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Norborn-2-en-7-ones as physiologically-triggered carbon monoxide-releasing prodrugs

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Abstract

A prodrug strategy for the release of the gasotransmitter CO at physiological pH, based upon 3a-bromo-norborn-2-en-7-one Diels–Alder cycloadducts of 2-bromomaleimides and 2,5-dimethyl-3,4-diphenylcyclopentadienone has been developed. Examples possessing protonated amine and diamine groups showed good water solubility and thermal stability. Half-lives for CO-release in TRIS-sucrose buffer at pH 7.4 ranged from 19 to 75 min at 37 °C and 31 to 32 h at 4 °C. Bioavailability in rats was demonstrated by oral gavage and oCOm-21 showed a dose dependent vasorelaxant effect in pre-contracted rat aortic rings with an EC50 of 1.6 ± 0.9 μM. Increased intracellular CO levels following oCOm-21 exposure were confirmed using a CO specific fluorescent probe.

Graphical abstract: Norborn-2-en-7-ones as physiologically-triggered carbon monoxide-releasing prodrugs

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Publication details

The article was received on 13 Apr 2017, accepted on 27 May 2017 and first published on 30 May 2017


Article type: Edge Article
DOI: 10.1039/C7SC01647F
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY-NC license
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    Norborn-2-en-7-ones as physiologically-triggered carbon monoxide-releasing prodrugs

    J. T. B. Kueh, N. J. Stanley, R. J. Hewitt, L. M. Woods, L. Larsen, J. C. Harrison, D. Rennison, M. A. Brimble, I. A. Sammut and D. S. Larsen, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C7SC01647F

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