The development of carbon monoxide prodrugs as therapeutic agents has recently gathered much interest due to CO's pleiotropic pharmacological effects. Past research in this area has relied on inhaled CO, metal-based CO-releasing molecules, and photo-sensitive organic CO-releasing molecules. To complement available methods, we have developed metal-free CO prodrugs, which release CO upon dissolution in water or in response to endogenous stimuli (esterase, physiological pH and ROS). The design strategy for such CO prodrugs is primarily based on the fact that norborna-2,5-dien-7-ones can readily undergo facial cheletropic reaction to extrude CO under physiological conditions, and we have successfully devised CO prodrugs as such by making precursors for norborna-2,5-dien-7-ones using inter-/intra-molecular Diels Alder cycloaddition or beta-elimination reactions. In this report, we expand on our earlier work and describe a general strategy by masking an aldehyde group (II, Figure 1) needed for the beta-elimination before the cheletropic reaction for CO release (I, Figure 1). Since the protected aldehyde group is no longer an electron-withdrawing group, the beta-elimination for CO release is prohibited. However, in the presence of an appropriate stimulus, the aldehyde group is regenerated for subsequent beta-elimination to release CO. We have conducted a proof of concept study by making an esterase-sensitive CO prodrug I-1 and a cysteine-triggered CO prodrug I-2. The CO release kinetics showed that I-1/2 are very stable with half-lives of more than 24 h in the absence of the stimuli, and yet start to release CO with half-lives of around 30 min in the presence of esterase or cysteine. The development of other CO prodrugs with different release triggers based on such a strategy and the application of such prodrugs for CO's biological studies are ongoing in our lab.

Stimuli-activated metal-free CO prodrugs: A general strategy

255th National Meeting (2018)

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