was investigated by modifications to the pyridinyl-phenyl backbone, and leaving groups. Optimal activity was seen with substitution at the 6 position of the pyridine ring. The reversibility of inhibition was tested by reactivation in the presence of cysteine with a bidentate thiosalicylate compound being an irreversible inhibitor. Five compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. The thiosalicylate compound was tested in vivo against the HT29 human colon tumor xenograft model. A modest decrease in tumor growth was observed compared with the untreated control tumor.
authors.affiliation: Formerly of AnorMED Inc., Langley, BC, Canada.
authors.forename: Yongbao
authors.initials: Y
authors.lastname: Zhu
authors.forename: Beth R
authors.initials: BR
authors.lastname: Cameron
authors.forename: Renee
authors.initials: R
authors.lastname: Mosi
authors.forename: Virginia
authors.initials: V
authors.lastname: Anastassov
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cox
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
authors.forename: Zefferino
authors.initials: Z
authors.lastname: Santucci
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D057056:Cysteine Proteases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006046:Gold / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID
chemical_list: D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D006046:Gold; D057056:Cysteine Proteases; D002401:Cathepsin B; D056657:Cathepsin K