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Biomimetic Radical Chemistry and Applications
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Biomimetic Radical Chemistry and Applications

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 74615

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Chryssostomos Chatgilialoglu

E-Mail Website1 Website2
Guest Editor
Research Director, ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy
Interests: free radical chemistry; biomimetic chemistry; organic synthesis; reaction mechanism; analytical protocols for biomarkers of radical stress; oxidative DNA damage; lipid modification; fatty acid-based lipidomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The enormous importance of free radical chemistry for a variety of biological events, including ageing and inflammation, has attracted a strong interest in understanding the related mechanistic steps at the molecular level. Modelling free radical chemical reactivity of biological systems is an important research area.

Some of the most interesting aspects of free radical chemistry that have emerged in the last two decades are radical enzyme mechanisms, cell signalling 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.

This Special Issue covers aspects of free radical chemistry in biological events revealed using biomimetic chemical models. These include: catalytic pathways and mechanisms of radical enzymes, prebiotic chemistry, radical-induced DNA lesions or protein modifications, including analytical protocols, repair processes, biological consequences, lipid peroxidation and isomerization, defence systems based on antioxidants, as well as bio-inspired synthetic strategies.

Research articles and reviews related to these topics in biomimetic radical chemistry and applications are welcome.

Dr. Chryssostomos Chatgilialoglu
Guest Editor

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Keywords

  • free radical
  • biomimetic chemistry
  • reactivity of biological systems
  • reaction mechanisms
  • biomarkers of radical stress
  • reactive oxygen species
  • biological damages
  • antioxidants and repair mechanisms
  • bio-inspired chemical synthesis and catalysis

Related Special Issue

Published Papers (18 papers)

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Research

Jump to: Review

28 pages, 5028 KiB  
Article
Radiation Induced One-Electron Oxidation of 2-Thiouracil in Aqueous Solutions
by Konrad Skotnicki, Katarzyna Taras-Goslinska, Ireneusz Janik and Krzysztof Bobrowski
Molecules 2019, 24(23), 4402; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24234402 - 02 Dec 2019
Cited by 5 | Viewed by 3259
Abstract
Oxidative damage to 2-thiouracil (2-TU) by hydroxyl (•OH) and azide (●N3) radicals produces various primary reactive intermediates. Their optical absorption spectra and kinetic characteristics were studied by pulse radiolysis with UV-vis spectrophotometric and conductivity detection and by [...] Read more.
Oxidative damage to 2-thiouracil (2-TU) by hydroxyl (•OH) and azide (●N3) radicals produces various primary reactive intermediates. Their optical absorption spectra and kinetic characteristics were studied by pulse radiolysis with UV-vis spectrophotometric and conductivity detection and by time-dependent density functional theory (TD-DFT) method. The transient absorption spectra recorded in the reactions of •OH with 2-TU depend on the concentration of 2-TU, however, only slightly on pH. At low concentrations, they are characterized by a broad absorption band with a weakly pronounced maxima located at λ = 325, 340 and 385 nm, whereas for high concentrations, they are dominated by an absorption band with λmax ≈ 425 nm. Based on calculations using TD-DFT method, the transient absorption spectra at low concentration of 2-TU were assigned to the ●OH-adducts to the double bond at C5 and C6 carbon atoms (3●, 4●) and 2c-3e bonded ●OH adduct to sulfur atom (1…●OH) and at high concentration of 2-TU also to the dimeric 2c-3e S-S-bonded radical in neutral form (2●). The dimeric radical (2●) is formed in the reaction of thiyl-type radical (6●) with 2-TU and both radicals are in an equilibrium with Keq = 4.2 × 103 M−1. Similar equilibrium (with Keq = 4.3 × 103 M−1) was found for pH above the pKa of 2-TU which involves admittedly the same radical (6●) but with the dimeric 2c-3e S-S bonded radical in anionic form (2●−). In turn, ●N3-induced oxidation of 2-TU occurs via radical cation with maximum spin location on the sulfur atom which subsequently undergoes deprotonation at N1 atom leading again to thiyl-type radical (6●). This radical is a direct precursor of dimeric radical (2●). Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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11 pages, 2811 KiB  
Article
Copper bis-Dipyridoquinoxaline Is a Potent DNA Intercalator that Induces Superoxide-Mediated Cleavage via the Minor Groove
by Zara Molphy, Vickie McKee and Andrew Kellett
Molecules 2019, 24(23), 4301; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24234301 - 26 Nov 2019
Cited by 5 | Viewed by 4553
Abstract
Herein, we report the synthesis, characterisation, X-ray crystallography, and oxidative DNA binding interactions of the copper artificial metallo-nuclease [Cu(DPQ)2(NO3)](NO3), where DPQ = dipyrido[3,2-f:2′,3′-h]quinoxaline. The cation [Cu(DPQ)2]2+ (Cu-DPQ), is a high-affinity [...] Read more.
Herein, we report the synthesis, characterisation, X-ray crystallography, and oxidative DNA binding interactions of the copper artificial metallo-nuclease [Cu(DPQ)2(NO3)](NO3), where DPQ = dipyrido[3,2-f:2′,3′-h]quinoxaline. The cation [Cu(DPQ)2]2+ (Cu-DPQ), is a high-affinity binder of duplex DNA and presents an intercalative profile in topoisomerase unwinding and viscosity experiments. Artificial metallo-nuclease activity occurs in the absence of exogenous reductant but is greatly enhanced by the presence of the reductant Na-L-ascorbate. Mechanistically, oxidative DNA damage occurs in the minor groove, is mediated aerobically by the Cu(I) complex and is dependent on both superoxide and hydroxyl radical generation. To corroborate cleavage at the minor groove, DNA oxidation of a cytosine–guanine (5′-CCGG-3′)-rich oligomer was examined in tandem with a 5-methylcytosine (5′-C5mCGG-3′) derivative where 5mC served to sterically block the major groove and direct damage to the minor groove. Overall, both the DNA binding affinity and cleavage mechanism of Cu-DPQ depart from Sigman’s reagent [Cu(1,10-phenanthroline)2]2+; however, both complexes are potent oxidants of the minor groove. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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10 pages, 2175 KiB  
Article
Two-Step Azidoalkenylation of Terminal Alkenes Using Iodomethyl Sulfones
by Nicolas Millius, Guillaume Lapointe and Philippe Renaud
Molecules 2019, 24(22), 4184; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224184 - 18 Nov 2019
Cited by 8 | Viewed by 3533
Abstract
The radical azidoalkylation of alkenes that was initially developed with α-iodoesters and α-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl aryl sulfones, the preparation of γ-azidosulfones was easily achieved. Facile conversion of these azidosulfones to homoallylic azides using a Julia–Kocienski [...] Read more.
The radical azidoalkylation of alkenes that was initially developed with α-iodoesters and α-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl aryl sulfones, the preparation of γ-azidosulfones was easily achieved. Facile conversion of these azidosulfones to homoallylic azides using a Julia–Kocienski olefination reaction is reported, making the whole process equivalent to the azidoalkenylation of terminal alkenes. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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7 pages, 1404 KiB  
Article
Axially Ligated Mesohemins as Bio-Mimicking Catalysts for Atom Transfer Radical Polymerization
by Liye Fu, Antonina Simakova, Sangwoo Park, Yi Wang, Marco Fantin and Krzysztof Matyjaszewski
Molecules 2019, 24(21), 3969; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24213969 - 02 Nov 2019
Cited by 4 | Viewed by 2875
Abstract
Copper is the most common metal catalyst used in atom transfer radical polymerization (ATRP), but iron is an excellent alternative due to its natural abundance and low toxicity compared to copper. In this work, two new iron-porphyrin-based catalysts inspired by naturally occurring proteins, [...] Read more.
Copper is the most common metal catalyst used in atom transfer radical polymerization (ATRP), but iron is an excellent alternative due to its natural abundance and low toxicity compared to copper. In this work, two new iron-porphyrin-based catalysts inspired by naturally occurring proteins, such as horseradish peroxidase, hemoglobin, and cytochrome P450, were synthesized and tested for ATRP. Natural protein structures were mimicked by attaching imidazole or thioether groups to the porphyrin, leading to increased rates of polymerization, as well as providing polymers with low dispersity, even in the presence of ppm amounts of catalysts. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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20 pages, 6013 KiB  
Article
New Insights into the Reaction Paths of Hydroxyl Radicals with Purine Moieties in DNA and Double-Stranded Oligodeoxynucleotides
by Chryssostomos Chatgilialoglu, Marios G. Krokidis, Annalisa Masi, Sebastian Barata-Vallejo, Carla Ferreri, Michael A. Terzidis, Tomasz Szreder and Krzysztof Bobrowski
Molecules 2019, 24(21), 3860; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24213860 - 26 Oct 2019
Cited by 22 | Viewed by 3822
Abstract
The reaction of hydroxyl radical (HO•) with DNA produces many primary reactive species and many lesions as final products. In this study, we have examined the optical spectra of intermediate species derived from the reaction of HO• with a variety [...] Read more.
The reaction of hydroxyl radical (HO•) with DNA produces many primary reactive species and many lesions as final products. In this study, we have examined the optical spectra of intermediate species derived from the reaction of HO• with a variety of single- and double-stranded oligodeoxynucleotides and ct-DNA in the range of 1 μs to 1 ms by pulse radiolysis using an Intensified Charged Coupled Device (ICCD) camera. Moreover, we applied our published analytical protocol based on an LC-MS/MS system with isotopomeric internal standards to enable accurate and precise measurements of purine lesion formation. In particular, the simultaneous measurement of the four purine 5′,8-cyclo-2′-deoxynucleosides (cPu) and two 8-oxo-7,8-dihydro-2′-deoxypurine (8-oxo-Pu) was obtained upon reaction of genetic material with HO• radicals generated either by γ-radiolysis or Fenton-type reactions. Our results contributed to the debate in the literature regarding absolute level of lesions, method of HO• radical generation, 5′R/5′S diastereomeric ratio in cPu, and relative abundance between cPu and 8-oxo-Pu. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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15 pages, 3106 KiB  
Article
Formation and Stabilization of Gold Nanoparticles in Bovine Serum Albumin Solution
by Iulia Matei, Cristina Maria Buta, Ioana Maria Turcu, Daniela Culita, Cornel Munteanu and Gabriela Ionita
Molecules 2019, 24(18), 3395; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24183395 - 18 Sep 2019
Cited by 31 | Viewed by 4718
Abstract
The formation and growth of gold nanoparticles (AuNPs) were investigated in pH 7 buffer solution of bovine serum albumin (BSA) at room temperature. The processes were monitored by UV-Vis, circular dichroism, Raman and electron paramagnetic resonance (EPR) spectroscopies. TEM microscopy and dynamic light [...] Read more.
The formation and growth of gold nanoparticles (AuNPs) were investigated in pH 7 buffer solution of bovine serum albumin (BSA) at room temperature. The processes were monitored by UV-Vis, circular dichroism, Raman and electron paramagnetic resonance (EPR) spectroscopies. TEM microscopy and dynamic light scattering (DLS) measurements were used to evidence changes in particle size during nanoparticle formation and growth. The formation of AuNPs at pH 7 in the absence of BSA was not observed, which proves that the albumin is involved in the first step of Au(III) reduction. Changes in the EPR spectral features of two spin probes, CAT16 and DIS3, with affinity for BSA and AuNPs, respectively, allowed us to monitor the particle growth and to demonstrate the protective role of BSA for AuNPs. The size of AuNPs formed in BSA solution increases slowly with time, resulting in nanoparticles of different morphologies, as revealed by TEM. Raman spectra of BSA indicate the interaction of albumin with AuNPs through sulfur-containing amino acid residues. This study shows that albumins act as both reducing agents and protective corona of AuNPs. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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11 pages, 10898 KiB  
Article
Stability and Catalase-Like Activity of a Mononuclear Non-Heme Oxoiron(IV) Complex in Aqueous Solution
by Balázs Kripli, Bernadett Sólyom, Gábor Speier and József Kaizer
Molecules 2019, 24(18), 3236; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24183236 - 05 Sep 2019
Cited by 8 | Viewed by 2499
Abstract
Heme-type catalase is a class of oxidoreductase enzymes responsible for the biological defense against oxidative damage of cellular components caused by hydrogen peroxide, where metal-oxo species are proposed as reactive intermediates. To get more insight into the mechanism of this curious reaction a [...] Read more.
Heme-type catalase is a class of oxidoreductase enzymes responsible for the biological defense against oxidative damage of cellular components caused by hydrogen peroxide, where metal-oxo species are proposed as reactive intermediates. To get more insight into the mechanism of this curious reaction a non-heme structural and functional model was carried out by the use of a mononuclear complex [FeII(N4Py*)(CH3CN)](CF3SO3)2 (N4Py* = N,N-bis(2-pyridylmethyl)- 1,2-di(2-pyridyl)ethylamine) as a catalyst, where the possible reactive intermediates, high-valent FeIV=O and FeIII–OOH are known and spectroscopically well characterized. The kinetics of the dismutation of H2O2 into O2 and H2O was investigated in buffered water, where the reactivity of the catalyst was markedly influenced by the pH, and it revealed Michaelis–Menten behavior with KM = 1.39 M, kcat = 33 s−1 and k2(kcat/KM) = 23.9 M−1s−1 at pH 9.5. A mononuclear [(N4Py)FeIV=O]2+ as a possible intermediate was also prepared, and the pH dependence of its stability and reactivity in aqueous solution against H2O2 was also investigated. Based on detailed kinetic, and mechanistic studies (pH dependence, solvent isotope effect (SIE) of 6.2 and the saturation kinetics for the initial rates versus the H2O2 concentration with KM = 18 mM) lead to the conclusion that the rate-determining step in these reactions above involves hydrogen-atom transfer between the iron-bound substrate and the Fe(IV)-oxo species. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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18 pages, 5618 KiB  
Article
Converging Fate of the Oxidation and Reduction of 8-Thioguanosine
by Katarzyna Taras-Goslinska, Fabrizio Vetica, Sebastián Barata-Vallejo, Virginia Triantakostanti, Bronisław Marciniak and Chryssostomos Chatgilialoglu
Molecules 2019, 24(17), 3143; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24173143 - 29 Aug 2019
Cited by 6 | Viewed by 3227
Abstract
Thione-containing nucleobases have attracted the attention of the scientific community for their application in oncology, virology, and transplantology. The detailed understanding of the reactivity of the purine derivative 8-thioguanosine (8-TG) with reactive oxygen species (ROS) and free radicals is crucial for its biological [...] Read more.
Thione-containing nucleobases have attracted the attention of the scientific community for their application in oncology, virology, and transplantology. The detailed understanding of the reactivity of the purine derivative 8-thioguanosine (8-TG) with reactive oxygen species (ROS) and free radicals is crucial for its biological relevance. An extensive investigation on the fate of 8-TG under both reductive and oxidative conditions is here reported, and it was tested by employing steady-state photooxidation, laser flash photolysis, as well as γ-radiolysis in aqueous solutions. The characterization of the 8-TG T1 excited state by laser flash photolysis and the photooxidation experiments confirmed that singlet oxygen is a crucial intermediate in the formation of the unexpected reduced product guanosine, without the formation of the usual oxygenated sulfinic or sulfonic acids. Furthermore, a thorough screening of different radiolytic conditions upon γ-radiation afforded the reduced product. These results were rationalized by performing control experiments in the predominant presence of each reactive species formed by radiolysis of water, and the mechanistic pathway scenario was postulated on these bases. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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12 pages, 1262 KiB  
Article
The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity
by Anna Vita Larocca, Gianluca Toniolo, Silvia Tortorella, Marios G. Krokidis, Georgia Menounou, Giuseppe Di Bella, Chryssostomos Chatgilialoglu and Carla Ferreri
Molecules 2019, 24(17), 3085; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24173085 - 25 Aug 2019
Cited by 3 | Viewed by 3529
Abstract
The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1–2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to [...] Read more.
The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1–2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to overcome the need for continuous infusion regimes. Multilamellar liposomes made of natural phosphatidylcholine were used for the incorporation of a mixture of somatostatin and sorbitol dissolved in citrate buffer at pH = 5. Lyophilization and reconstitution of the suspension were carried out, showing the flexibility of this preparation. Full characterization of this suspension was obtained as particle size, encapsulation efficiency and retarded release properties in aqueous medium and human plasma. Liposomal somatostatin incubated at 37 °C in the presence of Fe(II) and (III) salts were used as a biomimetic model of drug-cell membrane interaction, evidencing the free radical processes of peroxidation and isomerization that transform the unsaturated fatty acid moieties of the lipid vesicles. This study offers new insights into a liposomal delivery system and highlights molecular reactivity of sulfur-containing drugs with its carrier or biological membranes for pharmacological applications. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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17 pages, 2537 KiB  
Article
Why Does the Type of Halogen Atom Matter for the Radiosensitizing Properties of 5-Halogen Substituted 4-Thio-2′-Deoxyuridines?
by Paulina Spisz, Magdalena Zdrowowicz, Samanta Makurat, Witold Kozak, Konrad Skotnicki, Krzysztof Bobrowski and Janusz Rak
Molecules 2019, 24(15), 2819; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24152819 - 02 Aug 2019
Cited by 10 | Viewed by 3028
Abstract
Radiosensitizing properties of substituted uridines are of great importance for radiotherapy. Very recently, we confirmed 5-iodo-4-thio-2′-deoxyuridine (ISdU) as an efficient agent, increasing the extent of tumor cell killing with ionizing radiation. To our surprise, a similar derivative of 4-thio-2’-deoxyuridine, 5-bromo-4-thio-2′-deoxyuridine (BrSdU), does not [...] Read more.
Radiosensitizing properties of substituted uridines are of great importance for radiotherapy. Very recently, we confirmed 5-iodo-4-thio-2′-deoxyuridine (ISdU) as an efficient agent, increasing the extent of tumor cell killing with ionizing radiation. To our surprise, a similar derivative of 4-thio-2’-deoxyuridine, 5-bromo-4-thio-2′-deoxyuridine (BrSdU), does not show radiosensitizing properties at all. In order to explain this remarkable difference, we carried out a radiolytic (stationary and pulse) and quantum chemical studies, which allowed the pathways to all radioproducts to be rationalized. In contrast to ISdU solutions, where radiolysis leads to 4-thio-2’-deoxyuridine and its dimer, no dissociative electron attachment (DEA) products were observed for BrSdU. This observation seems to explain the lack of radiosensitizing properties of BrSdU since the efficient formation of the uridine-5-yl radical, induced by electron attachment to the modified nucleoside, is suggested to be an indispensable attribute of radiosensitizing uridines. A larger activation barrier for DEA in BrSdU, as compared to ISdU, is probably responsible for the closure of DEA channel in the former system. Indeed, besides DEA, the XSdU anions may undergo competitive protonation, which makes the release of X− kinetically forbidden. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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16 pages, 2127 KiB  
Article
Populations and Dynamics of Guanine Radicals in DNA strands—Direct versus Indirect Generation
by Evangelos Balanikas, Akos Banyasz, Gérard Baldacchino and Dimitra Markovitsi
Molecules 2019, 24(13), 2347; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24132347 - 26 Jun 2019
Cited by 25 | Viewed by 3643
Abstract
Guanine radicals, known to be involved in the damage of the genetic code and aging, are studied by nanosecond transient absorption spectroscopy. They are generated in single, double and four-stranded structures (G-quadruplexes) by one and two-photon ionization at 266 nm, corresponding [...] Read more.
Guanine radicals, known to be involved in the damage of the genetic code and aging, are studied by nanosecond transient absorption spectroscopy. They are generated in single, double and four-stranded structures (G-quadruplexes) by one and two-photon ionization at 266 nm, corresponding to a photon energy lower than the ionization potential of nucleobases. The quantum yield of the one-photon process determined for telomeric G-quadruplexes (TEL25/Na+) is (5.2 ± 0.3) × 10−3, significantly higher than that found for duplexes containing in their structure GGG and GG sequences, (2.1 ± 0.4) × 10−3. The radical population is quantified in respect of the ejected electrons. Deprotonation of radical cations gives rise to (G-H1)• and (G-H2)• radicals for duplexes and G-quadruplexes, respectively. The lifetimes of deprotonated radicals determined for a given secondary structure strongly depend on the base sequence. The multiscale non-exponential dynamics of these radicals are discussed in terms of inhomogeneity of the reaction space and continuous conformational motions. The deviation from classical kinetic models developed for homogeneous reaction conditions could also be one reason for discrepancies between the results obtained by photoionization and indirect oxidation, involving a bi-molecular reaction between an oxidant and the nucleic acid. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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11 pages, 2254 KiB  
Article
Anomeric Spironucleosides of β-d-Glucopyranosyl Uracil as Potential Inhibitors of Glycogen Phosphorylase
by Aggeliki Stathi, Michael Mamais, Evangelia D. Chrysina and Thanasis Gimisis
Molecules 2019, 24(12), 2327; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24122327 - 25 Jun 2019
Cited by 8 | Viewed by 2876
Abstract
In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) may prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry [...] Read more.
In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) may prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and important biological function (e.g., inhibition of GP). For this study, the Suárez radical methodology was successfully applied to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not previously constructed via a radical pathway, starting from 6-hydroxymethyl-β-d-glucopyranosyluracil. It was shown that, in the rigid pyranosyl conformation, the required [1,5]-radical translocation was a minor process. The stereochemistry of the spirocycles obtained was unequivocally determined based on the chemical shifts of key sugar protons in the 1H-NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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Review

Jump to: Research

15 pages, 2562 KiB  
Review
The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress
by Elena E. Pohl and Olga Jovanovic
Molecules 2019, 24(24), 4545; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24244545 - 12 Dec 2019
Cited by 28 | Viewed by 5992
Abstract
Reactive oxygen species (ROS) and their derivatives, reactive aldehydes (RAs), have been implicated in the pathogenesis of many diseases, including metabolic, cardiovascular, and inflammatory disease. Understanding how RAs can modify the function of membrane proteins is critical for the design of therapeutic approaches [...] Read more.
Reactive oxygen species (ROS) and their derivatives, reactive aldehydes (RAs), have been implicated in the pathogenesis of many diseases, including metabolic, cardiovascular, and inflammatory disease. Understanding how RAs can modify the function of membrane proteins is critical for the design of therapeutic approaches in the above-mentioned pathologies. Over the last few decades, direct interactions of RA with proteins have been extensively studied. Yet, few studies have been performed on the modifications of membrane lipids arising from the interaction of RAs with the lipid amino group that leads to the formation of adducts. It is even less well understood how various multiple adducts affect the properties of the lipid membrane and those of embedded membrane proteins. In this short review, we discuss a crucial role of phosphatidylethanolamine (PE) and PE-derived adducts as mediators of RA effects on membrane proteins. We propose potential PE-mediated mechanisms that explain the modulation of membrane properties and the functions of membrane transporters, channels, receptors, and enzymes. We aim to highlight this new area of research and to encourage a more nuanced investigation of the complex nature of the new lipid-mediated mechanism in the modification of membrane protein function under oxidative stress. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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16 pages, 1934 KiB  
Review
Thiyl Radical Reactions in the Chemical Degradation of Pharmaceutical Proteins
by Christian Schöneich
Molecules 2019, 24(23), 4357; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24234357 - 28 Nov 2019
Cited by 17 | Viewed by 6247
Abstract
Free radical pathways play a major role in the degradation of protein pharmaceuticals. Inspired by biochemical reactions carried out by thiyl radicals in various enzymatic processes, this review focuses on the role of thiyl radicals in pharmaceutical protein degradation through hydrogen atom transfer, [...] Read more.
Free radical pathways play a major role in the degradation of protein pharmaceuticals. Inspired by biochemical reactions carried out by thiyl radicals in various enzymatic processes, this review focuses on the role of thiyl radicals in pharmaceutical protein degradation through hydrogen atom transfer, electron transfer, and addition reactions. These processes can lead to the epimerization of amino acids, as well as the formation of various cleavage products and cross-links. Examples are presented for human insulin, human and mouse growth hormone, and monoclonal antibodies. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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21 pages, 801 KiB  
Review
The Dynamics of Hole Transfer in DNA
by Andrea Peluso, Tonino Caruso, Alessandro Landi and Amedeo Capobianco
Molecules 2019, 24(22), 4044; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224044 - 07 Nov 2019
Cited by 26 | Viewed by 3298
Abstract
High-energy radiation and oxidizing agents can ionize DNA. One electron oxidation gives rise to a radical cation whose charge (hole) can migrate through DNA covering several hundreds of Å, eventually leading to irreversible oxidative damage and consequent disease. Understanding the thermodynamic, kinetic and [...] Read more.
High-energy radiation and oxidizing agents can ionize DNA. One electron oxidation gives rise to a radical cation whose charge (hole) can migrate through DNA covering several hundreds of Å, eventually leading to irreversible oxidative damage and consequent disease. Understanding the thermodynamic, kinetic and chemical aspects of the hole transport in DNA is important not only for its biological consequences, but also for assessing the properties of DNA in redox sensing or labeling. Furthermore, due to hole migration, DNA could potentially play an important role in nanoelectronics, by acting as both a template and active component. Herein, we review our work on the dynamics of hole transfer in DNA carried out in the last decade. After retrieving the thermodynamic parameters needed to address the dynamics of hole transfer by voltammetric and spectroscopic experiments and quantum chemical computations, we develop a theoretical methodology which allows for a faithful interpretation of the kinetics of the hole transport in DNA and is also capable of taking into account sequence-specific effects. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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17 pages, 4435 KiB  
Review
Protein Chemical Labeling Using Biomimetic Radical Chemistry
by Shinichi Sato and Hiroyuki Nakamura
Molecules 2019, 24(21), 3980; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24213980 - 03 Nov 2019
Cited by 20 | Viewed by 8372
Abstract
Chemical labeling of proteins with synthetic low-molecular-weight probes is an important technique in chemical biology. To achieve this, it is necessary to use chemical reactions that proceed rapidly under physiological conditions (i.e., aqueous solvent, pH, low concentration, and low temperature) so that protein [...] Read more.
Chemical labeling of proteins with synthetic low-molecular-weight probes is an important technique in chemical biology. To achieve this, it is necessary to use chemical reactions that proceed rapidly under physiological conditions (i.e., aqueous solvent, pH, low concentration, and low temperature) so that protein denaturation does not occur. The radical reaction satisfies such demands of protein labeling, and protein labeling using the biomimetic radical reaction has recently attracted attention. The biomimetic radical reaction enables selective labeling of the C-terminus, tyrosine, and tryptophan, which is difficult to achieve with conventional electrophilic protein labeling. In addition, as the radical reaction proceeds selectively in close proximity to the catalyst, it can be applied to the analysis of protein–protein interactions. In this review, recent trends in protein labeling using biomimetic radical reactions are discussed. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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20 pages, 1330 KiB  
Review
Replication Stress and Consequential Instability of the Genome and Epigenome
by Pawlos S. Tsegay, Yanhao Lai and Yuan Liu
Molecules 2019, 24(21), 3870; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24213870 - 27 Oct 2019
Cited by 16 | Viewed by 4651
Abstract
Cells must faithfully duplicate their DNA in the genome to pass their genetic information to the daughter cells. To maintain genomic stability and integrity, double-strand DNA has to be replicated in a strictly regulated manner, ensuring the accuracy of its copy number, integrity [...] Read more.
Cells must faithfully duplicate their DNA in the genome to pass their genetic information to the daughter cells. To maintain genomic stability and integrity, double-strand DNA has to be replicated in a strictly regulated manner, ensuring the accuracy of its copy number, integrity and epigenetic modifications. However, DNA is constantly under the attack of DNA damage, among which oxidative DNA damage is the one that most frequently occurs, and can alter the accuracy of DNA replication, integrity and epigenetic features, resulting in DNA replication stress and subsequent genome and epigenome instability. In this review, we summarize DNA damage-induced replication stress, the formation of DNA secondary structures, peculiar epigenetic modifications and cellular responses to the stress and their impact on the instability of the genome and epigenome mainly in eukaryotic cells. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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13 pages, 1299 KiB  
Review
The Combination of Whole Cell Lipidomics Analysis and Single Cell Confocal Imaging of Fluidity and Micropolarity Provides Insight into Stress-Induced Lipid Turnover in Subcellular Organelles of Pancreatic Beta Cells
by Giuseppe Maulucci, Ofir Cohen, Bareket Daniel, Carla Ferreri and Shlomo Sasson
Molecules 2019, 24(20), 3742; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24203742 - 17 Oct 2019
Cited by 13 | Viewed by 3315
Abstract
Modern omics techniques reveal molecular structures and cellular networks of tissues and cells in unprecedented detail. Recent advances in single cell analysis have further revolutionized all disciplines in cellular and molecular biology. These methods have also been employed in current investigations on the [...] Read more.
Modern omics techniques reveal molecular structures and cellular networks of tissues and cells in unprecedented detail. Recent advances in single cell analysis have further revolutionized all disciplines in cellular and molecular biology. These methods have also been employed in current investigations on the structure and function of insulin secreting beta cells under normal and pathological conditions that lead to an impaired glucose tolerance and type 2 diabetes. Proteomic and transcriptomic analyses have pointed to significant alterations in protein expression and function in beta cells exposed to diabetes like conditions (e.g., high glucose and/or saturated fatty acids levels). These nutritional overload stressful conditions are often defined as glucolipotoxic due to the progressive damage they cause to the cells. Our recent studies on the rat insulinoma-derived INS-1E beta cell line point to differential effects of such conditions in the phospholipid bilayers in beta cells. This review focuses on confocal microscopy-based detection of these profound alterations in the plasma membrane and membranes of insulin granules and lipid droplets in single beta cells under such nutritional load conditions. Full article
(This article belongs to the Special Issue Biomimetic Radical Chemistry and Applications)
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