title: Vasorelaxing effects and inhibition of nitric oxide in macrophages by new iron-containing carbon monoxide-releasing molecules (CO-RMs).
abstract: Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo carbonyl complexes capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. Here we report on the chemical synthesis, CO releasing properties, cytotoxicity profile and pharmacological activities of four novel structurally related iron-allyl carbonyls. The major difference among the new CO-RMs tested was that three compounds (CORM-307, CORM-308 and CORM-314) were soluble in dimethylsulfoxide (DMSO), whereas a fourth one (CORM-319) was rendered water-soluble by reacting the iron-carbonyl with hydrogen tetrafluoroborate. We found that despite the fact all compounds liberated CO, CO-RMs soluble in DMSO caused a more pronounced toxic effect both in vascular and inflammatory cells as well as in isolated vessels. More specifically, iron carbonyls soluble in DMSO released CO with a fast kinetic and displayed a marked cytotoxic effect in smooth muscle cells and RAW 247.6 macrophages despite exerting a rapid and pronounced vasorelaxation ex vivo. In contrast, CORM-319 that is soluble in water and liberated CO with a slower rate, preserved smooth muscle cell viability, relaxed aortic tissue and exerted a significant anti-inflammatory effect in macrophages challenged with endotoxin. These data suggest that iron carbonyls can be used as scaffolds for the design and synthesis of pharmacologically active CO-RMs and indicate that increasing water solubility and controlling the rate of CO release are important parameters for limiting their potential toxic effects.
authors.affiliation: INSERM U955, Equipe 3, University of Paris-Est, Faculty of Medicine, 94010 Creteil, France. roberto.motterlini@inserm.fr
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Philip
authors.initials: P
authors.lastname: Sawle
authors.forename: Jehad
authors.initials: J
authors.lastname: Hammad
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mann
authors.forename: Tony R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Green
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D066298:In Vitro Techniques; D007501:Iron / Q000737:chemistry; D008264:Macrophages; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009942:Organometallic Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; D002248:Carbon Monoxide; D007501:Iron