title: Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry.
abstract: A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure-activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu(2)bpy)(2)(phox)]PF(6) (complex 1), with tBu(2)bpy = 4,4'-di-tert-buty-2,2'-bipyridine and Hphox = 2-(2'-hydroxyphenyl)oxazoline, displaying an LC(50) value in HeLa cells of 1.3 microM and 0.3 microM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively.
authors.affiliation: Fachbereich Chemie, Hans-Meerwein-Strasse, 35032, Marburg, Germany.
authors.forename: Seann P
authors.initials: SP
authors.lastname: Mulcahy
authors.forename: Katharina
authors.initials: K
authors.lastname: Gründler
authors.forename: Corazon
authors.initials: C
authors.lastname: Frias
authors.forename: Laura
authors.initials: L
authors.lastname: Wagner
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Eric
authors.initials: E
authors.lastname: Meggers
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D056831:Coordination Complexes / Q000737:chemistry* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009942:Organometallic Compounds / Q000737:chemistry* / Q000633:toxicity; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D009942:Organometallic Compounds; D012428:Ruthenium