Flavonoids are naturally occurring compounds found in fruits, vegetables, and other plant-based foods, and they are known for their health benefits, such as UV protection, antioxidant, anti-inflammatory, and antiproliferative properties. This study investigates whether flavonoids, such as quercetin and 2,3-dehydrosilybin, can act as photoactivatable carbon monoxide (CO)-releasing molecules under physiological conditions. CO has been recently recognized as an important signaling molecule. Here, we show that upon direct irradiation, CO was released from both flavonoids in PBS with chemical yields of up to 0.23 equiv, which increased to almost unity by sensitized photooxygenation involving singlet oxygen. Photoreleased CO reduced cellular toxicity caused by high flavonol concentrations, partially restored mitochondrial respiration, reduced superoxide production induced by rotenone and high flavonol levels, and influenced the G0/G1 and G2/M phases of the cell cycle, showing antiproliferative effects. The findings highlight the potential of quercetin and 2,3-dehydrosilybin as CO-photoreleasing molecules with chemopreventive and therapeutic implications in human pathology and suggest their possible roles in plant biology.

• Keywords
• 2,3-dehydrosilybin, carbon monoxide, cell cycle, mitochondrial respiration, oxidative stress, photoCORM, photoinduced release, quercetin,
• MeSH
• Cell Cycle drug effects   MeSH
• Flavonoids * chemistry   pharmacology   MeSH
• Humans MeSH
• Mitochondria metabolism   drug effects   MeSH
• Carbon Monoxide * chemistry   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• Quercetin chemistry   pharmacology   MeSH
• Plant Extracts * chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Flavonoids * MeSH
• Carbon Monoxide * MeSH
• Quercetin MeSH
• Plant Extracts * MeSH

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.

• Publication type
• Journal Article MeSH

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.

• Keywords
• carbon monoxide, fluorescein, irradiation, metabolism, proliferation, singlet oxygen, viability,
• MeSH
• Angiography MeSH
• Hep G2 Cells MeSH
• Citric Acid Cycle drug effects   radiation effects   MeSH
• Fluorescein chemistry   pharmacology   MeSH
• Photochemical Processes MeSH
• Cell Cycle Checkpoints drug effects   radiation effects   MeSH
• Humans MeSH
• Carbon Monoxide analysis   MeSH
• Gas Chromatography-Mass Spectrometry MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Singlet Oxygen analysis   MeSH
• Light MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fluorescein MeSH
• Carbon Monoxide MeSH
• Antineoplastic Agents MeSH
• Singlet Oxygen MeSH

Carbon monoxide (CO) is an endogenous signaling molecule that controls a number of physiological processes. To circumvent the inherent toxicity of CO, light-activated CO-releasing molecules (photoCORMs) have emerged as an alternative for its administration. However, their wider application requires photoactivation using biologically benign visible and near-infrared (NIR) light. In this work, a strategy to access such photoCORMs by fusing two CO-releasing flavonol moieties with a NIR-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 surpass the state-of-the-art by two orders of magnitude. Furthermore, the biocompatibility and applicability of the system in vitro and in vivo are demonstrated, and a mechanism 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.

• Keywords
• CO release, cyanine, near-infrared light, photoCORM, photorelease,
• Publication type
• Journal Article MeSH

Two photoactivatable dicarbonyl ruthenium(II) complexes based on an amide-functionalised bipyridine scaffold (4-position) equipped with an alkyne functionality or a green-fluorescent BODIPY (boron-dipyrromethene) dye have been prepared and used to investigate their light-induced decarbonylation. UV/Vis, FTIR and 13 C NMR spectroscopies as well as gas chromatography and multivariate curve resolution alternating least-squares analysis (MCR-ALS) were used to elucidate the mechanism of the decarbonylation process. Release of the first CO molecule occurs very quickly, while release of the second CO molecule proceeds more slowly. In vitro studies using two cell lines A431 (human squamous carcinoma) and HEK293 (human embryonic kidney cells) have been carried out in order to characterise the anti-proliferative and anti-apoptotic activities. The BODIPY-labelled compound allows for monitoring the cellular uptake, showing fast internalisation kinetics and accumulation at the endoplasmic reticulum and mitochondria.

• Keywords
• anti-apoptotic activity, anti-proliferative, cellular localisation, photoCORM, ruthenium(II),
• MeSH
• 2,2'-Dipyridyl chemistry   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Carbon Monoxide chemistry   MeSH
• Prodrugs chemistry   radiation effects   MeSH
• Ruthenium chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 2,2'-Dipyridyl MeSH
• Carbon Monoxide MeSH
• Prodrugs MeSH
• Ruthenium MeSH