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Bioorthogonal Metalloporphyrin-Catalyzed Selective Methionine Alkylation in the Lanthipeptide Nisin.Chembiochem : a European Journal of... Jan 2019Bioorthogonal catalytic modification of ribosomally synthesized and post-translationally modified peptides (RiPPs) is a promising approach to obtaining novel...
Bioorthogonal catalytic modification of ribosomally synthesized and post-translationally modified peptides (RiPPs) is a promising approach to obtaining novel antimicrobial peptides with improved properties and/or activities. Here, we present the serendipitous discovery of a selective and rapid method for the alkylation of methionines in the lanthipeptide nisin. Using carbenes, formed from water-soluble metalloporphyrins and diazoacetates, methionines are alkylated to obtain sulfonium ions. The formed sulfonium ions are stable, but can be further reacted to obtain functionalized methionine analogues, expanding the toolbox of chemical posttranslational modification even further.
Topics: Alkylation; Anti-Bacterial Agents; Catalysis; Iron; Metalloporphyrins; Methionine; Nisin; Ruthenium
PubMed: 30246492
DOI: 10.1002/cbic.201800493 -
ACS Sensors Oct 2019-Nitrosamines are environmental genotoxicants that are widely encountered in air, water, and food. Contamination of indoor and outdoor air with -nitrosamines has been...
-Nitrosamines are environmental genotoxicants that are widely encountered in air, water, and food. Contamination of indoor and outdoor air with -nitrosamines has been reported on many occasions. Conventional detection of airborne -nitrosamines requires sophisticated instrumentation, field sampling, and laboratory analysis. Herein, we report ultrasensitive carbon nanotube based chemiresistive sensors utilizing a cobalt(III) tetraphenylporphyrin selector element for the detection of -nitrosamines. Concentrations as low as 1 ppb -nitrosodimethylamine, -nitrosodiethylamine, and -nitrosodibutylamine were detected. We also demonstrate the integration of these sensors with a field deployable sensing node wherein the sensor response can be read online remotely.
Topics: Air Pollutants; Carcinogens; Cobalt; Metalloporphyrins; Nanotubes, Carbon; Nitrosamines
PubMed: 31573183
DOI: 10.1021/acssensors.9b01532 -
Astrobiology Jul 2022Metal complexes of porphyrins and porphyrin-type compounds are ubiquitous in all three domains of life, with hemes and chlorophylls being the best-known examples. Their...
Metal complexes of porphyrins and porphyrin-type compounds are ubiquitous in all three domains of life, with hemes and chlorophylls being the best-known examples. Their diagenetic transformation products are found as geoporphyrins, in which the characteristic porphyrin core structure is retained and which can be up to 1.1 billion years old. Because of this, and their relative ease of detection, metalloporphyrins appear attractive as chemical biosignatures in the search for extraterrestrial life. In this study, we investigated the stability of solid chlorido(2,3,7,8,12,13,17,18-octaethylporphyrinato)iron(III) [FeCl(oep)], which served as a model for heme-like molecules and iron geoporphyrins. [FeCl(oep)] was exposed to a variety of astrobiologically relevant extreme conditions, namely: aqueous acids and bases, oxidants, heat, and radiation. Key results are: (1) the [Fe(oep)] core is stable over the pH range 0.0-13.5 even at 80°C; (2) the oxidizing power follows the order ClO > HO > ClO > HNO > ClO; (3) in an inert atmosphere, the iron porphyrin is thermally stable to near 250°C; (4) at high temperatures, carbon dioxide gas is not inert but acts as an oxidant, forming carbon monoxide; (5) a decomposition layer is formed on ultraviolet irradiation and protects the [FeCl(oep)] underneath; (6) an NaCl/NaHCO salt mixture has a protective effect against X-rays; and (7) no such effect is observed when [FeCl(oep)] is exposed to iron ion particle radiation. The relevance to potential iron porphyrin biosignatures on Mars, Europa, and Enceladus is discussed.
Topics: Heme; Hydrogen Peroxide; Iron; Metalloporphyrins; Oxidants; Porphyrins
PubMed: 35647896
DOI: 10.1089/ast.2021.0144 -
Accounts of Chemical Research May 2020The oxygen reduction reaction (ORR) is a multiproton/multielectron transformation in which dioxygen (O) is reduced to water or hydrogen peroxide and serves as the...
The oxygen reduction reaction (ORR) is a multiproton/multielectron transformation in which dioxygen (O) is reduced to water or hydrogen peroxide and serves as the cathode reaction in most fuel cells. The ORR (O + 4e + 4H → 2HO) involves up to nine substrates and thus requires navigating a complicated reaction landscape, typically with several high-energy intermediates. Many catalysts can perform this reaction, though few operate with fast rates and at low overpotentials (close to the thermodynamic potential). Attempts to optimize these parameters, both in homogeneous and heterogeneous electrocatalytic systems, have focused on modifying catalyst design and understanding kinetic/thermodynamic relationships between catalytic intermediates. One such method for analyzing and predicting catalyst reactivity and efficiency has been the development of "molecular scaling relationships". Here, we share our experience deriving and utilizing molecular scaling relationships for soluble, iron-porphyrin-catalyzed O reduction in organic solvents. These relationships correlate turnover frequencies (TOF) and effective overpotentials (η), properties uniquely defined for homogeneous catalysts. Following a general introduction of scaling relationships for both homogeneous and heterogeneous electrocatalysis, we describe the components of such scaling relationships: (i) the overall thermochemistry of the reaction and (ii) the rate and rate law of the catalyzed reaction. We then show how connecting these thermodynamic and kinetic parameters reveals molecular scaling relationships for iron-porphyrin-catalyzed O reduction. For example, the log(TOF) responds steeply to changes in η that result from different catalyst reduction potentials (18.5 decades in TOF/V in η) but much less dramatically to changes in η that arise from varying the p of the acid buffer (5.1 decades in TOF/V in η). Thus, a single scaling relationship is not always sufficient for describing molecular electrocatalysis. This is particularly evident when the catalyst identity and reaction conditions are coupled. Using these multiple scaling relationships, we demonstrate that the metrics of turnover frequency and effective overpotential can be predictably tuned to achieve faster rates at lowered overpotentials. This Account uses a collection of related stories describing our research on soluble iron-porphyrin-catalyzed ORR to show how molecular scaling relationships can be derived and used for any electrocatalytic reaction. Such scaling relationships are powerful tools that connect the thermochemistry, mechanism, and rate law for a catalytic system. We hope that this collection shows the utility and simplicity of the molecular scaling approach for understanding catalysis, for enabling direct comparisons between catalyst systems, and for optimizing catalytic processes.
Topics: Catalysis; Electrochemistry; Iron; Kinetics; Metalloporphyrins; Oxidation-Reduction; Oxygen; Thermodynamics
PubMed: 32281786
DOI: 10.1021/acs.accounts.0c00044 -
Toxicology and Applied Pharmacology Jul 2017Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are...
Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Administration, Oral; Animals; Antioxidants; Antiparkinson Agents; Behavior, Animal; Biological Availability; Biomarkers; Blood-Brain Barrier; Brain; Capillary Permeability; Disease Models, Animal; Dopamine; Drug Design; Drug Evaluation, Preclinical; Half-Life; Injections, Intraperitoneal; MPTP Poisoning; Male; Metalloporphyrins; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Oxidative Stress; Rotarod Performance Test
PubMed: 28400118
DOI: 10.1016/j.taap.2017.04.004 -
Journal of the American Chemical Society May 2019The catalytic reduction of O to HO is important for energy transduction in both synthetic and natural systems. Herein, we report a kinetic and thermochemical study of...
The catalytic reduction of O to HO is important for energy transduction in both synthetic and natural systems. Herein, we report a kinetic and thermochemical study of the oxygen reduction reaction (ORR) catalyzed by iron tetraphenylporphyrin (Fe(TPP)) in N, N'-dimethylformamide using decamethylferrocene as a soluble reductant and para-toluenesulfonic acid ( pTsOH) as the proton source. This work identifies and characterizes catalytic intermediates and their thermochemistry, providing a detailed mechanistic understanding of the system. Specifically, reduction of the ferric porphyrin, [Fe(TPP)] forms the ferrous porphyrin, Fe(TPP), which binds O reversibly to form the ferric-superoxide porphyrin complex, Fe(TPP)(O). The temperature dependence of both the electron transfer and O binding equilibrium constants has been determined. Kinetic studies over a range of concentrations and temperatures show that the catalyst resting state changes during the course of each catalytic run, necessitating the use of global kinetic modeling to extract rate constants and kinetic barriers. The rate-determining step in oxygen reduction is the protonation of Fe(TPP)(O) by pTsOH, which proceeds with a substantial kinetic barrier. Computational studies indicate that this barrier for proton transfer arises from an unfavorable preassociation of the proton donor with the superoxide adduct and a transition state that requires significant desolvation of the proton donor. Together, these results are the first example of oxygen reduction by iron tetraphenylporphyrin where the pre-equilibria among ferric, ferrous, and ferric-superoxide intermediates have been quantified under catalytic conditions. This work gives a generalizable model for the mechanism of iron porphyrin-catalyzed ORR and provides an unusually complete mechanistic study of an ORR reaction. More broadly, this study also highlights the kinetic challenges for proton transfer to catalytic intermediates in organic media.
Topics: Catalysis; Density Functional Theory; Kinetics; Metalloporphyrins; Models, Chemical; Oxidation-Reduction; Oxygen; Thermodynamics
PubMed: 31042028
DOI: 10.1021/jacs.9b02640 -
Antioxidants & Redox Signaling May 2014Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O2·(-); no wonder, thus, that their... (Review)
Review
SIGNIFICANCE
Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O2·(-); no wonder, thus, that their mimics are remarkably efficacious in essentially any animal model of oxidative stress injuries thus far explored.
RECENT ADVANCES
Structure-activity relationship (half-wave reduction potential [E1/2] versus log kcat), originally reported for Mn porphyrins (MnPs), is valid for any other class of SOD mimics, as it is dominated by the superoxide reduction and oxidation potential. The biocompatible E1/2 of ∼+300 mV versus normal hydrogen electrode (NHE) allows powerful SOD mimics as mild oxidants and antioxidants (alike O2·(-)) to readily traffic electrons among reactive species and signaling proteins, serving as fine mediators of redox-based signaling pathways. Based on similar thermodynamics, both SOD enzymes and their mimics undergo similar reactions, however, due to vastly different sterics, with different rate constants.
CRITICAL ISSUES
Although log kcat(O2·(-)) is a good measure of therapeutic potential of SOD mimics, discussions of their in vivo mechanisms of actions remain mostly of speculative character. Most recently, the therapeutic and mechanistic relevance of oxidation of ascorbate and glutathionylation and oxidation of protein thiols by MnP-based SOD mimics and subsequent inactivation of nuclear factor κB has been substantiated in rescuing normal and killing cancer cells. Interaction of MnPs with thiols seems to be, at least in part, involved in up-regulation of endogenous antioxidative defenses, leading to the healing of diseased cells.
FUTURE DIRECTIONS
Mechanistic explorations of single and combined therapeutic strategies, along with studies of bioavailability and translational aspects, will comprise future work in optimizing redox-active drugs.
Topics: Animals; Drug Design; Humans; Metalloporphyrins; Molecular Mimicry; Oxidation-Reduction; Signal Transduction; Structure-Activity Relationship; Superoxide Dismutase
PubMed: 23875805
DOI: 10.1089/ars.2012.5147 -
Chemical & Pharmaceutical Bulletin 2017The specific intermolecular interaction between an anionic tetraarylporphyrin and per-O-methylated β-cyclodextrin (TMe-β-CD) paved the way to produce a functional... (Review)
Review
The specific intermolecular interaction between an anionic tetraarylporphyrin and per-O-methylated β-cyclodextrin (TMe-β-CD) paved the way to produce a functional supramolecule that works as a strong carbon monoxide (CO)-depleting agent in living organisms. The supramolecular complex, hemoCD, that is composed of meso-tetrakis(4-sulfonatophenyl)porphinatoiron(II) and a TMe-β-CD dimer linked by a pyridine linker, captured internal CO from carboxyhemoglobin during its circulation in the blood of animals. HemoCD thus produced the pseudo-knockdown (loss-of-functional) state of endogenous CO in the animals. This unique property led us to investigate the biological function of endogenous CO as a gaseous signal mediator in living systems. In this paper, we introduce our recent study on the hemoCD complex as a biological CO-depleting agent.
Topics: Animals; Carbon Monoxide; Cyclodextrins; Ferrous Compounds; Humans; Macromolecular Substances; Metalloporphyrins; Molecular Structure
PubMed: 28381673
DOI: 10.1248/cpb.c16-00767 -
PloS One 2014Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins...
Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP), water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1) also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.
Topics: Acute Kidney Injury; Animals; Apoptosis; Caspase 3; Cisplatin; Cytoprotection; DNA Fragmentation; Heme Oxygenase-1; Kidney Tubules; Male; Metalloporphyrins; Mice; Mice, Inbred C57BL; Nitrates; Oxidative Stress
PubMed: 24454954
DOI: 10.1371/journal.pone.0086057 -
Amino Acids Jan 2012The most efficacious Mn(III) porphyrinic (MnPs) scavengers of reactive species have positive charges close to the Mn site, whereby they afford thermodynamic and... (Review)
Review
The most efficacious Mn(III) porphyrinic (MnPs) scavengers of reactive species have positive charges close to the Mn site, whereby they afford thermodynamic and electrostatic facilitation for the reaction with negatively charged species such as O (2) (•-) and ONOO(-). Those are Mn(III) meso tetrakis(N-alkylpyridinium-2-yl)porphyrins, more specifically MnTE-2-PyP(5+) (AEOL10113) and MnTnHex-2-PyP(5+) (where alkyls are ethyl and n-hexyl, respectively), and their imidazolium analog, MnTDE-2-ImP(5+) (AEOL10150, Mn(III) meso tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin). The efficacy of MnPs in vivo is determined not only by the compound antioxidant potency, but also by its bioavailability. The former is greatly affected by the lipophilicity, size, structure, and overall shape of the compound. These porphyrins have the ability to both eliminate reactive oxygen species and impact the progression of oxidative stress-dependent signaling events. This will effectively lead to the regulation of redox-dependent transcription factors and the suppression of secondary inflammatory- and oxidative stress-mediated immune responses. We have reported on the inhibition of major transcription factors HIF-1α, AP-1, SP-1, and NF-κB by Mn porphyrins. While the prevailing mechanistic view of the suppression of transcription factors activation is via antioxidative action (presumably in cytosol), the pro-oxidative action of MnPs in suppressing NF-κB activation in nucleus has been substantiated. The magnitude of the effect is dependent upon the electrostatic (porphyrin charges) and thermodynamic factors (porphyrin redox ability). The pro-oxidative action of MnPs has been suggested to contribute at least in part to the in vitro anticancer action of MnTE-2-PyP(5+) in the presence of ascorbate, and in vivo when combined with chemotherapy of lymphoma. Given the remarkable therapeutic potential of metalloporphyrins, future studies are warranted to further our understanding of in vivo action/s of Mn porphyrins, particularly with respect to their subcellular distribution.
Topics: Animals; Humans; Manganese; Metalloporphyrins; Oxidation-Reduction; Oxidative Stress; Transcriptional Activation
PubMed: 20473774
DOI: 10.1007/s00726-010-0603-6