title: Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity.
abstract: Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(eta6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.
authors.affiliation: School of Chemistry, University of Edinburgh, West Mains Road, EH9 3JJ Edinburgh, United Kingdom.
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Erwin P L
authors.initials: EP
authors.lastname: van der Geer
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernández
authors.forename: Michael
authors.initials: M
authors.lastname: Melchart
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deeth
authors.forename: Rhona
authors.initials: R
authors.lastname: Aird
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guichard
authors.forename: Francesca P A
authors.initials: FP
authors.lastname: Fabbiani
authors.forename: Patricia
authors.initials: P
authors.lastname: Lozano-Casal
authors.forename: Iain D H
authors.initials: ID
authors.lastname: Oswald
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: Simon
authors.initials: S
authors.lastname: Parsons
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006157:Guanosine Monophosphate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D012428:Ruthenium / Q000737:chemistry / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009942:Organometallic Compounds; D012428:Ruthenium; D006157:Guanosine Monophosphate