CO prodrugs: a new scaffold of adamantane-fused norbornen-7-ones with tunable water solubility

We have had a long-standing interest in developing organic prodrugs for controlled delivery of CO for various therapeutic applications. Based on an earlier approach of taking advantage of a cheletropic extrusion reaction of norbornadienone to release CO, a new structural scaffold of CO prodrugs has been designed using an adamantane moiety instead of aryl groups for stabilizing a critical precursor structure, cyclopentadienone. This approach allows for elimination of multiple aromatic groups on the previous scaffolds and offers a handle for installing additional moieties for improving solubility. Specifically, prodrugs with different solubilizing groups have been synthesized and assessed for their water solubility and potency in inhibiting inflammation using TNF-α as a marker. In cell-culture studies, varying potency was observed in a fashion consistent with the polarity of a prodrug being a key factor affecting membrane permeability and thus the local concentration of CO intracellularly. However, these prodrugs all offer systemic availability of CO in animal models even if the prodrug does not appear to have the ability to traverse cellular membrane. Such results suggest that member permeability is not a major factor in determining the ability to deliver CO systemically. Further, caution is needed in directly extrapolating results from cell culture to animal models, especially for such a gaseous active principal.