3-Hydroxyflavones and 3-Hydroxy-4-oxoquinolines as Carbon Monoxide-Releasing Molecules

Carbon monoxide-releasing molecules (CORMs) that enable the delivery of controlled amounts of CO are of strong current interest for applications in biological systems. In this review, we examine the various conditions under which CO is released from 3-hydroxyflavones and 3-hydroxy-4-oxoquinolines to advance the understanding of how these molecules, or derivatives thereof, may be developed as CORMs. Enzymatic pathways from quercetin dioxygenases and 3-hydroxy-4-oxoquinoline dioxygenases leading to CO release are examined, along with model systems for these enzymes. Base-catalyzed and non-redox-metal promoted CO release, as well as UV and visible light-driven CO release from 3-hydroxyflavones and 3-hydroxy-4-oxoquinolines, are summarized. The visible light-induced CO release reactivity of recently developed extended 3-hydroxyflavones and a 3-hydroxybenzo[g]quinolone, and their uses as intracellular CORMs, are discussed. Overall, this review provides insight into the chemical factors that affect the thermal and photochemical dioxygenase-type CO release reactions of these heterocyclic compounds

Properties of Flavonol-based PhotoCORM in Aqueous Buffered Solutions: Influence of Metal Ions, Surfactants and Proteins on Visible Light-induced CO Release

The properties of the extended flavonol 3-hydroxy-2-phenyl-benzo[g]chromen-4-one (2a) in DMSO : aqueous buffer solutions at pH = 7.4, including in the presence of metal ions, surfactants and serum albumin proteins, have been examined. Absorption and emission spectral studies of 2a in 1 : 1 DMSO : PBS buffer (pH = 7.4) indicate that a mixture of neutral and anionic forms of the flavonol are present. Notably, in 1 : 1 DMSO : TRIS buffer (pH = 7.4) only the neutral form of the flavonol is present. These results indicate that the nature of the buffer influences the acid/base equilibrium properties of 2a. Introduction of a Zn(II) complex of 2a− to a 1 : 1 DMSO : aqueous buffer (TRIS or PBS, pH = 7.4) solution produces absorption and emission spectral features consistent with the presence of a mixture of neutral 2a along with Zn(II)-coordinated or free 2a−. The nature of the anionic species present depends on the buffer composition. PBS buffered solutions (pH = 7.4) containing the surfactants CTAB or SDS enable 2a to be solubilized at a much lower percentage of DMSO (3.3–4.0%). Solutions containing the cationic surfactant CTAB include a mixture of 2a and 2a− whereas only the neutral flavonol is present in SDS-containing buffered solution. Compound 2a is also solubilized in TRIS buffer solutions at low cocentrations of DMSO (3.3%, pH = 7.4) in the presence of serum albumin proteins. Stern–Volmer analysis of the quenching of the inherent protein fluorescence indicates static binding of 2a to the proteins. The binding constant for this interaction is lower than that found for naturally-occurring flavonols (quercetin or morin) or 3-hydroxyflavone. Compound 2a binds to Site I of bovine and human serum albumin proteins as indicated by competition studies with warfarin and ibuprofen, as well as by docking investigations. The quantum yield for CO release from 2a (λirr = 419 nm) under aqueous conditions ranges from 0.0006(3) when the compound is bound to bovine serum albumin to 0.017(1) when present as a zinc complex in a 1 : 1 DMSO : H2O solution. Overall, the results of these studies demonstrate that 2a is a predictable visible light-induced CO release compound under a variety of aqueous conditions, including in the presence of proteins

A bipyridine-ligated zinc(II) complex with bridging flavonolate ligation: synthesis, characterization, and visible-light-induced CO release reactivity

Metal-flavonolate compounds are of significant current interest as synthetic models for quercetinase enzymes and as bioactive compounds of importance to human health. Zinc-3-hydroxyflavonolate compounds, including those of quercetin, kampferol, and morin, generally exhibit bidentate coordination to a single ZnII center. The bipyridine-ligated zinc-flavonolate compound reported herein, namely bis(μ-4-oxo-2-phenyl-4H-chromen-3-olato)-κ3O3:O3,O4;κ3O3,O4:O3-bis[(2,2′-bipyridine-κ2N,N′)zinc(II)] bis(perchlorate), {[Zn2(C15H9O3)2(C10H8N2)2](ClO4)2}n, (1), provides an unusual example of bridging 3-hydroxyflavonolate ligation in a dinuclear metal complex. The symmetry-related ZnII centers of (1) exhibit a distorted octahedral geometry, with weak coordination of a perchlorate anion trans to the bridging deprotonated O atom of the flavonolate ligand. Variable-concentration conductivity measurements provide evidence that, when (1) is dissolved in CH3CN, the complex dissociates into monomers. 1H NMR resonances for (1) dissolved in d6-DMSO were assigned via HMQC to the H atoms of the flavonolate and bipyridine ligands. In CH3CN, (1) undergoes quantitative visible-light-induced CO release with a quantum yield [0.004 (1)] similar to that exhibited by other mononuclear zinc-3-hydroxyflavonolate complexes. Mass spectroscopic identification of the [(bpy)2Zn(O-benzoylsalicylate)]+ ion provides evidence of CO release from the flavonol and of ligand exchange at the ZnII center.A bipyridine-ligated zinc-flavonolate complex exhibiting bridging flavonolate coordination has been characterized by single-crystal X-ray crystallography. In acetonitrile, this compound dissociates into monomers and undergoes visible-light-induced CO release. © International Union of Crystallography, 2017

CO Sense and Release Flavonols: Progress toward the Development of an Analyte Replacement PhotoCORM for Use in Living Cells

Carbon monoxide (CO) is a signaling molecule in humans. Prior research suggests that therapeutic levels of CO can have beneficial effects in treating a variety of physiological and pathological conditions. To facilitate understanding of the role of CO in biology, molecules that enable fluorescence detection of CO in living systems have emerged as an important class of chemical tools. A key unmet challenge in this field is the development of fluorescent analyte replacement probes that replenish the CO that is consumed during detection. Herein, we report the first examples of CO sense and release molecules that involve combining a common CO-sensing motif with a light-triggered CO-releasing flavonol scaffold. A notable advantage of the flavonol-based CO sense and release motif is that it is trackable via fluorescence in both its pre- and postsensing (pre-CO release) forms. In vitro studies revealed that the PdCl2 and Ru(II)-containing CORM-2 used in the CO sensing step can result in metal coordination to the flavonol, which minimizes the subsequent CO release reactivity. However, CO detection followed by CO release is demonstrated in living cells, indicating that a cellular environment mitigates the flavonol/metal interactions

N3-ligated Nickel(II) Diketonate Complexes: Synthesis, Characterization and Evaluation of O2 Reactivity

Interest in O2-dependent aliphatic carbon–carbon (C–C) bond cleavage reactions of first row divalent metal diketonate complexes stems from the desire to further understand the reaction pathways of enzymes such as DKE1 and to extract information to develop applications in organic synthesis. A recent report of O2-dependent aliphatic C–C bond cleavage at ambient temperature in Ni(II) diketonate complexes supported by a tridentate nitrogen donor ligand [(MBBP)Ni(PhC(O)CHC(O)Ph)]Cl (7-Cl; MBBP = 2,6-bis(1-methylbenzimidazol-2-yl)pyridine) in the presence of NEt3 spurred our interest in further examining the chemistry of such complexes. A series of new TERPY-ligated Ni(II) diketonate complexes of the general formula [(TERPY)Ni(R2-1,3-diketonate)]ClO4 (1: R = CH3; 2: R = C(CH3)3; 3: R = Ph) was prepared under air and characterized using single crystal X-ray crystallography, elemental analysis, 1H NMR, ESI-MS, FTIR, and UV-vis. Analysis of the reaction mixtures in which these complexes were generated using 1H NMR and ESI-MS revealed the presence of both the desired diketonate complex and the bis-TERPY derivative [(TERPY)2Ni](ClO4)2 (4). Through selective crystallization 1–3 were isolated in analytically pure form. Analysis of reaction mixtures leading to the formation of the MBBP analogs [(MBBP)Ni(R2-1,3-diketonate)]X (X = ClO4: 5: R = CH3; 6: R = C(CH3)3; 7-ClO4: R = Ph; X = Cl: 7-Cl: R = Ph) using 1H NMR and ESI-MS revealed the presence of [(MBBP)2Ni](ClO4)2 (8). Analysis of aerobic acetonitrile solutions of analytically pure 1–3, 5 and 6 containing NEt3 and in some cases H2O using 1H NMR and UV-vis revealed evidence for the formation of additional bis-ligand complexes (4 and 8) but suggested no oxidative diketonate cleavage reactivity. Analysis of the organic products generated from 3, 7-ClO4 and 7-Cl revealed unaltered dibenzoylmethane. Our results therefore indicate that N3-ligated Ni(II) complexes of unsubstituted diketonate ligands do not exhibit O2-dependent aliphatic C–C bond clevage at room temperature, including in the presence of NEt3 and/or H2O

Mononuclear N\u3csub\u3e3\u3c/sub\u3eS(thioether)-Ligated Copper(II) Methoxide Complexes: Synthesis, Characterization, and Hydrolytic Reactivity

Mononuclear copper(II) methoxide complexes supported by N3S(thioether) chelate ligands having two internal hydrogen bond donors have been prepared, comprehensively characterized, and evaluated for hydrolytic reactivity

Evaluation of the Influence of a Thioether Substituent on the Solid State and Solution Properties of N\u3csub\u3e3\u3c/sub\u3eS-ligated Copper(II) Complexes

Admixture of a N3S(thioether) ligand having two internal hydrogen bond donors (pbnpa: N-2-(phenylthio)ethyl-N,N-bis-((6-neopentylamino-2-pyridyl)methyl)amine; ebnpa: N-2-(ethylthio)ethyl-N,N-bis-((6-neopentylamino-2-pyridyl)methyl)amine) with equimolar amounts of Cu(ClO4)2·6H2O and NaX (X = Cl−, NCO−, or N3−) in CH3OH/H2O yielded the mononuclear Cu(II) derivatives [(pbnpa)Cu–Cl]ClO4 (1), [(ebnpa)Cu–Cl]ClO4 (2), [(pbnpa)Cu–NCO]ClO4 (3), [(ebnpa)Cu–NCO]ClO4 (4), [(pbnpa)Cu–N3]ClO4 (5), and [(ebnpa)Cu–N3]ClO4 (6). Each complex was characterized by FTIR, UV-VIS, EPR, and elemental analysis. Complexes 1, 2, 3 and 6 were characterized by X-ray crystallography. The structural studies revealed that [(pbnpa)Cu–X]ClO4 derivatives (1, 3) exhibit a distorted square pyramidal type geometry, whereas [(ebnpa)Cu–X]ClO4 complexes (2, 6) may be classified as distorted trigonal bipyramidal. EPR studies in CH3OH/CH3CN solution revealed that 1–6 exhibit an axial type spectrum with g∥ \u3e g⊥ \u3e 2.0 and A∥ = 15–17 mT, consistent with a square pyramidal based geometry for the Cu(II) center in each complex. A second species detected in the EPR spectra of 2 and 6 has a smaller A∥ value, consistent with greater spin delocalization on to sulfur, and likely results from geometric distortion of the [(ebnpa)Cu(II)–X]+ ions present in 2 and 6

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

Mononuclear Nitrogen/sulfur-ligated Cobalt(II) Methoxide Complexes: Structural, EPR, Paramagnetic 1H NMR, and Electrochemical Investigations

The first examples of mononuclear nitrogen/sulfur-ligated Co(II) alkoxide complexes, species of relevance to a reactive intermediate observed for Co(II)-substituted liver alcohol dehydrogenase, have been isolated and characterized by multiple methods including X-ray crystallography, EPR, paramagnetic 1H NMR, and cyclic voltammetry

Poly[1-ethyl-3-methyl­imidazolium [tri-μ-chlorido-chromate(II)]]

The title compound, {(C6H11N2)[CrCl3]}n, was generated via mixing of the ionic liquid 1-ethyl-3-methyl­imidazolium chloride with CrCl2 in ethanol. Crystals were obtained by a diffusion method. In the crystal structure, the anion forms one-dimensional chains of chloride-bridged Jahn–Teller distorted chromium(II) centers extending along the [100] direction. The imidazolium cations are positioned between these chains