title: Mass Spectrometry Uncovers Molecular Reactivities of Coordination and Organometallic Gold(III) Drug Candidates in Competitive Experiments That Correlate with Their Biological Effects.
abstract: The reactivity of three cytotoxic organometallic gold(III) complexes with cyclometalated C,N,N and C,N ligands (either six- or five-membered metallacycles), as well as that of two representative gold(III) complexes with N-donor ligands, with biological nucleophiles has been studied by ESI-MS on ion trap and time-of-flight instruments. Specifically, the gold compounds were reacted with mixtures of nucleophiles containing l-histidine (imine), l-methionine (thioether), l-cysteine (thiol), l-glutamic acid (carboxylic acid), methylseleno-l-cysteine (selenoether), and in situ generated seleno-l-cysteine (selenol) to judge the preference of the gold compounds for binding to selenium-containing amino acid residues. Moreover, the gold compounds' reactivity was studied with proteins and nucleic acid building blocks. These experiments revealed profound differences between the coordination and organometallic families and even within the family of organometallics, which allowed insights to be gained into the compounds mechanisms of action. In particular, interactions with seleno-l-cysteine appear to reflect well the compounds' inhibition properties of the seleno-enzyme thioredoxin reductase and to a certain extent their antiproliferative effects in vitro. Therefore, mass spectrometry is successfully applied for linking the molecular reactivity and target preferences of metal-based drug candidates to their biological effects. Finally, this experimental setup is applicable to any other metallodrug that undergoes ligand substitution reactions and/or redox changes as part of its mechanism of action.
authors: Department of Analytical Chemistry, University of Vienna , Waehringer Str. 38, 1090 Vienna, Austria.
authors: Samuel M
authors: SM
authors: Meier
authors: Department of Analytical Chemistry, University of Vienna , Waehringer Str. 38, 1090 Vienna, Austria.
authors: Christopher
authors: C
authors: Gerner
authors: Bernhard K
authors: BK
authors: Keppler
authors: University of Sassari , Dipartimento di Chimica e Farmacia, Via Vienna 2, Sassari I-07100, Italy.
authors: Maria Agostina
authors: MA
authors: Cinellu
authors: School of Chemistry, Cardiff University , Main Building, Park Place, CF10 3AT Cardiff, United Kingdom.
authors: Angela
authors: A
authors: Casini
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002417:Cattle; D045304:Cytochromes c / Q000737:chemistry; D004355:Drug Stability; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D006736:Horses; D050607:Organogold Compounds / Q000737:chemistry*; D017279:Selenocysteine / Q000031:analogs & derivatives / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D054481:Thioredoxin Reductase 1 / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D050607:Organogold Compounds; D025801:Ubiquitin; D014867:Water; D017279:Selenocysteine; D006147:Guanine; D006160:Guanosine Triphosphate; C014542:9-ethylguanine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D054481:Thioredoxin Reductase 1