Carbon monoxide (CO) is an endogenouss ignaling molecule that controls an umber of physiological processes. To circumventt he inherentt oxicity of CO, light-activated CO-releasing molecules (photoCORMs)h ave emerged as an alternative for its administration. However,t heir wider application requires photoactivation using biologically benign visible and near-infrared (NIR) light.I nt his work, a strategy to access such photoCORMs by fusing two CO-releasing flavonol moieties with aN IR-absorbing cyanine dye is presented. These hybrids liberate two molecules of CO in high chemical yields upon activation with NIR light up to 820 nm and exhibit excellent uncaging cross-sections, which surpasst he state-of-the-art by two orders of magnitude.F urthermore, the biocompatibility and applicabilityo ft he system in vitro and in vivo are demonstrated, andamechanism of CO release is proposed. It is hoped that this strategy will stimulate the discovery of new classes of photoCORMs and accelerate the translation of CO-based phototherapy into practice.

Carbon monoxide (CO) is an endogenous signaling molecule that regulates diverse physiological processes. The therapeutic potential of CO is hampered by its intrinsic toxicity, and its administration poses a significant challenge. Photoactivatable CO-releasing molecules (photoCORMs) are an excellent tool to overcome the side effects of untargeted CO administration and provide precise spatial and temporal control over its release. Here, we studied the CO release mechanism of a small library of derivatives based on 3-hydroxy-2-phenyl-4H-benzo[g]chromen-4-one (flavonol), previously developed as an efficient photo-CORM, by steady-state and femto/nanosecond transient absorption spectroscopies. The main objectives of the work were to explore in detail how to enhance the efficiency of CO photorelease from flavonols, bathochromically shift their absorption bands, control their acid−base properties and solubilities in aqueous solutions, and minimize primary or secondary photochemical side-reactions, such as self-photooxygenation. The best photoCORM performance was achieved by combining substituents, which simultaneously bathochromically shift the chromophore absorption spectrum, enhance the formation of the productive triplet state, and suppress the singlet oxygen production by shortening flavonol triplet-state lifetimes. In addition, the cell toxicity of selected flavonol compounds was analyzed using in vitro hepatic HepG2 cells.

Carbon monoxide (CO) is an endogenous signaling molecule with a remarkable therapeutic potential hindered by its inherent toxicity. The cross‐breeding of a CO‐releasing flavonol moiety with a cyanine dye enabled access to the family of CO‐releasing molecules activatable upon irradiation with near‐infrared light up to 820 nm. These hybrids liberate two molecules of CO with efficiencies surpassing those of the state‐of‐the‐art systems by two orders of magnitude. The biocompatibility and applicability of this system were showcased both in vitro and in vivo. The cover image was created by Lenka Štacková, Peter Štacko, and Orazio Angelo Arcidiacono. More information can be found in the Full Paper by P. Štacko, P. Klán, et al. on page 13184.