Azido derivatives of sesquiterpene lactones: Synthesis, anticancer proliferation, and chemistry of nitrogen-centered radicals.

Sesquiterpene lactones (SLs) such as parthenolide (PTL) and dehydroleucodine (DhL) selectively kill cancer cells without exerting normal tissue toxicity, potentially due to presence of α-methylene-γ-lactone (αMγL) fragment. We hypothesize that the addition of an azido group to the αMγL fragment of PTL or DhL further augments their anticancer properties as well as radiation sensitivity of cancer cells. Azido-SLs containing the azido group at the C14 methyl position of PTL (i.

How a Single 5 eV Electron Can Induce Double-Strand Breaks in DNA: A Time-Dependent Density Functional Theory Study.

Low-energy (<20 eV) electrons (LEEs) can resonantly interact with DNA to form transient anions (TAs) of fundamental units, inducing single-strand breaks (SSBs), and cluster damage, such as double-strand breaks (DSBs). Shape resonances, which arise from electron capture in a previously unfilled orbital, can induce only a SSB, whereas a single core-excited resonance (i.e.

Photochemical and Single Electron Transfer Generation of 2'-Deoxycytidin-4-yl Radical from Oxime Esters.

A 2'-deoxycytidin-4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogen bonds, is produced in a variety of DNA damaging processes. We describe here the independent generation of dC· from oxime esters under UV-irradiation or single electron transfer conditions. Support for this σ-type iminyl radical generation is provided by product studies carried out under aerobic and anaerobic conditions, as well as electron spin resonance (ESR) characterization of dC· in a homogeneous glassy solution at low temperature.

Pathways of the Dissociative Electron Attachment Observed in 5- and 6-Azidomethyluracil Nucleosides: Nitrogen (N) Elimination vs Azide Anion (N) Elimination.

5-Azidomethyl-2'-deoxyuridine (5-AmdU, ) has been successfully employed for the metabolic labeling of DNA and fluorescent imaging of live cells. 5-AmdU also demonstrated significant radiosensitization in breast cancer cells via site-specific nitrogen-centered radical (π-aminyl (U-5-CH-NH), , and σ-iminyl (U-5-CH═N), ) formation. This work shows that these nitrogen-centered radicals are not formed via the reduction of the azido group in 6-azidomethyluridine (6-AmU, ).

Proton-Transfer Reactions in One-Electron-Oxidized G-Quadruplexes: A Density Functional Theory Study.

Recently, G-quadruplexes (Gq) formed in B-DNA as secondary structures are found to be important therapeutic targets and material for developing nanodevices. Gq are guanine-rich and thus susceptible to oxidative damage by producing short-lived intermediate radicals via proton-transfer reactions. Understanding the mechanisms of radical formation in Gq is of fundamental interest to understand the early stages of DNA damage.

Modulation of the Directionality of Hole Transfer between the Base and the Sugar-Phosphate Backbone in DNA with the Number of Sulfur Atoms in the Phosphate Group.

This work shows that S atom substitution in phosphate controls the directionality of hole transfer processes between the base and sugar-phosphate backbone in DNA systems. The investigation combines synthesis, electron spin resonance (ESR) studies in supercooled homogeneous solution, pulse radiolysis in aqueous solution at ambient temperature, and density functional theory (DFT) calculations of in-house synthesized model compound dimethylphosphorothioate (DMTP(O)═S) and nucleotide (5'--methoxyphosphorothioyl-2'-deoxyguanosine (G-P(O)═S)). ESR investigations show that DMTP(O)═S reacts with Cl to form the σσ* adduct radical -P-S[Formula: see text]Cl, which subsequently reacts with DMTP(O)═S to produce [-P-S[Formula: see text]S-P-].

Ne-22 Ion-Beam Radiation Damage to DNA: From Initial Free Radical Formation to Resulting DNA-Base Damage.

We report on the physicochemical processes and the products of DNA damage involved in Ne-22 ion-beam radiation of hydrated (12 ± 3 HO/nucleotide) salmon testes DNA at 77 K. Free radicals trapped at 77 K were identified using electron spin resonance (ESR) spectroscopy. The measurement of DNA damage using two different techniques of mass spectrometry revealed the formation of numerous DNA products.

Electron-Induced Repair of 2'-Deoxyribose Sugar Radicals in DNA: A Density Functional Theory (DFT) Study.

In this work, we used ωB97XD density functional and 6-31++G** basis set to study the structure, electron affinity, populations via Boltzmann distribution, and one-electron reduction potentials (E°) of 2'-deoxyribose sugar radicals in aqueous phase by considering 2'-deoxyguanosine and 2'-deoxythymidine as a model of DNA. The calculation predicted the relative stability of sugar radicals in the order C4' > C1' > C5' > C3' > C2'. The Boltzmann distribution populations based on the relative stability of the sugar radicals were not those found for ionizing radiation or OH-radical attack and are good evidence the kinetic mechanisms of the processes drive the products formed.

Site of Azido Substitution in the Sugar Moiety of Azidopyrimidine Nucleosides Influences the Reactivity of Aminyl Radicals Formed by Dissociative Electron Attachment.

In this work, electron-induced site-specific formation of neutral π-type aminyl radicals (RNH·) and their reactions with pyrimidine nucleoside analogs azidolabeled at various positions in the sugar moiety, e.g., at 2'-, 3'-, 4'-, and 5'- sites along with a model compound 3-azido-1-propanol (3AZPrOH), were investigated.

One Way Traffic: Base-to-Backbone Hole Transfer in Nucleoside Phosphorodithioate.

Invited for the cover of this issue are the groups of Roman Dembinski, Mehran Mostafavi, and Amitava Adhikary at the Polish Academy of Sciences, Université Paris-Saclay, and Oakland University. The image depicts a doughnut as a way of illustrating the hole transfer process. Read the full text of the article at 10.

One-electron oxidation of ds(5'-GGG-3') and ds(5'-G(8OG)G-3') and the nature of hole distribution: a density functional theory (DFT) study.

Of particular interest in radiation-induced charge transfer processes in DNA is the extent of hole localization immediately after ionization and subsequent relaxation. To address this, we considered double stranded oligomers containing guanine (G) and 8-oxoguanine (8OG), i.e.

One Way Traffic: Base-to-Backbone Hole Transfer in Nucleoside Phosphorodithioate.

The directionality of the hole-transfer processes between DNA backbone and base was investigated by using phosphorodithioate [P(S )=S] components. ESR spectroscopy in homogeneous frozen aqueous solutions and pulse radiolysis in aqueous solution at ambient temperature confirmed initial formation of G -P(S )=S. The ionization potential of G-P(S )=S was calculated to be slightly lower than that of guanine in 5'-dGMP.

Reaction of Electrons with DNA: Radiation Damage to Radiosensitization.

This review article provides a concise overview of electron involvement in DNA radiation damage. The review begins with the various states of radiation-produced electrons: Secondary electrons (SE), low energy electrons (LEE), electrons at near zero kinetic energy in water (quasi-free electrons, (e)) electrons in the process of solvation in water (presolvated electrons, e), and fully solvated electrons (e). A current summary of the structure of e, and its reactions with DNA-model systems is presented.

Excited States of One-Electron Oxidized Guanine-Cytosine Base Pair Radicals: A Time Dependent Density Functional Theory Study.

One-electron oxidized guanine (G) in DNA generates several short-lived intermediate radicals via proton transfer reactions resulting in the formation of neutral guanine radicals. The identification of these radicals in DNA is of fundamental interest to understand the early stages of DNA damage. Herein, we used time-dependent density functional theory (TD-ωB97XD-PCM/6-31G(3df,p)) to calculate the vertical excitation energies of one-electron oxidized G and G-cytosine (C) base pair in various protonation states: G, G(N1-H), and G(N2-H), as well as G-C, G(N1-H)-(H)C, G(N1-H)-(N4-H)C), G(N1-H)-C, and G(N2-H)-C in aqueous phase.

Structural, Spectroscopic, Electrochemical, and Magnetic Properties for Manganese(II) Triazamacrocyclic Complexes.

We report the synthesis of [Mn(tacud)](OTf) () (tacud = 1,4,8-triazacycloundecane), [Mn(tacd)](OTf) () (tacd = 1,4,7-triazacyclodecane), and [Mn(tacn)](OTf) () (tacn = 1,4,7-triazacyclononane). Electrochemical measurements on the Mn redox couple show that complex has the largest anodic potential of the set ( = 1.16 V vs NHE, Δ = 106 mV) compared to ( = 0.

Observation of dissociative quasi-free electron attachment to nucleoside via excited anion radical in solution.

Damage to DNA via dissociative electron attachment has been well-studied in both the gas and condensed phases; however, understanding this process in bulk solution at a fundamental level is still a challenge. Here, we use a picosecond pulse of a high energy electron beam to generate electrons in liquid diethylene glycol and observe the electron attachment dynamics to ribothymidine at different stages of electron relaxation. Our transient spectroscopic results reveal that the quasi-free electron with energy near the conduction band effectively attaches to ribothymidine leading to a new absorbing species that is characterized in the UV-visible region.

Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells.

Two classes of azido-modified pyrimidine nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2'-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2'-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells.

Thermally Induced Oxidation of [Fe(tacn)](OTf) (tacn = 1,4,7-triazacyclononane).

We previously reported the spin-crossover (SC) properties of [Fe(tacn)](OTf) () (tacn = 1,4,7-triazacyclononane) [ , 2115]. Upon heating under dynamic vacuum, undergoes oxidation to generate a low spin iron(III) complex. The oxidation of the iron center was found to be facilitated by initial oxidation of the ligand via loss of an H atom.

Direct observation of the oxidation of DNA bases by phosphate radicals formed under radiation: a model of the backbone-to-base hole transfer.

In irradiated DNA, by the base-to-base and backbone-to-base hole transfer processes, the hole (i.e., the unpaired spin) localizes on the most electropositive base, guanine.

SOMO-HOMO Level Inversion in Biologically Important Radicals.

Conventionally, the singly occupied molecular orbital (SOMO) of a radical species is considered to be the highest occupied molecular orbital (HOMO), but this is not the case always. In this study, we considered a number of radicals from smallest diatomic anion radicals such as superoxide anion radical to one-electron oxidized DNA related base radicals that show the SOMO is energetically lower than one or more doubly occupied molecular orbitals (MOs) (SOMO-HOMO level inversion). The electronic configurations are calculated employing the B3LYP/6-31++G** method, with the inclusion of aqueous phase via the integral equation formalism of the polarized continuum model solvation model.

Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines.

Photochemical precursors that produce dA and dG(N-H) are needed to investigate their reactivity. The synthesis of two 1,1-diphenylhydrazines (1, 2) and their use as photochemical sources of dA and dG(N-H) is presented. Trapping studies indicate production of these radicals with good fidelity, and 1 was incorporated into an oligonucleotide via solid-phase synthesis.

Modulating the Catalytic Activity of Cerium Oxide Nanoparticles with the Anion of the Precursor Salt.

In this work, we tested our hypothesis that surface chemistry and antioxidant properties of cerium nanoparticles (CNPs) are affected by presence of counterions. We first employed various precursor cerium (III) (Ce(III)) salts with different counterions (acetate, nitrate, chloride, sulfate) to synthesize CNPs following the same wet chemical methodology. Electron spin resonance (ESR) studies provided evidence for the formation of radicals from counterions (e.

Cytosine Iminyl Radical (cytN) Formation via Electron-Induced Debromination of 5-Bromocytosine: A DFT and Gaussian 4 Study.

Halogen-substituted pyrimidines, such as 5-bromouracil and 5-iodouracil, have been used as radio therapeutic (RT) agents in cancer treatment. The radiosensitizing activity of 5-bromouracil is attributed to its reaction with electron which produce the highly reactive uracil-5-yl radical by dissociating the C5-Br bond. Using density functional methods and highly accurate Gaussian 4 (G4) theory, herein, we show that 5-bromocytosine (5-Brcyt) after reaction with electron, also, leads to the formation of cytosine-5-yl radical.

Prehydrated One-Electron Attachment to Azido-Modified Pentofuranoses: Aminyl Radical Formation, Rapid H-Atom Transfer, and Subsequent Ring Opening.

Methyl 2-azido-2-deoxy-α-d-lyxofuranoside (1a) and methyl 2-azido-2-deoxy-β-d-ribofuranoside (2) were prepared from d-xylose or d-arabinose, respectively. Employing ESR and DFT/B3LYP/6-31G* calculations, we investigated (i) aminyl radical (RNH·) formation and (ii) reaction pathways of RNH·. Prehydrated electron attachment to 1a and 2 at 77 K produced transient azide anion radical (RN·) which reacts via rapid N loss at 77 K, forming nitrene anion radical (RN·).

Gamma and Ion-Beam Irradiation of DNA: Free Radical Mechanisms, Electron Effects, and Radiation Chemical Track Structure.

The focus of our laboratory's investigation is to study the direct-type DNA damage mechanisms resulting from γ-ray and ion-beam radiation-induced free radical processes in DNA which lead to molecular damage important to cellular survival. This work compares the results of low LET (γ-) and high LET (ion-beam) radiation to develop a chemical track structure model for ion-beam radiation damage to DNA. Recent studies on protonation states of cytosine cation radicals in the N1-substituted cytosine derivatives in their ground state and 5-methylcytosine cation radicals in ground as well as in excited state are described.