Visible-Light-Activated Carbon Monoxide Release from Porphyrin-Flavonol Hybrids.

We report on porphyrin-flavonol hybrids consisting of a porphyrin antenna and four covalently bound 3-hydroxyflavone (flavonol) groups, which act as highly efficient photoactivatable carbon monoxide (CO)-releasing molecules (photoCORMs). These bichromophoric systems enable activation of the UV-absorbing flavonol chromophore by visible light up to 650 nm and offer precise spatial and temporal control of CO administration. The physicochemical properties of the porphyrin antenna system can also be tuned by inserting a metal cation. Our computational study revealed that the process occurs via endergonic triplet-triplet energy transfer from porphyrin to flavonol and may become feasible thanks to flavonol energy stabilization upon intramolecular proton transfer. This mechanism was also indirectly supported by steady-state and transient absorption spectroscopy techniques. Additionally, the porphyrin-flavonol hybrids were found to be biologically benign. With four flavonol CO donors attached to a single porphyrin chromophore, high CO release yields, excellent uncaging cross sections, low toxicity, and CO therapeutic properties, these photoCORMs offer exceptional potential for their further development and future biological and medical applications.

Common xanthene fluorescent dyes are visible-light activatable CO-releasing molecules.

Fluorescein, eosin Y, and rose bengal are dyes used in clinical medicine and considered (photo-)chemically stable. Upon extensive irradiation with visible light in aqueous solutions, we found that these compounds release carbon monoxide (CO) - a bioactive gasotransmitter - in 40-100% yields along with the production of low-mass secondary photoproducts, such as phthalic and formic acids, in a multistep degradation process. Such photochemistry should be considered in applications of these dyes, and they could also be utilized as visible-light activatable CO-releasing molecules (photoCORMs) with biological implications.

Structure-Photoreactivity Relationship of 3-Hydroxyflavone-Based CO-Releasing Molecules.

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 photoCORM, 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.

Antiproliferative and Cytotoxic Activities of Fluorescein-A Diagnostic Angiography Dye.

Fluorescein is a fluorescent dye used as a diagnostic tool in various fields of medicine. Although fluorescein itself possesses low toxicity, after photoactivation, it releases potentially toxic molecules, such as singlet oxygen (1O2) and, as we demonstrate in this work, also carbon monoxide (CO). As both of these molecules can affect physiological processes, the main aim of this study was to explore the potential biological impacts of fluorescein photochemistry. In our in vitro study in a human hepatoblastoma HepG2 cell line, we explored the possible effects on cell viability, cellular energy metabolism, and the cell cycle. We observed markedly lowered cell viability (≈30%, 75-2400 µM) upon irradiation of intracellular fluorescein and proved that this decrease in viability was dependent on the cellular oxygen concentration. We also detected a significantly decreased concentration of Krebs cycle metabolites (lactate and citrate < 30%; 2-hydroxyglutarate and 2-oxoglutarate < 10%) as well as cell cycle arrest (decrease in the G2 phase of 18%). These observations suggest that this photochemical reaction could have important biological consequences and may account for some adverse reactions observed in fluorescein-treated patients. Additionally, the biological activities of both 1O2 and CO might have considerable therapeutic potential, particularly in the treatment of cancer.