Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments. This has led to the development of light-induced CO-releasing molecules (photoCORMs). A goal in this field of research is the development of molecules that exhibit a combination of controlled CO release, favorable biological properties (e.g., low toxicity and trackability in cells), and structural tunability to affect CO release. Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM. We show that 3-hydroxyflavone-based compounds are easily synthesized and modified to impart changes in absorption features and quantum yield for CO release, exhibit low toxicity, are trackable in cells, and can exhibit both O2-dependent and -independent CO release reactivity.

While interactions between carbon monoxide (CO) and mitochondria have been previously studied, the methods used to deliver CO (gas or CO-releasing metal carbonyl compounds) lack subcellular targeting and/or controlled delivery. Thus, the effective concentration needed to produce changes in mitochondrial bioenergetics is yet to be fully defined. To evaluate the influence of mitochondrial-targeted versus intracellularly released CO on mitochondrial oxygen consumption rates, we developed and characterized flavonol-based CO donor compounds that differ at their site of release. These molecules are metal-free, visible light triggered CO donors (photoCORMs) that quantitatively release CO and are trackable in cells via confocal microscopy. Our studies indicate that at a concentration of 10 μM, the mitochondrial-localized and cytosolic CO-releasing compounds are similarly effective in terms of decreasing ATP production, maximal respiration, and the reserve capacity of A549 cells. This concentration is the lowest to impart changes in mitochondrial bioenergetics for any CO-releasing molecule (CORM) reported to date. The results reported herein demonstrate the feasibility of using a structurally tunable organic photoCORM framework for comparative intracellular studies of the biological effects of carbon monoxide.

Irradiation of 3-hydroxyflavonolato (3-Hfl) complexes of Mn II , Co II , Ni II and Cu II (1-4) at 300 nm under aerobic conditions results in dioxygenase-type reactivity and the formation of the corresponding divalent metal O-benzoylsalicylato (Obs) complexes 8-11 and CO. The latter were characterized by using multiple methods, including elemental analysis, Xray crystallography, NMR and/or EPR spectroscopy, mass spectrometry and IR spectroscopy. Compounds 1-4 serve as catalysts for the photoinduced reactivity of 3-hydroxyflavonol (3-HflH) to produce O-benzoylsalicylic acid as the major [a]

Two types of zinc flavonolato complexes ([(6-PhTPA)Zn(flavonolato)]ClO and Zn(flavonolato)) of four extended flavonols have been prepared, characterized, and evaluated for visible light-induced CO release reactivity. Zinc coordination of each flavonolato anion results in a red-shift of the lowest energy absorption feature and in some cases enhanced molar absorptivity relative to the free flavonol. The zinc-coordinated flavonolato ligands undergo visible light-induced CO release with enhanced reaction quantum yields relative to the neutral flavonols. Most notable is the discovery that both types of zinc flavonolato derivatives undergo similar visible light-induced CO release reactivity in solution and in the solid state. A solid film of a Zn(flavonolato) derivative was evaluated as an in situ CO release agent for aerobic oxidative palladium-catalyzed alkoxycarbonylation to produce esters in ethanol. The CO release product was found to undergo ester alcolysis under the conditions of the carbonylation reaction.

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