Bioactive properties of iron-containing carbon monoxide-releasing molecules

Philip Sawle, Jehad Hammad, Ian J S Fairlamb, Benjamin Moulton, Ciara T O'Brien, Jason M Lynam, Anne K Duhme-Klair, Roberta Foresti, Roberto Motterlini

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73 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)403-10
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
Publication statusPublished - Jul 2006


  • Animals
  • Carbon Monoxide
  • Cell Line
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Iron Compounds
  • Mice
  • Organometallic Compounds
  • Comparative Study
  • Journal Article


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