title: Catalysis of regioselective reduction of NAD+ by ruthenium(II) arene complexes under biologically relevant conditions.
abstract: Ruthenium(II) arene anticancer complexes [(eta6-arene)Ru(en)Cl]PF6 (arene is hexamethylbenzene, p-cymene, indan; en is ethylenediamine) can catalyse regioselective reduction of NAD+ by formate in water to form 1,4-NADH, at pD 7.2, 37 degrees C, and in the presence of air. The catalytic activity is markedly dependent on the arene, with the hexamethylbenzene (hmb) complex showing the highest activity. For [(eta 6-hmb)Ru(en)Cl]PF6, the rate of reaction is independent of NAD+ concentration and shows saturation kinetics with respect to formate concentration. A Km value of 58 mM and a turnover frequency at saturation of 1.46 h(-1) were observed. Removal of chloride and performing the reaction under argon led to higher reaction rates. Lung cancer cells (A549) were found to be remarkably tolerant to formate even at millimolar concentrations. The possibility of using ruthenium arene complexes coadministered with formate as catalytic drugs is discussed.
authors.affiliation: School of Chemistry, University of Edinburgh, West Mains Road, EH9 3JJ, Edinburgh, UK.
authors.forename: Yaw Kai
authors.initials: YK
authors.lastname: Yan
authors.forename: Michael
authors.initials: M
authors.lastname: Melchart
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Anna F A
authors.initials: AF
authors.lastname: Peacock
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry* / Q000502:physiology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D012428:Ruthenium / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D009942:Organometallic Compounds; D009243:NAD; D012428:Ruthenium; C091695:hexamethylbenzene