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

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molecules Review The Two Faces of the Guanyl Radical: Molecular Context and Behavior Chryssostomos Chatgilialoglu 1,2 1 ISOF, Consiglio Nazionale delle Ricerche, 40129 Bologna, Italy; [email protected]; Tel.: +39-051-6398309 2 Center of Advanced Technologies, Adam Mickiewicz University, 61-712 Pozna´n,Poland 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 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. Keywords: guanine; guanyl radical; tautomerism; guanine radical cation; oligonucleotides; DNA; G-quadruplex; time-resolved spectroscopies; reactive oxygen species (ROS); oxidation 1. The Guanine Sink Citation: Chatgilialoglu, C. The Two The free radical chemistry associated with guanine (Gua) and its derivatives, guano- Faces of the Guanyl Radical: sine (Guo), 2’-deoxyguanosine (dGuo), guanosine-50-monophosphate (GMP), and 20- Molecular Context and Behavior. deoxyguanosine-50-monophosphate (dGMP), is of particular interest due to its biological Molecules 2021, 26, 3511. https:// relevance. Indeed, this reactivity is by far the most involved in oxidative DNA damage, doi.org/10.3390/molecules26123511 initiated by reactive oxygen species (ROS) generated by normal cellular metabolism, or by exogenous sources such as ionizing or ultraviolet irradiation [1–3]. In the thirty years Academic Editor: Nicola Borbone since the discovery of long-range charge transport in DNA, as reviewed by Barton and coworkers [4–6], a large body of experimental data have accumulated showing that the Received: 6 April 2021 one-electron oxidation of DNA produces a hole that can migrate through the double helix Accepted: 1 June 2021 Published: 9 June 2021 with the final destination at the G sites [4–10]. Among the four common DNA bases (A, G, T, and C), G is the most readily oxidized to the G radical cation (G•+), which is also the putative initial intermediate in the oxidative DNA damage. Thus, there have been numer- Publisher’s Note: MDPI stays neutral •+ with regard to jurisdictional claims in ous studies on the formation and behavior of G as a nucleoside and in oligonucleotides •+ published maps and institutional affil- (ODNs) using spectroscopic and product studies. Upon formation of G , fast deprotona- • iations. tion occurs by the loss of a proton to give the guanyl radical G(-H) , also named the guanine radical or neutral guanine radical. The main objective of this review is to summarize the behavior of G(-H)• in nucleosides and nucleotides and give an overview of its formation in a macromolecular environment, such as single-stranded (ss), double-stranded (ds) ODNs, and G-quadruplex arrangements. Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. 2. The Two Tautomers of the Guanyl Radical This article is an open access article • distributed under the terms and The guanyl radical G(-H) corresponds to any intermediate that has lost an H-atom – + • conditions of the Creative Commons or an electron/proton (e /H ) couple from the G moiety. G(-H) is one of the most re- Attribution (CC BY) license (https:// current and intensively studied transient species. The reason is obvious, as dGuo (1, 0 creativecommons.org/licenses/by/ R = 2 -deoxyribose) is one of the building blocks of DNA with the lowest oxidation po- • 4.0/). tential (Figure1). The chemistry of G(-H) depends on the molecular context where it Molecules 2021, 26, 3511. https://doi.org/10.3390/molecules26123511 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 24 and intensively studied transient species. The reason is obvious, as dGuo (1, R = 2′-deoxy- ribose) is one of the building blocks of DNA with the lowest oxidation potential (Figure 1). The chemistry of G(-H)• depends on the molecular context where it belongs (free base, nucleoside in ribo or deoxyribo forms, ss- or ds-ODNs including multi-G sequences, RNA, DNA, and G-quadruplex). Although numerous mechanistic studies have been performed during recent years, the emerging picture is still incomplete, with several unanswered questions and divergent opinions. The extrapolation of its chemistry from simple nucleo- sides to more complex environments (e.g., DNA) can be misleading. This situation often generates confusion to the newcomers in the field. In the present article, the existing di- chotomies among mechanistic insights are examined and critically discussed to give a rea- soned overview of the guanyl radical structure and behavior. Figure 1 shows two tautomeric structures of G(-H)•: form 2 or G(N1-H)• that has lost H from the N1 position, and form 3 or G(N2-H)• that has lost H from the N2 position. The acronyms G(N1-H)• and G(N2-H)• have been commonly used in the recent literature and Molecules 2021, 26, 3511 2 of 25 are used throughout this review; alternative acronyms have been used: G•, N1G•, (G-H1)• or the aminic form for G(N1-H)•, and N(2)G•, N2G•, (G-H2)•, G(N2-H)• or the iminic form for G(N2-H)•. Figure 1 also shows the distribution of the unpaired electron in the SOMO belongsof G(N1-H) (free• base,(A) and nucleoside G(N2-H) in• ribo(B) computed or deoxyribo at the forms, B3LYP/6-311G** ss- or ds-ODNs level including [11]. In multi-G A, the sequences,unpaired electron RNA, DNA, is mainly and G-quadruplex).localized at the Although N3, O6, C5, numerous and C8 mechanisticatoms (spin studies densities have of been0.30, 0.34, performed 0.21, and during 0.27, recentrespectively), years, the whereas, emerging in B picture, the unpaired is still incomplete,electron is mainly with sev- lo- eralcalized unanswered at the N3, C5, questions C8, and and N2 divergentatoms (spin opinions. densities The of 0.34, extrapolation 0.29, 0.22, and of its 0.39, chemistry respec- fromtively) simple [11]. As nucleosides each tautomer to more has complex various environmentsresonance forms (e.g., (discussed DNA) can in besome misleading. detail in Thisreference situation [11]), often the reported generates drawings confusion for to theradicals newcomers 2 and 3 in, where the field. the Inunpaired the present electron article, is theplaced existing in the dichotomies C5 position, among are chosen mechanistic for a fa insightscile distinction are examined of the andtwo criticallytautomers discussed (Figure to1). give a reasoned overview of the guanyl radical structure and behavior. 6O O O N 5 N N 1NH N NH 8 3 N N N N 2 NH2 N NH2 N NH R R R 1, G 2, G(N1-H)• 3, G(N2-H)• AB Figure 1. Structure 1 represents thethe guanineguanine moietymoiety inin guanosineguanosine (Guo),(Guo), 220-deoxyguanosine′-deoxyguanosine (dGuo), guanosine-5(dGuo), guanosine-50- monophosphate′- monophosphate (GMP), 2 0(GMP),-deoxyguanosine-5 2′-deoxyguanosine-50-monophosphate′-monophosphate (dGMP), or(dGMP), 30,50-cyclic or guanosine3′,5′-cyclic guanosine monophosphate monophosphate (cGMP);the (cGMP); atom the numbering atom numbering of the guanine of the guanine moiety ismoiety given is in given red. in red. The corresponding guanyl radicals G(N1-H)• (2) or G(N2-H)• (3); the part of the molecule The corresponding guanyl radicals G(N1-H)• (2) or G(N2-H)• (3); the part of the molecule involved involved in tautomerization is highlighted in red. SOMO of the two forms of guanyl radical G(N1- in tautomerization is highlighted in red. SOMO of the two forms of guanyl radical G(N1-H)• (A) and H)• (A) and G(N2-H)• (B) computed at the B3LYP/6-311G** level (taken from ref [11]). G(N2-H)• (B) computed at the B3LYP/6-311G** level (taken from ref [11]). 3. One-Electron Oxidation of Guanine Derivatives Figure1 shows two tautomeric structures of G(-H) •: form 2 or G(N1-H)• that has lost H fromIn the the guanine N1 position, derivatives and form 1 (G),3 orthe G(N2-H) two pKa• valuesthat has of lost2.5 and H from 9.3 are the related N2 position. to the Theprotonation acronyms and G(N1-H) deprotonation• and G(N2-H) steps, respective• have beenly commonly[12,13]. Early used work in the by recentpulse radiolysis literature andstudies are with used both throughout conductometric this review; and optical alternative detection acronyms showed have that been the used:one-electron G•, N1G ox-•, • • •− • • •− • 2 • (G-Hidations1) orof Guo the aminic and dGuo form by for the G(N1-H) powerful, andSO4 N or(2)G the, milder N2G , Br (G-H2 oxidants2) , G(N (see-H) Appen-or the iminic form for G(N2-H)•. Figure1 also shows the distribution of the unpaired electron in the SOMO of G(N1-H)• (A) and G(N2-H)• (B) computed at the B3LYP/6-311G** level [11]. In A, the unpaired electron is mainly localized at the N3, O6, C5, and C8 atoms (spin densities of 0.30, 0.34, 0.21, and 0.27, respectively), whereas, in B, the unpaired electron is mainly localized at the N3, C5, C8, and N2 atoms (spin densities of 0.34, 0.29, 0.22, and 0.39, respectively) [11].
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  • New Blatter-Type Radicals from a Bench-Stable Carbene

    New Blatter-Type Radicals from a Bench-Stable Carbene

    ARTICLE Received 6 Aug 2016 | Accepted 28 Feb 2017 | Published 15 May 2017 DOI: 10.1038/ncomms15088 OPEN New Blatter-type radicals from a bench-stable carbene Jacob A. Grant1, Zhou Lu2, David E. Tucker1, Bryony M. Hockin1, Dmitry S. Yufit1, Mark A. Fox1, Ritu Kataky1, Victor Chechik2 & AnnMarie C. O’Donoghue1 Stable benzotriazinyl radicals (Blatter’s radicals) recently attracted considerable interest as building blocks for functional materials. The existing strategies to derivatize Blatter’s radicals are limited, however, and synthetic routes are complex. Here, we report that an inexpensive, commercially available, analytical reagent Nitron undergoes a previously unrecognized transformation in wet acetonitrile in the presence of air to yield a new Blatter-type radical with an amide group replacing a phenyl at the C(3)-position. This one-pot reaction of Nitron provides access to a range of previously inaccessible triazinyl radicals with excellent benchtop stabilities. Mechanistic investigation suggests that the reaction starts with a hydrolytic cleavage of the triazole ring followed by oxidative cyclization. Several derivatives of Nitron were prepared and converted into Blatter-type radicals to test the synthetic value of the new reaction. These results significantly expand the scope of using functionalized benzotriazinyls as stable radical building blocks. 1 Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK. 2 Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. Correspondence and requests for materials should be addressed to V.C. (email: [email protected]) or to A.M.C.O’D. (email: [email protected]). NATURE COMMUNICATIONS | 8:15088 | DOI: 10.1038/ncomms15088 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15088 1 latter’s radical 1 (Fig.