title: Bioactive properties of iron-containing carbon monoxide-releasing molecules.
abstract: Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro-(glycinato)ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that eta-4-(4-bromo-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone CORM-F3 is substituted with a chloride group [eta-4-(4-chloro-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F8)], the rate of CO release is significantly decreased (4.5-fold), and a further decrease is observed when the 4- and 6-positions are substituted with a methyl group [eta-4-(4-methyl-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F11)] or a hydrogen [eta-4-(4-chloro-2-pyrone)tricarbonyl iron (0) (CORM-F7)], respectively. Interestingly, the compounds containing halogens at the 4-position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared with other CO-RMs when tested in RAW246.7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity.
authors.affiliation: Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Sawle
authors.forename: Jehad
authors.initials: J
authors.lastname: Hammad
authors.forename: Ian J S
authors.initials: IJ
authors.lastname: Fairlamb
authors.forename: Benjamin
authors.initials: B
authors.lastname: Moulton
authors.forename: Ciara T
authors.initials: CT
authors.lastname: O'Brien
authors.forename: Jason M
authors.initials: JM
authors.lastname: Lynam
authors.forename: Anne K
authors.initials: AK
authors.lastname: Duhme-Klair
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D058085:Iron Compounds / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism
chemical_list: D058085:Iron Compounds; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide