Issue 8, 2017

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
13 Apr 2017
Accepted
27 May 2017
First published
30 May 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2017,8, 5454-5459

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, 8, 5454 DOI: 10.1039/C7SC01647F

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