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International Journal of Molecular... Apr 2023Renal immune injury is a frequent cause of end-stage renal disease, and, despite the progress made in understanding underlying pathogenetic mechanisms, current... (Review)
Review
Renal immune injury is a frequent cause of end-stage renal disease, and, despite the progress made in understanding underlying pathogenetic mechanisms, current treatments to preserve renal function continue to be based mainly on systemic immunosuppression. Small molecules, naturally occurring biologic agents, show considerable promise in acting as disease modifiers and may provide novel therapeutic leads. Certain naturally occurring or synthetic Metalloporphyrins (Mps) can act as disease modifiers by increasing heme oxygenase (HO) enzymatic activity and/or synthesis of the inducible HO isoform (HO-1). Depending on the metal moiety of the Mp employed, these effects may occur in tandem or can be discordant (increased HO-1 synthesis but inhibition of enzyme activity). This review discusses effects of Mps, with varying redox-active transitional metals and cyclic porphyrin cores, on mechanisms underlying pathogenesis and outcomes of renal immune injury.
Topics: Heme Oxygenase (Decyclizing); Metalloporphyrins; Heme Oxygenase-1; Kidney
PubMed: 37047787
DOI: 10.3390/ijms24076815 -
Antioxidants & Redox Signaling May 2014Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in... (Review)
Review
SIGNIFICANCE
Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease.
RECENT ADVANCES
Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment.
CRITICAL ISSUES
Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders.
FUTURE DIRECTIONS
Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.
Topics: Animals; Antioxidants; Central Nervous System Diseases; Humans; Metalloporphyrins; Oxidation-Reduction; Oxidative Stress
PubMed: 23706004
DOI: 10.1089/ars.2013.5413 -
Chemical Reviews Mar 2018As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive... (Review)
Review
As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O and its derived intermediates such as hydrogen peroxide to afford a variety of metal-oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal-oxo species, are the basis for the various biological functions of O-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron-oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs.
Topics: Hemeproteins; Iron; Metalloporphyrins; Models, Molecular; Oxygen; Quantum Theory; Reactive Oxygen Species
PubMed: 29286645
DOI: 10.1021/acs.chemrev.7b00373 -
The Cochrane Database of Systematic... 2003Metalloporphyrins are heme analogues that inhibit heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin. By preventing the formation of... (Review)
Review
BACKGROUND
Metalloporphyrins are heme analogues that inhibit heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin. By preventing the formation of bilirubin, they have the potential to reduce the level of unconjugated bilirubin in neonates and thereby reduce the risk of neonatal encephalopathy and long term neurodevelopmental impairment from bilirubin toxicity to the nervous system.
OBJECTIVES
1. To determine the efficacy of metalloporphyrins in reducing bilirubin levels, reducing the need for phototherapy or exchange transfusion and reducing the incidence of bilirubin encephalopathy in neonates with unconjugated hyperbilirubinemia when compared to placebo, phototherapy or exchange transfusion. 2. To determine the nature and frequency of side effects of metalloporphyrins when used to treat unconjugated hyperbilirubinemia in neonates.
SEARCH STRATEGY
We searched Medline (1966 - January 2003) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (2003, issue 1). We hand-searched the articles cited in each publication obtained. We hand searched the abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) for the years 1985 - 2002.
SELECTION CRITERIA
We included only randomized controlled studies, in which preterm or term neonates (age 28 days of life or less) with unconjugated hyperbilirubinemia due to any cause were randomly allocated to receive a metalloporphyrin in the treatment arm(s), and to receive a placebo or a conventional treatment (phototherapy or exchange transfusion) or no treatment for hyperbilirubinemia in the comparison arm(s). Any preparation of metalloporphyrin could be used, in any form, by any route, at any dose.
DATA COLLECTION AND ANALYSIS
Two authors extracted data independently. Data were entered into Revman by one author and checked by a second author. Prespecified subgroup analyses were planned in term versus preterm infants, hemolytic versus non-hemolytic causes of jaundice and according to the type of metalloporphyrin used.
MAIN RESULTS
Three small studies, enrolling a total of 170 infants, were eligible for inclusion in this review. None blinded intervention or outcome assessment. In all three studies some patients were excluded after randomization. Metalloporphyrin-treated infants appeared to have short-term benefits compared to controls, including a lower maximum plasma bilirubin level in one study, a lower frequency of severe hyperbilirubinemia in one study, a decreased need for phototherapy, fewer plasma bilirubin measurements and a shorter duration of hospitalization. None of the enrolled infants required an exchange transfusion in the two studies that described this outcome. None of the studies reported on neonatal kernicterus, death, long-term neurodevelopmental outcomes or iron deficiency anemia. Though a small number of metalloporphyrin-treated as well as control infants developed a photosensitivity rash, the trials were too small to rule out an increase in the risk of photosensitivity or other adverse effects from metalloporphyrin treatment. No subgroup analyses were possible due to the small number of included trials.
REVIEWER'S CONCLUSIONS
Treatment of neonatal unconjugated hyperbilirubinemia with metalloporphyrins may reduce neonatal bilirubin levels and decrease the need for phototherapy and hospitalization. There is no evidence to support or refute the possibility that treatment with a metalloporphyrin decreases the risk of neonatal kernicterus or of long-term neurodevelopmental impairment due to bilirubin encephalopathy. There is no evidence to support or refute the possibility that cutaneous photosensitivity is increased with metalloporphyrin treatment. Routine treatment of neonatal unconjugated hyperbilirubinemia with a metalloporphyrin cannot be recommended at present.
Topics: Humans; Hyperbilirubinemia; Infant, Newborn; Metalloporphyrins; Randomized Controlled Trials as Topic
PubMed: 12804504
DOI: 10.1002/14651858.CD004207 -
European Journal of Pharmacology May 2008Peroxynitrite is well-recognized as being capable of inducing damaging cellular effects and has been identified as a mediator of cell damage in numerous disease states,... (Review)
Review
Peroxynitrite is well-recognized as being capable of inducing damaging cellular effects and has been identified as a mediator of cell damage in numerous disease states, including cardiovascular diseases. Metalloporphyrins are a class of molecule that represents an exciting new pharmacological approach to reducing peroxynitrite levels. These compounds catalyze the conversion of the harmful peroxynitrite molecules into less toxic derivatives and can be considered the reasonable intervention to reduce the toxicity of peroxynitrite. Several compounds have been synthesized and tested with promising results. Differences in the metalloporphyrin structure affect their reactivity. Iron-based metalloporphyrins display the highest rate of peroxynitrite decomposition with the narrowest scope of side reactions, whereas manganese-based metalloporphyrins react slower and with more pronounced secondary reactions, notably functioning as superoxide dismutase mimetics. This review examines the evidence that peroxynitrite is operative in patients with cardiovascular disease focusing on metalloporphyrin peroxynitrite decomposition catalysts and the evidence for their utility in the pharmacological treatment of major cardiovascular diseases. The data suggest that modification of peroxynitrite-induced cardiovascular injury is an intriguing and useful treatment approach.
Topics: Animals; Cardiovascular Diseases; Catalysis; Free Radical Scavengers; Humans; Metalloporphyrins; Myocardial Reperfusion Injury; Peroxynitrous Acid
PubMed: 18395709
DOI: 10.1016/j.ejphar.2008.02.078 -
Biosensors Oct 2018In recent years, scientific advancements have constantly increased at a significant rate in the field of biomedical science. Keeping this in view, the application of... (Review)
Review
In recent years, scientific advancements have constantly increased at a significant rate in the field of biomedical science. Keeping this in view, the application of porphyrins and metalloporphyrins in the field of biomedical science is gaining substantial importance. Porphyrins are the most widely studied tetrapyrrole-based compounds because of their important roles in vital biological processes. The cavity of porphyrins containing four pyrrolic nitrogens is well suited for the binding majority of metal ions to form metalloporphyrins. Porphyrins and metalloporphyrins possess peculiar photochemical, photophysical, and photoredox properties which are tunable through structural modifications. Their beneficial photophysical properties, such as the long wavelength of emission and absorption, high singlet oxygen quantum yield, and low in vivo toxicity, have drawn scientists' interest to discover new dimensions in the biomedical field. Applications of porphyrins and metalloporphyrins have been pursued in the perspective of contrast agents for magnetic resonance imaging (MRI), photodynamic therapy (PDT) of cancer, bio-imaging, and other biomedical applications. This review discusses photophysics and the photochemistry of porphyrins and their metal complexes. Secondly, it explains the current developments and mode of action for contrast agents for MRI. Moreover, the application of porphyrin and metalloporphyrin-based molecules as a photosensitizer in PDT of cancer, the mechanism of the generation of reactive oxygen species (ROS), factors that determine the efficiency of PDT, and the developments to improve this technology are delineated. The last part explores the most recent research and developments on metalloporphyrin-based materials in bio-imaging, drug delivery, and the determination of ferrochelatase in bone marrow indicating their prospective clinical applications.
Topics: Humans; Magnetic Resonance Imaging; Metalloporphyrins; Photochemistry; Photochemotherapy; Photosensitizing Agents; Porphyrins
PubMed: 30347683
DOI: 10.3390/bios8040095 -
International Journal of Biological... Jan 2021Metalloporphyrins (FeTBAP, MnTBAP, FeTMPyP and MnTMPyP) have been proposed as effective therapeutic agents in ONOO-related disease including type 2 diabetes (T2D). As...
Metalloporphyrins (FeTBAP, MnTBAP, FeTMPyP and MnTMPyP) have been proposed as effective therapeutic agents in ONOO-related disease including type 2 diabetes (T2D). As these metalloporphyrins share the structural similarities of the planar aromatic conjugation with a valuable class of inhibitors against amyloids fibrillation, they might be effective inhibitors via aromatic π-π stacking interactions with amyloid peptides. Here, we found that the anionic metalloporphyrins (FeTBAP and MnTBAP) are effective inhibitors against hIAPP fibrillation, while, the cationic metalloporphyrins (FeTMPyP and MnTMPyP) only have limited inhibitory effects. Besides, the porphyrin with iron center is more effective than the one with manganese center. Our results favor the electrostatic attraction contributes the main reason to the inhibitory effect between the anionic porphyrins and hIAPP, followed by the π-π stacking interactions between aromatic ring of porphyrins and hIAPP and the stronger coordination ability of iron center to hIAPP. Additionally, by comparison with FeTBAP, which can completely inhibit cytotoxicity induced by hIAPP via stabilizing hIAPP monomers, MnTBAP fails to reverse the cytotoxicity due to that it can only delay the transition of hIAPP from α-helix to β-sheet rich oligomers. Our results provide theoretical significance for further designing or screening of metalloporphyrins as bifunctional antidiabetic drugs.
Topics: Amyloid; Circular Dichroism; Humans; Islet Amyloid Polypeptide; Metalloporphyrins; Microscopy, Atomic Force; Models, Molecular; Molecular Structure; Protein Aggregates; Protein Conformation; Protein Conformation, beta-Strand; Protein Stability; Structure-Activity Relationship
PubMed: 33253743
DOI: 10.1016/j.ijbiomac.2020.11.161 -
Molecules (Basel, Switzerland) Jul 2016Synthetic and bioinspired metalloporphyrins are a class of redox-active catalysts able to emulate several enzymes such as cytochromes P450, ligninolytic peroxidases, and... (Review)
Review
Synthetic and bioinspired metalloporphyrins are a class of redox-active catalysts able to emulate several enzymes such as cytochromes P450, ligninolytic peroxidases, and peroxygenases. Their ability to perform oxidation and degradation of recalcitrant compounds, including aliphatic hydrocarbons, phenolic and non-phenolic aromatic compounds, sulfides, and nitroso-compounds, has been deeply investigated. Such a broad substrate specificity has suggested their use also in the bleaching of textile plant wastewaters. In fact, industrial dyes belong to very different chemical classes, being their effective and inexpensive oxidation an important challenge from both economic and environmental perspective. Accordingly, we review here the most widespread synthetic metalloporphyrins, and the most promising formulations for large-scale applications. In particular, we focus on the most convenient approaches for immobilization to conceive economical affordable processes. Then, the molecular routes of catalysis and the reported substrate specificity on the treatment of the most diffused textile dyes are encompassed, including the use of redox mediators and the comparison with the most common biological and enzymatic alternative, in order to depict an updated picture of a very promising field for large-scale applications.
Topics: Adsorption; Catalysis; Coloring Agents; Cytochrome P-450 Enzyme System; Enzymes, Immobilized; Heme; Metalloporphyrins; Molecular Structure; Oxidation-Reduction; Peroxidases; Sorption Detoxification; Substrate Specificity; Textiles; Wastewater
PubMed: 27455229
DOI: 10.3390/molecules21070964 -
Chemical Society Reviews Apr 2011Metalloporphyrins are a class of versatile catalysts with the capability to functionalize saturated C-H bonds via several well-defined atom/group transfer processes,... (Review)
Review
Metalloporphyrins are a class of versatile catalysts with the capability to functionalize saturated C-H bonds via several well-defined atom/group transfer processes, including oxene, nitrene, and carbene C-H insertions. The corresponding hydroxylation, amination, and alkylation reactions provide direct approaches for the catalytic conversion of abundant hydrocarbons into value-added functional molecules through C-O, C-N, and C-C bond formations, respectively. This tutorial review describes metalloporphyrin-based catalytic systems for the functionalization of different types of sp(3) C-H bonds, both inter- and intramolecularly, including challenging primary C-H bonds. Additional features of metalloporphyrin-catalyzed C-H functionalization include unusual selectivities and high turnover numbers.
Topics: Alkylation; Amination; Carbon; Catalysis; Hydrogen; Hydroxylation; Metalloporphyrins
PubMed: 21088785
DOI: 10.1039/c0cs00070a -
The Journal of Pharmacology and... Apr 2021Oxidative stress plays a crucial role in the pathogenesis of Parkinson disease (PD), and one strategy for neuroprotective therapy for PD is to scavenge reactive species...
Oxidative stress plays a crucial role in the pathogenesis of Parkinson disease (PD), and one strategy for neuroprotective therapy for PD is to scavenge reactive species using a catalytic antioxidant. Previous studies in our laboratory revealed that pretreatment of lipophilic metalloporphyrins showed protective effects in a mouse PD model. In this study, we optimized the formulations of these metalloporphyrins to deliver them orally and tested their efficacy on disease outcomes in a second species after initiation of an insult (i.e., disease modification). In this study, a pharmaceutical formulation of two metalloporphyrin catalytic antioxidants, AEOL11207 and AEOL11114, was tested for oral drug delivery. Both compounds showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier after intravenous or oral delivery. AEOL11207 and AEOL11114 bioavailabilities were calculated to be 24% and 25%, respectively, at a dose of 10 mg/kg via the oral route. In addition, both compounds significantly attenuated 6-hydroxydopamine (6-OHDA)-induced neurotoxic damage, including dopamine depletion, cytokine production, and microglial activation in the striata; dopaminergic neuronal loss in the substantia nigra; oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain; and rotation behavioral abnormality in rats. These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity 1-3 days postlesioning, suggesting disease-modifying properties and translational potential for PD. SIGNIFICANCE STATEMENT: Two catalytic antioxidants showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier. Both compounds significantly attenuated dopamine depletion, cytokine production, microglial activation, dopaminergic neuronal loss, oxidative/nitrative stress indices, and behavioral abnormality in a Parkinson disease rat model. The results suggest that both metalloporphyrins possess disease-modifying properties that may be useful in treating Parkinson disease.
Topics: Administration, Oral; Animals; Antioxidants; Blood-Brain Barrier; Male; Metalloporphyrins; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 33500265
DOI: 10.1124/jpet.120.000229