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

作者：Kueh Jui Thiang Brian; Stanley Nathan J; Hewitt Russell J; Woods Laura M; Larsen Lesley; Harrison Joanne C; Rennison David; Brimble Margaret A; Sammut Ivan A^*; Larsen David S^*

来源：Chemical Science, 2017, 8(8): 5454-5459.

DOI：10.1039/c7sc01647f

A prodrug strategy for the release of the gasotransmitter CO at physiological pH, based upon 3a-bromonorborn-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 degrees C and 31 to 32 h at 4 degrees 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 mu M. Increased intracellular CO levels following oCOm-21 exposure were confirmed using a CO specific fluorescent probe.

• 出版日期2017-8