Photoinduced CO Release Research Articles

Quantifying CO-release from a photo-CORM using 19F NMR: An investigation into light-induced CO delivery

Carbon monoxide (CO) is an innate signaling molecule that can regulate immune responses and interact with crucial elements of the circadian clock. Moreover, pharmacologically, CO has been substantiated for its therapeutic advantages in animal models of diverse pathological conditions. Given that an excessive level of CO can be toxic, it is imperative to quantify the necessary amount for therapeutic use accurately. However, estimating gaseous CO is notably challenging. Therefore, novel techniques are essential to quantify CO in therapeutic applications and overcome this obstacle precisely. The classical Myoglobin (Mb) assay technique has been extensively used to determine the amount of CO-release from CO-releasing molecules (CORMs) within therapeutic contexts. Nevertheless, specific challenges arise when applying the Mb assay to evaluate CORMs featuring innovative molecular architectures. Here, we report a fluorinated photo-CORM (CORM-FBS) for the photo-induced CO-release. We employed the 19F NMR spectroscopy approach to monitor the release of CO as well as quantitative evaluation of CO release. This new 19F NMR approach opens immense opportunities for researchers to develop reliable techniques for identifying molecular structures, quantitative studies of drug metabolism, and monitoring the reaction process.

Neutral and Cationic Re(I) Complexes with Pnictogen-Based Coligands and Tunable Functionality: From Phosphorescence to Photoinduced CO Release.

In this work, we have explored Re(I) complexes featuring triphenylpnictogen (PnPh3, Pn = P, As, or Sb)-based coligands and bidentate (neutral or monoanionic) luminophores derived from 1,10-phenantroline (phen), as well as from 2-(3-(tert-butyl)-1H-1,2,4-triazol-5-yl)pyridine (H(N-tBu)). The effect of the increasingly heavy elements on the structural parameters, photoexcited-state properties, and electrochemical behavior as well as the hybridization defects and polarization of the Pn atoms was related to the charges of the main luminophores (i.e., phen vs N-tBu) and explored in terms of photoluminescence spectroscopy, X-ray diffractometry, and quantum-chemical methods. Therefore, an in-depth analysis of the bonding, crystal packing, excited-state energies, and lifetimes was assessed in liquid solutions, frozen glassy matrices, and crystalline phases along with a semiquantitative photoactivation study. Notably, by changing the main ligand from phen to N-tBu, an increase in radiative and radiationless deactivation rates (kr and knr, respectively) at 77 K together with a faster photoinduced CO release and fragmentation at room temperature was detected. In addition, a progressively red-shifted phosphorescence was observed with the growing atomic number of the pnictogen atom, along with a boost in kr and knr at 77 K. Down the Vth main group and upon coordination of the Pn atom to the Re(I) center, an increasingly prominent jump of s-orbital participation on the binding sxp3.00-orbitals of the Pn atoms is evidenced. Based on these findings, the ability of these complexes to act as tunable photoluminescent labels able to perform as light-driven CO-releasing molecules is envisioned.

β-Cyclodextrin and cucurbit[7]uril as protective encapsulation agents of the CO-releasing molecule [CpMo(CO)3Me

The CO releasing ability of the complex [CpMo(CO)3Me] (1) (Cp = η5-C5H5) has been assessed using a deoxymyoglobin-carbonmonoxymyoglobin assay. In the dark, CO release was shown to be promoted by the reducing agent sodium dithionite in a concentration-dependent manner. At lower dithionite concentrations, where dithionite-induced CO release was minimised, irradiation at 365 nm with a low-power UV lamp resulted in a strongly enhanced release of CO (half-life (t1/2) = 6.3 min), thus establishing complex 1 as a photochemically activated CO-releasing molecule. To modify the CO release behaviour of the tricarbonyl complex, the possibility of obtaining inclusion complexes between 1 and β-cyclodextrin (βCD) or cucurbit[7]uril (CB7) by liquid-liquid interfacial precipitation (1@βCD(IP)), liquid antisolvent precipitation (1@CB7), and mechanochemical ball-milling (1@βCD(BM)) was evaluated. All these methods led to the isolation of a true inclusion compound (albeit mixed with nonincluded 1 for 1@βCD(BM)), as evidenced by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), FT-IR and FT-Raman spectroscopies, and 13C{1H} magic angle spinning (MAS) NMR. PXRD showed that 1@βCD(IP) was microcrystalline with a channel-type crystal packing structure. High resolution mass spectrometry studies revealed the formation of aqueous phase 1 : 1 complexes between 1 and CB7. For 1@βCD(IP) and 1@CB7, the protective effects of the hosts led to a decrease in the CO release rates with respect to nonincluded 1. βCD had the strongest effect, with a ca. 10-fold increase in t1/4 for dithionite-induced CO release, and a ca. 2-fold increase in t1/2 for photoinduced CO release.

Carbon Monoxide Controllable Targeted Gas Therapy for Synergistic Anti-inflammation.

SummaryCarbon monoxide (CO) plays an important role in the regulation of a variety of physiological processes and thus is regarded as a promising pharmaceutical agent. Nevertheless, therapeutic applications of CO are severely hampered by the difficulty of the delivery of controlled amounts of CO to biological targets. To address this deficiency, we present a spatiotemporally controllable CO-releasing platform (designated as Neu-MnO2/Fla) for synergistic anti-inflammation. With the assistance of neutrophil membrane coating, Neu-MnO2/Fla can target to inflammatory sites. Subsequently, excess H2O2 at the inflamed tissues can be decomposed into oxygen because of MnO2 as nanozymes possessing catalase (CAT) activity, which not only relieves oxidative stress but also achieves in situ rapid photo-induced CO release. The in vitro and in vivo results indicate our CO-releasing platform exhibits a strong synergistic anti-inflammatory effect. Our work will shed light on targeted CO release to avoid side effects of therapeutic applications of CO.

An enzyme-responsive and photoactivatable carbon-monoxide releasing molecule for bacterial infection theranostics.

Infections caused by pathogenic bacteria, especially the drug-resistant bacteria, are posing a devastating threat to public health, which underscores the urgent needs for advanced strategies to effectively prevent and treat these intractable issues. Here we report a feasible and effective theranostic platform based on an enzyme-sensitive and photoactivatable carbon monoxide releasing molecule (CORM-Ac) for the successive detection and elimination of bacterial infection. The extracellular bacterial lipase can trigger the excited state intramolecular proton transfer (ESIPT) via elimination of the ester group in CORM-Ac, thus providing a fluorescence switch for an early warning of infection. Subsequently, the potent bactericidal therapy against the model bacterial strains, Staphylococcus aureus (S. aureus) and notorious methicillin-resistant Staphylococcus aureus (MRSA), was readily realized via photoinduced release of CO. In addition, the CORM-Ac and CORM showed good biocompatibility within a wide range of concentrations. The results of an infected animal wound test also demonstrated that the CORM-Ac-loaded gauze was effective in indicating the wound infection and accelerating the wound healing via the photoinduced CO release. The simplicity, functional integration, good biocompatibility and broad adaptability make CORM-Ac very attractive for bacterial theranostic applications.

Synthesis, characterization and photoinduced CO-release by manganese(i) complexes

Three new photoCORM, two with non two with nonbonding pyridine and one with benzyl group, were synthesised, and their CO-releasing properties evaluated for with regards to their elusive binding mode.

Green‐Light‐Induced PhotoCORM: Lysozyme Binding Affinity towards MnI and ReI Carbonyl Complexes and Biological Activity Evaluation

Reaction of N‐(2‐pyridylmethylene)benzene‐1,4‐diamine (L) with [MBr(CO)5] (M = MnI and ReI) affords complexes of the type [MBr(CO)3L] [M = MnI (1) and ReI (2)]. Complex 1 releases CO upon illumination with light in the range of 525–468 nm. No photo induced CO release is detected from 2. Reactive azide complex 3, obtained by bromide's ligand exchange, reacts with the electron‐poor alkyne dimethyl acetylene dicarboxylate giving triazolato complex 4 ([Mn(triazolateCOOMe,COOMe)(CO)3L]) via the free catalyst [3+2] cycloaddition coupling. Complex 1 exhibits interesting antifungal activity (MIC = 30 nM) against Candida albicans and Cryptococcus neoformans as well as cytotoxic activity of 12.56 µg/mL against noncancerous human embryonic kidney cells. Reactivity of the complexes towards hen egg white lysozyme is studied by electrospray ionization mass spectrometry.

Ultrafast Intersystem Crossing vs Internal Conversion in α-Diimine Transition Metal Complexes: Quantum Evidence.

Whereas third row transition metal carbonyl α-diimine complexes display luminescent properties and possess low-lying triplet metal-to-ligand charge transfer (MLCT) states efficiently accessible by a spin-vibronic mechanism, first row analogues hold low-lying metal-centered (MC) excited states that could quench these properties. Upon visible irradiation, different functions are potentially stimulated, namely, luminescence, electron transfer, or photoinduced CO release, the branching ratio of which is governed by the energetics, the character, and the early time dynamics of the photoactive excited states. Simulations of ultrafast nonadiabatic quantum dynamics, including spin-vibronic effects, of [M(imidazole)(CO)3(phenanthroline)]+ (M = Mn, Re) highlight the role of the metal atom. An ultrafast intersystem crossing process, driven by spin-orbit coupling, populates the low-lying triplet states of [Re(imidazole)(CO)3(phen)]+ within the first tens of fs. In contrast, efficient internal conversion between the two lowest 1MLCT states of [Mn(imidazole)(CO)3(phen)]+ is mediated within 50 fs by vibronic coupling with upper MC and MLCT states.

Reactivity of visible-light induced CO releasing thiourea-based Mn(I) tricarbonyl bromide (CORM-NS1) towards lysozyme

The synthesis of visible-light induced carbon monoxide releasing complexes (photoCORMs) with some perquisites such as solubility in water or in a medium suitable for drug delivery (H2O/DMSO), dark stability under the aerated conditions and CO releasing upon the illumination, is the major challenge for the phototherapeutic CO applications. The reaction of N-(2-thiazolyl)-1H-benzotriazole-1-carbothioamide (HL) with [MnBr(CO)5] affords fac-[MnBr(CO)3(HL)] (CORM-NS1). The aerated DMSO solution of CORM-NS1 is stable for 16 h. The process of the photo induced CO release is studied using two excitation wavelengths, 468 and 525 nm and quantitatively estimated by the myoglobin assay and commercial gas sensor. The electronic structure of CORM-NS1 is calculated at PCM/TD-B3LYP/def2-SVP (or LANL2DZ) level of theory. Interaction of CORM-NS1 with hen egg white lysozyme (HEWL), as a biocompatible carrier, is studied in the dark and upon illumination by means of ESI-MS. In the dark, an adduct peak corresponding to binding of Mn(CO)3 fragment to HEWL is observed, which disappears upon the illumination with either the green or blue light.

Electrochemically probing the correlation between photo-induced CO-releasing behaviours and their LUMO energies of three diiron carbonyl complexes

Three diiron carbonyl complexes with different carbonyl ligands have been synthesized. Pentacarbonyl and tetracarbonyl complexes 2 and 3 were prepared by the substitution of the bound CO of complex 1 by PPh3. The photo-induced CO-releasing behaviours of these complexes correlate linearly to their reduction potentials and further to the energy level of their LUMOs. The more negative the reduction potentials, the more reactive the complexes. The photo-induced CO-release can be further promoted when a nucleophile is presented such as thiopronin.

Photoinduced Carbon Monoxide Release from Half-Sandwich Iron(II) Carbonyl Complexes by Visible Irradiation: Kinetic Analysis and Mechanistic Investigation.

Three half-sandwich iron(II) complexes, [Fe(η(5) -Cp)(cis-CO)2 X] (X(-) =Cl(-) , Br(-) , I(-) ), were synthesized and characterized. The kinetics of the CO-releasing behaviour of these complexes upon illumination by visible irradiation in various media was investigated. Our results indicated that the CO release was significantly affected by the auxiliary ligands. Of the three light sources used (blue, green, and red), blue light exhibited the highest efficiency. In the photoinduced CO release, the solvents and exogenous nucleophiles in the media were involved, which allowed their CO-releasing reaction to comply with pseudo first-order model rather than the characteristic zero-order model for a photochemical reaction. In aqueous media (D2 O), an intermediate bearing the core of {Fe(II) (cis-CO)2 } involving cleavage of cyclopentadiene was detected. Despite the non-absorption of the red light, its illumination combined with nucleophilic substitution did cause considerable CO release. Assessment of the cytotoxicity of the three complexes indicated that they showed good biocompatibility.

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.

Live-Fibroblast IR Imaging of a Cytoprotective PhotoCORM Activated with Visible Light

Carbon monoxide releasing molecules (CORMs) are an emerging class of pharmaceutical compounds currently evaluated in several preclinical disease models. There is general consensus that the therapeutic effects elicited by the molecules may be directly ascribed to the biological function of the released CO. It remains unclear, however, if cellular internalization of CORMs is a critical event in their therapeutic action. To address the problem of cellular delivery, we have devised a general strategy which entails conjugation of a CO-releasing molecule (here a photoactivated CORM) to the 5'-OH ribose group of vitamin B12. Cyanocobalamin (B12) functions as the biocompatible water-soluble scaffold which actively transports the CORM against a concentration gradient into the cells. The uptake and cellular distribution of this B12-photoCORM conjugate is demonstrated via synchrotron FTIR spectromicroscopy measurements on living cells. Intracellular photoinduced CO release prevents fibroblasts from dying under conditions of hypoxia and metabolic depletion, conditions that may occur in vivo during insufficient blood supply to oxygen-sensitive tissues such as the heart or brain.

Synthesis, Spectroscopic Properties, and Photoinduced CO-Release Studies of Functionalized Ruthenium(II) Polypyridyl Complexes: Versatile Building Blocks for Development of CORM–Peptide Nucleic Acid Bioconjugates

A series of ruthenium(II) dicarbonyl complexes of formula [RuCl2(L)(CO)2] (L = bpy(CH3,CH3) = 4,4'-dimethyl-2,2'-bipyridine, bpy(CH3,CHO) = 4'-methyl-2,2'-bipyridine-4-carboxyaldehyde, bpy(CH3,COOH) = 4'-methyl-2,2'-bipyridine-4-carboxylic acid, CppH = 2-(pyridin-2-yl)pyrimidine-4-carboxylic acid, dppzcH = dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylic acid), and [RuCl(L)(CO)2](+) (L = tpy(COOH) = 6-(2,2':6',2″-terpyridine-4'-yloxy)hexanoic acid) has been synthesized. In addition, a high-yield synthesis of a peptide nucleic acid (PNA) monomer containing the 2-(pyridin-2-yl)pyrimidine ligand was also developed, and this compound was used to prepare the first Ru(II) dicarbonyl complex, [RuCl2(Cpp-L-PNA)(CO)2],(Cpp-L-PNA = tert-butyl-N-[2-(N-9-fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoyl]glycinate) attached to a PNA monomer backbone. Such metal-complex PNA-bioconjugates are attracting profound interest for biosensing and biomedical applications. Characterization of all complexes has been undertaken by IR and NMR spectroscopy, mass spectrometry, elemental analysis, and UV-vis spectroscopy. Investigation of the CO-release properties of the Ru(II) complexes in water/dimethyl sulfoxide (49:1) using the myoglobin assay showed that they are stable under physiological conditions in the dark for at least 60 min and most of them even for up to 15 h. In contrast, photoinduced CO release was observed upon illumination at 365 nm, the low-energy shoulder of the main absorption maximum centered around 300 nm, establishing these compounds as a new class of PhotoCORMs. While the two 2,2'-bipyridine complexes release 1 equiv of CO per mole of complex, the terpyridine, 2-(2'-pyridyl)pyrimidine, and dipyrido[3,2-a:2',3'-c]phenazine complexes are less effective CO releasers. Attachment of the 2-(2'-pyridyl)pyrimidine complex to a PNA backbone as in [RuCl2(Cpp-L-PNA)CO2] did not significantly change the spectroscopic or CO-release properties compared to the parent complex. Thus, a novel class of Ru(II)-based PhotoCORMs has been established which can be coupled to carrier delivery vectors such as PNA to facilitate cellular uptake without loss of the inherent CORM properties of the parent compound.

Synthesis, characterization, and photoinduced CO-release reactivity of a Pb(II) flavonolate complex: Comparisons to Group 12 analogs

The synthesis, characterization, and photoinduced CO-release reactivity of [(6-Ph2TPA)Pb(3-Hfl)]ClO4 (1; 6-Ph2TPA=N,N-bis((6-phenyl-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine; 3-Hfl=anion of 3-hydroxyflavone) is reported and compared with Group 12 analogues ([(6-Ph2TPA)M(3-Hfl)]ClO4 (M=Hg(II) (2), Cd(II) (3), Zn(II) (4)). The Pb(II) complex exhibits unique features within this group of complexes in terms of its structural and spectroscopic features involving the coordinated flavonolate ligand. Similar to the Group 12 compounds, irradiation of 1 at 300nm in an O2-containing environment results in the quantitative release of CO and the formation of a Pb(II) O-benzoylsalicylate (O-bs, depside) complex via a photoinduced dioxygenase-type reaction. Comparison of the quantum yield for the reaction of the Pb(II) flavonolate complex (Φ=0.21(6)) versus the reactions of the structurally-related Group 12 metal complexes (6-Ph2TPA)M(3-Hfl)]ClO4 (M=Hg(II) (2, Φ=0.31(2)), Cd(II) (3, Φ=0.28(2)), Zn(II) (4), Φ=0. 09(1)) revealed that flavonolate complexes of a heavy metal ion (Cd(II), Hg(II), Pb(II)) exhibit a higher reaction quantum yield than the Zn(II) derivative. Both Pb(II) and Zn(II) flavonolate complexes were found to be catalysts for the oxidative photoinduced degradation of 3-hydroxyflavone. The combined results of these investigations suggest that metal contaminants typically present in soil, including toxic heavy metal ions, might facilitate the oxidative decomposition of plant-derived flavonols via photoinduced reactions.

Photoinduced CO release, cellular uptake and cytotoxicity of a tris(pyrazolyl)methane (tpm) manganese tricarbonyl complex

Cell viability studies of HT29 colon cancer cells treated with the CO-releasing compound [Mn(CO)(3)(tpm)]PF(6) revealed a significant photoinduced cytotoxicity comparable to that of established agent 5-fluorouracil (5-FU), while controls kept in the dark were unaffected at up to 100 microM.