pH-Sensitive metal-free carbon monoxide prodrugs with tunable and predictable release rates

Abstract

Carbon monoxide prodrugs with triggered release profiles are highly desirable for targeted CO delivery to minimize their untoward side-effects. Herein, we describe a series of pH-sensitive metal-free CO prodrugs which are stable under acidic conditions and yet begin to release CO in response to increases in pH with tunable and predictable release rates.

Studies towards Non‐toxic, Water Soluble, Vasoactive Norbornene Organic Carbon Monoxide Releasing Molecules

“…Following on from our work, Wang and co‐workers reported similar norborn‐2‐en‐7‐ones that respond to pH (Figure 1B and C) [19–20] . In a mixed DMSO‐PBS solution these prodrugs were shown to release CO either by activation at physiological pH [19] or through a double‐trigger in which both physiological pH and the presence of an enzyme is required [20] …”

“…Selected examples of existing CORMs that selectively release at physiological pH. (A) water soluble oCOms by Larsen and co-workers; [18] (B) pH sensitive organic CORMs by Wang and co-workers; [19] (C) pH and enzyme sensitive organic CORMs by Wang and co-workers. [20] The corresponding expired by-product could be synthesised by base-induced aromatisation of silyl-protected cycloadduct 10 followed by removal of the silyl-groups under acidic conditions to give BP-24.…”

“…Following on from our work, Wang and co-workers reported similar norborn-2-en-7-ones that respond to pH ( Figure 1B and C). [19][20] In a mixed DMSO-PBS solution these prodrugs were shown to release CO either by activation at physiological pH [19] or through a double-trigger in which both physiological pH and the presence of an enzyme is required. [20] The bioavailability of our oCOms was demonstrated in rats as evidenced by an increase in carboxyhaemoglobin following administration by oral gavage of oCOm-21.…”

CO-independent modification of K + channels by tricarbonyldichlororuthenium(II) dimer (CORM-2)

“…1) or more recently developed metal-free CORMs (e.g., Palao et al, 2016; Ji et al, 2017). Among the metal-based CORMs, metal-carbonyl adduct formation is not specific for ruthenium but was also observed for iridium (Catarino et al, 2016).…”

Towards “CO in a pill”: Pharmacokinetic studies of carbon monoxide prodrugs in mice

“…We are very interested in developing metal-free organic prodrugs of CO for therapeutic applications. By taking advantage of a Diels-Alder reaction, we have developed bimolecular [11,46] and unimolecular CO prodrugs [4,47] with tunable release rates, triggered release by pH, esterase, and ROS [10,[47][48][49], targeted release [11], and the ability to carry two payloads in one molecule [50][51][52]. The Larsen lab has also reported a class of organic CO prodrugs, which are pH-sensitive [53].…”