Molecules

Editorial

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8 pages, 815 KiB

Open AccessEditorial

Biomimetic Radical Chemistry and Applications

by Chryssostomos Chatgilialoglu

Molecules 2022, 27(7), 2042; https://doi.org/10.3390/molecules27072042 - 22 Mar 2022

Cited by 3 | Viewed by 1666

Abstract

Some of the most interesting aspects of free radical chemistry that emerged in the last two decades are radical enzyme mechanisms, cell signaling cascades, antioxidant activities, and free radical-induced damage of biomolecules. In addition, identification of modified biomolecules opened the way for the [...] Read more.

Some of the most interesting aspects of free radical chemistry that emerged in the last two decades are radical enzyme mechanisms, cell signaling cascades, antioxidant activities, and free radical-induced damage of biomolecules. In addition, identification of modified biomolecules opened the way for the evaluation of in vivo damage through biomarkers. When studying free radical-based chemical mechanisms, it is very important to establish biomimetic models, which allow the experiments to be performed in a simplified environment, but suitably designed to be in strict connection with cellular conditions. The 28 papers (11 reviews and 17 articles) published in the two Special Issues of Molecules on “Biomimetic Radical Chemistry and Applications (2019 and 2021)” show a remarkable range of research in this area. The biomimetic approach is presented with new insights and reviews of the current knowledge in the field of radical-based processes relevant to health, such as biomolecular damages and repair, signaling and biomarkers, biotechnological applications, and novel synthetic approaches. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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Research

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17 pages, 2872 KiB

Open AccessArticle

Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors

by Anna Banasiak, Nicolò Zuin Fantoni, Andrew Kellett and John Colleran

Molecules 2022, 27(3), 645; https://doi.org/10.3390/molecules27030645 - 19 Jan 2022

Cited by 3 | Viewed by 2602

Abstract

Several classes of copper complexes are known to induce oxidative DNA damage that mediates cell death. These compounds are potentially useful anticancer agents and detailed investigation can reveal the mode of DNA interaction, binding strength, and type of oxidative lesion formed. We recently [...] Read more.

Several classes of copper complexes are known to induce oxidative DNA damage that mediates cell death. These compounds are potentially useful anticancer agents and detailed investigation can reveal the mode of DNA interaction, binding strength, and type of oxidative lesion formed. We recently reported the development of a DNA electrochemical biosensor employed to quantify the DNA cleavage activity of the well-studied [Cu(phen)₂]²⁺ chemical nuclease. However, to validate the broader compatibility of this sensor for use with more diverse—and biologically compatible—copper complexes, and to probe its use from a drug discovery perspective, analysis involving new compound libraries is required. Here, we report on the DNA binding and quantitative cleavage activity of the [Cu(TPMA)(N,N)]²⁺ class (where TPMA = tris-2-pyridylmethylamine) using a DNA electrochemical biosensor. TPMA is a tripodal copper caging ligand, while N,N represents a bidentate planar phenanthrene ligand capable of enhancing DNA interactions through intercalation. All complexes exhibited electroactivity and interact with DNA through partial (or semi-) intercalation but predominantly through electrostatic attraction. Although TPMA provides excellent solution stability, the bulky ligand enforces a non-planar geometry on the complex, which sterically impedes full interaction. [Cu(TPMA)(phen)]²⁺ and [Cu(TPMA)(DPQ)]²⁺ cleaved 39% and 48% of the DNA strands from the biosensor surface, respectively, while complexes [Cu(TPMA)(bipy)]²⁺ and [Cu(TPMA)(PD)]²⁺ exhibit comparatively moderate nuclease efficacy (ca. 26%). Comparing the nuclease activities of [Cu(TPMA)(phen)] ²⁺ and [Cu(phen)₂]²⁺ (ca. 23%) confirms the presence of TPMA significantly enhances chemical nuclease activity. Therefore, the use of this DNA electrochemical biosensor is compatible with copper(II) polypyridyl complexes and reveals TPMA complexes as a promising class of DNA damaging agent with tuneable activity due to coordinated ancillary phenanthrene ligands. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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19 pages, 4064 KiB

Open AccessArticle

Model Systems for Evidencing the Mediator Role of Riboflavin in the UVA Cross-Linking Treatment of Keratoconus

by Mihaela Monica Constantin, Cătălina Gabriela Corbu, Sorin Mocanu, Elena Irina Popescu, Marin Micutz, Teodora Staicu, Raluca Şomoghi, Bogdan Trică, Vlad Tudor Popa, Aurica Precupas, Iulia Matei and Gabriela Ionita

Molecules 2022, 27(1), 190; https://doi.org/10.3390/molecules27010190 - 29 Dec 2021

Cited by 3 | Viewed by 2077

Abstract

Riboflavin under UVA radiation generates reactive oxygen species (ROS) that can induce various changes in biological systems. Under controlled conditions, these processes can be used in some treatments for ocular or dermal diseases. For instance, corneal cross-linking (CXL) treatment of keratoconus involves UVA [...] Read more.

Riboflavin under UVA radiation generates reactive oxygen species (ROS) that can induce various changes in biological systems. Under controlled conditions, these processes can be used in some treatments for ocular or dermal diseases. For instance, corneal cross-linking (CXL) treatment of keratoconus involves UVA irradiation combined with riboflavin aiming to induce the formation of new collagen fibrils in cornea. To reduce the damaging effect of ROS formed in the presence of riboflavin and UVA, the CXL treatment is performed with the addition of polysaccharides (dextran). Hyaluronic acid is a polysaccharide that can be found in the aqueous layer of the tear film. In many cases, keratoconus patients also present dry eye syndrome that can be reduced by the application of topical solutions containing hyaluronic acid. This study presents physico-chemical evidence on the effect of riboflavin on collagen fibril formation revealed by the following methods: differential scanning microcalorimetry, rheology, and STEM images. The collagen used was extracted from calf skin that contains type I collagen similar to that found in the eye. Spin trapping experiments on collagen/hyaluronic acid/riboflavin solutions evidenced the formation of ROS species by electron paramagnetic resonance measurements. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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14 pages, 2213 KiB

Open AccessArticle

The Time Scale of Electronic Resonance in Oxidized DNA as Modulated by Solvent Response: An MD/QM-MM Study

by Alessandro Landi, Amedeo Capobianco and Andrea Peluso

Molecules 2021, 26(18), 5497; https://doi.org/10.3390/molecules26185497 - 10 Sep 2021

Cited by 5 | Viewed by 1981

Abstract

The time needed to establish electronic resonant conditions for charge transfer in oxidized DNA has been evaluated by molecular dynamics simulations followed by QM/MM computations which include counterions and a realistic solvation shell. The solvent response is predicted to take ca. 800–1000 ps [...] Read more.

The time needed to establish electronic resonant conditions for charge transfer in oxidized DNA has been evaluated by molecular dynamics simulations followed by QM/MM computations which include counterions and a realistic solvation shell. The solvent response is predicted to take ca. 800–1000 ps to bring two guanine sites into resonance, a range of values in reasonable agreement with the estimate previously obtained by a kinetic model able to correctly reproduce the observed yield ratios of oxidative damage for several sequences of oxidized DNA. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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12 pages, 2618 KiB

Open AccessArticle

Biomimetic Ketone Reduction by Disulfide Radical Anion

by Sebastian Barata-Vallejo, Konrad Skotnicki, Carla Ferreri, Bronislaw Marciniak, Krzysztof Bobrowski and Chryssostomos Chatgilialoglu

Molecules 2021, 26(18), 5429; https://doi.org/10.3390/molecules26185429 - 7 Sep 2021

Cited by 5 | Viewed by 2866

Abstract

The conversion of ribonucleosides to 2′-deoxyribonucleosides is catalyzed by ribonucleoside reductase enzymes in nature. One of the key steps in this complex radical mechanism is the reduction of the 3′-ketodeoxynucleotide by a pair of cysteine residues, providing the electrons via a disulfide radical [...] Read more.

The conversion of ribonucleosides to 2′-deoxyribonucleosides is catalyzed by ribonucleoside reductase enzymes in nature. One of the key steps in this complex radical mechanism is the reduction of the 3′-ketodeoxynucleotide by a pair of cysteine residues, providing the electrons via a disulfide radical anion (RSSR^•−) in the active site of the enzyme. In the present study, the bioinspired conversion of ketones to corresponding alcohols was achieved by the intermediacy of disulfide radical anion of cysteine (CysSSCys)^•− in water. High concentration of cysteine and pH 10.6 are necessary for high-yielding reactions. The photoinitiated radical chain reaction includes the one-electron reduction of carbonyl moiety by disulfide radical anion, protonation of the resulting ketyl radical anion by water, and H-atom abstraction from CysSH. The (CysSSCys)^•− transient species generated by ionizing radiation in aqueous solutions allowed the measurement of kinetic data with ketones by pulse radiolysis. By measuring the rate of the decay of (CysSSCys)^•− at λ_max = 420 nm at various concentrations of ketones, we found the rate constants of three cyclic ketones to be in the range of 10⁴–10⁵ M⁻¹s⁻¹ at ~22 °C. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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14 pages, 2244 KiB

Open AccessArticle

Disproportionation of H₂O₂ Mediated by Diiron-Peroxo Complexes as Catalase Mimics

by Dóra Lakk-Bogáth, Patrik Török, Flóra Viktória Csendes, Soma Keszei, Beatrix Gantner and József Kaizer

Molecules 2021, 26(15), 4501; https://doi.org/10.3390/molecules26154501 - 26 Jul 2021

Cited by 3 | Viewed by 2038

Abstract

Heme iron and nonheme dimanganese catalases protect biological systems against oxidative damage caused by hydrogen peroxide. Rubrerythrins are ferritine-like nonheme diiron proteins, which are structurally and mechanistically distinct from the heme-type catalase but similar to a dimanganese KatB enzyme. In order to gain [...] Read more.

Heme iron and nonheme dimanganese catalases protect biological systems against oxidative damage caused by hydrogen peroxide. Rubrerythrins are ferritine-like nonheme diiron proteins, which are structurally and mechanistically distinct from the heme-type catalase but similar to a dimanganese KatB enzyme. In order to gain more insight into the mechanism of this curious enzyme reaction, non-heme structural and functional models were carried out by the use of mononuclear [Fe^II(L_1–4)(solvent)₃](ClO₄)₂ (1–4) (L₁ = 1,3-bis(2-pyridyl-imino)isoindoline, L₂ = 1,3-bis(4′-methyl-2-pyridyl-imino)isoindoline, L₃ = 1,3-bis(4′-Chloro-2-pyridyl-imino)isoindoline, L₄ = 1,3-bis(5′-chloro-2-pyridyl-imino)isoindoline) complexes as catalysts, where the possible reactive intermediates, diiron-perroxo [Fe^III₂(μ-O)(μ-1,2-O₂)(L₁-L₄)₂(Solv)₂]²⁺ (5–8) complexes are known and well-characterized. All the complexes displayed catalase-like activity, which provided clear evidence for the formation of diiron-peroxo species during the catalytic cycle. We also found that the fine-tuning of iron redox states is a critical issue, both the formation rate and the reactivity of the diiron-peroxo species showed linear correlation with the Fe^III/Fe^II redox potentials. Their stability and reactivity towards H₂O₂ was also investigated and based on kinetic and mechanistic studies a plausible mechanism, including a rate-determining hydrogen atom transfer between the H₂O₂ and diiron-peroxo species, was proposed. The present results provide one of the first examples of a nonheme diiron-peroxo complex, which shows a catalase-like reaction. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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Review

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34 pages, 7484 KiB

Open AccessReview

Photo- and Radiation-Induced One-Electron Oxidation of Methionine in Various Structural Environments Studied by Time-Resolved Techniques

by Bronislaw Marciniak and Krzysztof Bobrowski

Molecules 2022, 27(3), 1028; https://doi.org/10.3390/molecules27031028 - 2 Feb 2022

Cited by 10 | Viewed by 2333

Abstract

Oxidation of methionine (Met) is an important reaction that plays a key role in protein modifications during oxidative stress and aging. The first steps of Met oxidation involve the creation of very reactive and short-lived transients. Application of complementary time-resolved radiation and photochemical [...] Read more.

Oxidation of methionine (Met) is an important reaction that plays a key role in protein modifications during oxidative stress and aging. The first steps of Met oxidation involve the creation of very reactive and short-lived transients. Application of complementary time-resolved radiation and photochemical techniques (pulse radiolysis and laser flash photolysis together with time-resolved CIDNP and ESR techniques) allowed comparing in detail the one-electron oxidation mechanisms initiated either by ^●OH radicals and other one-electron oxidants or the excited triplet state of the sensitizers e.g., 4-,3-carboxybenzophenones. The main purpose of this review is to present various factors that influence the character of the forming intermediates. They are divided into two parts: those inextricably related to the structures of molecules containing Met and those related to external factors. The former include (i) the protection of terminal amine and carboxyl groups, (ii) the location of Met in the peptide molecule, (iii) the character of neighboring amino acid other than Met, (iv) the character of the peptide chain (open vs cyclic), (v) the number of Met residues in peptide and protein, and (vi) the optical isomerism of Met residues. External factors include the type of the oxidant, pH, and concentration of Met-containing compounds in the reaction environment. Particular attention is given to the neighboring group participation, which is an essential parameter controlling one-electron oxidation of Met. Mechanistic aspects of oxidation processes by various one-electron oxidants in various structural and pH environments are summarized and discussed. The importance of these studies for understanding oxidation of Met in real biological systems is also addressed. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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25 pages, 3143 KiB

Open AccessReview

The Reductive Dehydroxylation Catalyzed by IspH, a Source of Inspiration for the Development of Novel Anti-Infectives

by Hannah Jobelius, Gabriella Ines Bianchino, Franck Borel, Philippe Chaignon and Myriam Seemann

Molecules 2022, 27(3), 708; https://doi.org/10.3390/molecules27030708 - 21 Jan 2022

Cited by 7 | Viewed by 3183

Abstract

The non-mevalonate or also called MEP pathway is an essential route for the biosynthesis of isoprenoid precursors in most bacteria and in microorganisms belonging to the Apicomplexa phylum, such as the parasite responsible for malaria. The absence of this pathway in mammalians makes [...] Read more.

The non-mevalonate or also called MEP pathway is an essential route for the biosynthesis of isoprenoid precursors in most bacteria and in microorganisms belonging to the Apicomplexa phylum, such as the parasite responsible for malaria. The absence of this pathway in mammalians makes it an interesting target for the discovery of novel anti-infectives. As last enzyme of this pathway, IspH is an oxygen sensitive [4Fe-4S] metalloenzyme that catalyzes 2H⁺/2e^- reductions and a water elimination by involving non-conventional bioinorganic and bioorganometallic intermediates. After a detailed description of the discovery of the [4Fe-4S] cluster of IspH, this review focuses on the IspH mechanism discussing the results that have been obtained in the last decades using an approach combining chemistry, enzymology, crystallography, spectroscopies, and docking calculations. Considering the interesting druggability of this enzyme, a section about the inhibitors of IspH discovered up to now is reported as well. The presented results constitute a useful and rational help to inaugurate the design and development of new potential chemotherapeutics against pathogenic organisms. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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31 pages, 7548 KiB

Open AccessFeature PaperReview

Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification

by Eduardo Fuentes-Lemus, Per Hägglund, Camilo López-Alarcón and Michael J. Davies

Molecules 2022, 27(1), 15; https://doi.org/10.3390/molecules27010015 - 21 Dec 2021

Cited by 41 | Viewed by 6092

Abstract

Covalent crosslinks within or between proteins play a key role in determining the structure and function of proteins. Some of these are formed intentionally by either enzymatic or molecular reactions and are critical to normal physiological function. Others are generated as a consequence [...] Read more.

Covalent crosslinks within or between proteins play a key role in determining the structure and function of proteins. Some of these are formed intentionally by either enzymatic or molecular reactions and are critical to normal physiological function. Others are generated as a consequence of exposure to oxidants (radicals, excited states or two-electron species) and other endogenous or external stimuli, or as a result of the actions of a number of enzymes (e.g., oxidases and peroxidases). Increasing evidence indicates that the accumulation of unwanted crosslinks, as is seen in ageing and multiple pathologies, has adverse effects on biological function. In this article, we review the spectrum of crosslinks, both reducible and non-reducible, currently known to be formed on proteins; the mechanisms of their formation; and experimental approaches to the detection, identification and characterization of these species. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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29 pages, 7791 KiB

Open AccessReview

Direct and Indirect Chemiluminescence: Reactions, Mechanisms and Challenges

by Marina A. Tzani, Dimitra K. Gioftsidou, Michael G. Kallitsakis, Nikolaos V. Pliatsios, Natasa P. Kalogiouri, Panagiotis A. Angaridis, Ioannis N. Lykakis and Michael A. Terzidis

Molecules 2021, 26(24), 7664; https://doi.org/10.3390/molecules26247664 - 17 Dec 2021

Cited by 34 | Viewed by 6242

Abstract

Emission of light by matter can occur through a variety of mechanisms. When it results from an electronically excited state of a species produced by a chemical reaction, it is called chemiluminescence (CL). The phenomenon can take place both in natural and artificial [...] Read more.

Emission of light by matter can occur through a variety of mechanisms. When it results from an electronically excited state of a species produced by a chemical reaction, it is called chemiluminescence (CL). The phenomenon can take place both in natural and artificial chemical systems and it has been utilized in a variety of applications. In this review, we aim to revisit some of the latest CL applications based on direct and indirect production modes. The characteristics of the chemical reactions and the underpinning CL mechanisms are thoroughly discussed in view of studies from the very recent bibliography. Different methodologies aiming at higher CL efficiencies are summarized and presented in detail, including CL type and scaffolds used in each study. The CL role in the development of efficient therapeutic platforms is also discussed in relation to the Reactive Oxygen Species (ROS) and singlet oxygen (¹O₂) produced, as final products. Moreover, recent research results from our team are included regarding the behavior of commonly used photosensitizers upon chemical activation under CL conditions. The CL prospects in imaging, biomimetic organic and radical chemistry, and therapeutics are critically presented in respect to the persisting challenges and limitations of the existing strategies to date. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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25 pages, 3630 KiB

Open AccessReview

The Two Faces of the Guanyl Radical: Molecular Context and Behavior

by Chryssostomos Chatgilialoglu

Molecules 2021, 26(12), 3511; https://doi.org/10.3390/molecules26123511 - 9 Jun 2021

Cited by 9 | Viewed by 2699

Abstract

The guanyl radical or neutral guanine radical G(-H)^• results from the loss of a hydrogen atom (H^•) or an electron/proton (e^–/H⁺) couple from the guanine structures (G). The guanyl radical exists in two tautomeric forms. As [...] Read more.

The guanyl radical or neutral guanine radical G(-H)^• results from the loss of a hydrogen atom (H^•) or an electron/proton (e^–/H⁺) couple from the guanine structures (G). The guanyl radical exists in two tautomeric forms. As the modes of formation of the two tautomers, their relationship and reactivity at the nucleoside level are subjects of intense research and are discussed in a holistic manner, including time-resolved spectroscopies, product studies, and relevant theoretical calculations. Particular attention is given to the one-electron oxidation of the GC pair and the complex mechanism of the deprotonation vs. hydration step of GC^•+ pair. The role of the two G(-H)^• tautomers in single- and double-stranded oligonucleotides and the G-quadruplex, the supramolecular arrangement that attracts interest for its biological consequences, are considered. The importance of biomarkers of guanine DNA damage is also addressed. Full article

(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications 2021)

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