Stacey N. Anderson

A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs).

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.

Solution or solid – it doesn't matter: visible light-induced CO release reactivity of zinc flavonolato complexes

Two types of zinc flavonolato complexes ([(6-Ph2TPA)Zn(flavonolato)]ClO4 and Zn(flavonolato)2) 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)2 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.

Influence of supporting ligand microenvironment on the aqueous stability and visible light-induced CO-release reactivity of zinc flavonolato species

The visible light-induced CO-release reactivity of the zinc flavonolato complex [(6-Ph2TPA)Zn(3-Hfl)]ClO4 (1) has been investigated in 1 : 1 H2O : DMSO. Additionally, the effect of ligand secondary microenvironment on the aqueous stability and visible light-induced CO-release reactivity of zinc flavonolato species has been evaluated through the preparation, characterization, and examination of the photochemistry of compounds supported by chelate ligands with differing secondary appendages, [(TPA)Zn(3-Hfl)]ClO4 (3; TPA = tris-2-(pyridylmethyl)amine) and [(bnpapa)Zn(3-Hfl)]ClO4 (4; bnpapa = N,N-bis((6-neopentylamino-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine)). Compound 3 undergoes reaction in 1 : 1 H2O : DMSO resulting in the release of the free neutral flavonol. Irradiation of acetonitrile solutions of 3 and 4 at 419 nm under aerobic conditions results in quantitative, photoinduced CO-release. However, the reaction quantum yields under these conditions are lower than that exhibited by 1, with 4 exhibiting an especially low quantum yield. Overall, the results of this study indicate that positioning a zinc flavonolato moiety within a hydrophobic microenvironment is an important design strategy toward further developing such compounds as CO-release agents for use in biological systems. Graphical Abstract

Mitochondrial-Localized Versus Cytosolic Intracellular CO-Releasing Organic PhotoCORMs: Evaluation of CO Effects Using Bioenergetics

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.