ROS-mediated carbon monoxide and drug release from drug-conjugated carboxyboranes

Abstract

Elevated levels of reactive oxygen species (ROS) are associated with several detrimental diseases. Therefore, using this condition for selective treatments could be a great advantage in fighting these disorders. Here, we present amine carboxyboranes as a class of molecules for therapeutic CO gas generation and for delivering drug molecules in the presence of ROS. Our findings indicate amine carboxyboranes to be very slow CO releasers at physiological pH and temperature without any inducers but generate CO faster when reacted with a non-radical ROS (HO). Furthermore, a radical ROS (˙OH) dramatically expedites the production of CO from amine carboxyboranes. A decomposition profile shows the release of the amine group during the decarbonylation process from drug-conjugated carboxyboranes. This suggests that the carboxyborane moiety can be a useful tool for the delivery of amine-containing drugs to disease sites which display abundant ROS levels.

Carbon monoxide formation from trimethylamine-boranecarboxylate: DFT studies of SNi and chelotropic mechanisms

“…5,6 The fundamental structural unit of amine carboxyboranes is an amine-boron coordinate covalent bond. This type of bond allows structural modication by exchange of the amine group, 7,8 and as described herein, it has a strong effect on the attached carboxyl moiety.…”

“…The main physiological effect of amine carboxyboranes is thought to result from carbon monoxide released during a fragmentation reaction that also forms the free amine and, eventually, borate ion. 7 Hence the designation as a carbon monoxide releasing molecule, or CORM. Despite the obvious toxic effects of CO at high levels, CO at low concentrations has been shown to be a transmitter molecule that performs critical physiological functions.…”

“…Despite the obvious toxic effects of CO at high levels, CO at low concentrations has been shown to be a transmitter molecule that performs critical physiological functions. [9][10][11] Although a product and kinetic study has been reported, 7 the mechanism of CO formation is not known. The present computational study provides a simple molecular model for trimethylamine boranecarboxylate fragmentation that provides insight into the kinetics of the reaction.…”

“…In contrast to the forcing conditions employed in most decarbonylations, amine carboxyborane decarbonylation occurs, albeit slowly, in neutral or alkaline aqueous solution at room temperature. 7 The rate of decarbonylation of a given CORM pro-drug under physiological conditions is a crucial pharmacological feature: too fast, and a toxic dose of CO will be delivered all at once; too slow, and the CORM will be excreted before delivering the CO payload. The impetus for the present study was a report that aqueous titration of TMA-BH 2 COOH must be carried out at high speed "owing to a tendency for the compounds to undergo hydrolysis as evidenced by formation of gas bubbles".…”

Crystal structure of memantine–carboxyborane

“…Our attempt was to mask the compound with an additional moiety that can be removed under certain conditions, therefore releasing the drug. With this goal, memantinecarboxyborane was synthesized since the carboxyborate group is known to decompose into carbon monoxide and boric acid, leaving the drug molecule itself (Ayudhya et al, 2017(Ayudhya et al, , 2018. The single crystal structure of the said compound, (I), was solved and its features are described in this report.…”