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

Abstract

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 (RN3•−) which reacts via rapid N2 loss at 77 K, forming nitrene anion radical (RN•−). Rapid protonation of RN•− at 77 K formed RNH• and −OH. 15N-labeled-1a confirmed this mechanism. Investigations employing in-house synthesized site-specifically deuterated derivatives of 1a (e.g., CH3 (1b), C4 (1c), and C5 (1d)) established that: (a) a facile intramolecular H-atom transfer from C5 to RNH• generated C5• and RNH2. C5• formation had a small deuterium kinetic isotope effect suggesting that this reaction does not occur via direct H-atom abstraction. (b) Subsequently, C5• underwent a facile unimolecular conversion to ring-opened C4• under a reductive environment. Identification of ring-opened C4• intermediate confirms the mechanism of C5′• mediated unaltered base release associated with DNA-strand break. However, for 2, ESR studies established thermally-activated intermolecular H-atom abstraction by RNH• from methyl group at C1. Thus, sugar ring configuration strongly influence site and pathways of RNH• mediated reactions in pentafuranoses.

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

“…23–25 Furthermore, G• + is an important intermediate in DNA radiation damage that includes the radiation-induced charge transfer processes in DNA. 22–25, 30–33 As a result, following our ongoing work on studies of various types of DNA-radicals employing ESR, 22–29 we have provided the evidence of formation of G• + in the presence of CNPs.…”

“…Following our works, 22–29, 31, 36–38 a Varian Century Series X-band (9.3 GHz) ESR spectrometer with an E-4531 dual cavity, 9-inch magnet, and a 200 mW Klystron was used for the ESR studies. For the field calibration, Fremy’s salt ( g center = 2.0056, A (N) = 13.09 G) was employed.…”

“…To obtain a simulated spectrum that matches the corresponding experimentally recorded spectrum, we employed the Bruker programs (WIN-EPR, SIMFONIA). 22–29, 31, 36–38 …”

Azido- and Triazolyl-modified Nucleoside/tide Analogues: Chemistry, Fluorescent Properties, and Anticancer Activities

“…These results showed that one electron-induced aminyl radicals in AmdU 18 augment radiation damage to cells. In hypoxic microenvironment, RNH• formed from electron addition to AmdU 18 can be involved in the H-atom abstraction reactions that might cause DNA-strand breaks and/or crosslink formation 9,42,73 leading to lesions that can induce apoptosis of cancer cells. 16,19,[134][135][136] On the other hand, in the aerobic cells, the aminyl radical generated from AmdU 18 can react with oxygen to generate aminylperoxyl radical RNHOO• and eventually lead to aminoxyl (nitroxyl) radicals RNHO•, 137 which also can lead to DNA damage.…”

“…The formation of neutral and reactive aminyl radicals on prehydrated one-electron attachment to azido-modified nucleosides in γ-irradiated aqueous glassy (7.5 M LiCl) systems was characterized using electron spin resonance spectroscopy (ESR). 42,73 γ-Irradiated chloride ion in glassy system at 77 K produced chlorine radical and electron The azido group in 3'-AZT 22 rather than the thymine moiety was proved to be the predominant site of electron capture, as a result of the higher electron affinity of the azido group in 22 than the most electron affinic DNA base, thymine. 42 The formation of the reactive aminyl radicals in γ-irradiated system and their subsequent reactions provides a plausible mechanism for the radiosensitizing effects of 3'-AZT 60,70,72,75 and meanwhile suggest that the azido-modified nucleoside/tide analogues are possible to be explored as potential radiosensitizing agents in hypoxia (bioreductive) microenvironments.…”