title: The biological activity of Zeise's salt and its derivatives.
abstract: With the aim to design new biologically active bioinorganic drugs of aspirin, whose mode of action is based on the inhibition of the cyclooxygenase(COX) enzymes, derivatives of Zeise's salt were synthesized in this structure-activity relationship study. Surprisingly, not only these Zeise-aspirin compounds but also Zeise's salt itself showed high inhibitory potency against COX enzymes in in vitro assays. In contrast, potassium tetrachloroplatinate and cisplatin did not influence the enzyme activity at equimolar concentrations. It was demonstrated by LC-ESI tandem-mass spectrometry that Zeise's salt platinates the essential amino acids Tyr385 (active site of the enzyme) and Ser516 (will be acetylated by aspirin) of COX-1, thereby strongly impairing the function of the enzyme. This finding demonstrates for the first time that Zeise's salt is pharmacologically active and is a potent enzyme inhibitor.
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin (Germany).
authors.forename: Sandra
authors.initials: S
authors.lastname: Meieranz
authors.forename: Maria
authors.initials: M
authors.lastname: Stefanopoulou
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rubner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bensdorf
authors.forename: Dominic
authors.initials: D
authors.lastname: Kubutat
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D001241:Aspirin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D012492:Salts / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D009944:Organoplatinum Compounds; D012492:Salts; D051545:Cyclooxygenase 1; D001241:Aspirin
keywords: COX inhibition; Zeise’s salt; cellular distribution; cytotoxicity; stability