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

Irradiation of coumarin-3-carboxylic acid in acetonitrile and methanol solutions at 355 nm results in complex multistep photochemical transformations, strongly dependent on the solvent properties and oxygen content. A number of reaction intermediates, which themselves undergo further (photo)chemical reactions, were identified by steady-state and transient absorption spectroscopy, mass spectrometry, and NMR and product analyses. The triplet excited compound in acetonitrile undergoes decarboxylation to give a 3-coumarinyl radical that traps molecular oxygen to form 3-hydroxycoumarin as the major but chemically reactive intermediate. This compound is oxygenated by singlet oxygen, produced by coumarin-3-carboxylic acid sensitization, followed by a pyrone ring-opening reaction to give an oxalic acid derivative. The subsequent steps lead to the production of salicylaldehyde, carbon monoxide, and carbon dioxide as the final products. When 3-coumarinyl radical is not trapped by oxygen in degassed acetonitrile, it abstracts hydrogen from the solvent and undergoes triplet-sensitized [2 + 2] cycloaddition. The reaction of 3-coumarinyl radical with oxygen is largely suppressed in aerated methanol as a better H-atom donor, and coumarin is obtained as the primary product in good yields. Because coumarin derivatives are used in many photophysical and photochemical applications, this work provides detailed and sometimes surprising insights into their complex phototransformations.

• Keywords
• Coumarin, Photochemistry, Photooxidation, Singlet oxygen,
• MeSH
• Acetonitriles chemistry   MeSH
• Coumarins * MeSH
• Oxygen MeSH
• Methanol * MeSH
• Solvents chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetonitriles MeSH
• coumarin-3-carboxylic acid MeSH Browser
• Coumarins * MeSH
• Oxygen MeSH
• Methanol * MeSH
• Solvents 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