Edaravone containing isoindoline nitroxides for the potential treatment of cardiovascular ischaemia

James Walker, Kathryn Fairfull-Smith, Kazunori Anzai, Shannen Lau, Paul White, Peter Scammells, Steven Eric Bottle

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Abstract

A novel antioxidant for the potential treatment of ischaemia was designed by incorporating an isoindoline nitroxide into the framework of the free radical scavenger edaravone. 5-(3-Methyl-pyrazol-5-ol-1-yl)-1,1,3,3-tetramethylisoindolin-2-yloxyl 7 was prepared by N-arylation of 3-methy1-5-pyrazolone with 5-iodo-1,1,3,3-tetramethylisoindoline-2-yloxyl 8 in the presence of catalytic copper(I)iodide. Evaluation of 7, its methoxyamine derivative 10 and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) against edaravone I in ischaemic rat atrial cardiomyocytes revealed significant decreases in cell death after prolonged ischaemia for each agent; however the protective effect of the novel antioxidant 7 (showing greater than 85 reduction in cell death at 100 mu M) was significantly enhanced over that of edaravone 1 alone. Furthermore, the activity for 7 was found to be equal to or greater than the potent cardioprotective agent N(6)-cyclopentyladenosine (CPA). The methoxyamine adduct 10 and edaravone 1 showed no difference between the extent of reduction in cell death whilst CTMIO had only a modest protective effect.
Original languageEnglish
Pages (from-to)436 - 441
Number of pages6
JournalMedChemComm
Volume2
Issue number5
Publication statusPublished - 2011

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