Product and Pulse Radiolysis Studies on Radical-Ion Splitting of N(1)−C(5‘)-Linked Dimer Hydrates of 5-Substituted Uracils by One-Electron Reduction in Anoxic Aqueous Solution

Abstract

Steady-state gamma-radiolysis, pulse radiolysis, and cyclic voltammetry have been performed to identify the mechanism by which N(1)-C(5')-linked homodimer hydrates [1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)thymine (2a) and [1-(5'-fluoro-6'-hydroxy-5',6'-dihydrouracil-5'-yl)-5-fluorouracil (2b)], N(1)-C(6')-linked dimer hydrate [1-(5'-hydroxy-5',6'-dihydrothymin-6'-yl)thymine (3a)], and N(1)-C(5')-linked heterodimer hydrate [1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)-5-fluorouracil (2ba)] undergo radiolytic reductive splitting to regenerate the parent monomers in anoxic aqueous solution. Radiolytic reductions of the thymine homodimer hydrates 2a and 3a by hydrated electrons (e(aq)-) regenerated the parent thymine (1a) almost quantitatively, while the 5-fluorouracil homodimer hydrates cis-2b and trans-2b afforded 1-(uracil-5'-yl)-5-fluorouracil efficiently along with a small amount of the parent 5-fluorouracil (1b). In contrast to 2b, the heterodimer hydrate analogue 2ba with noneliminating 5'-methyl substituent releases 5-fluorouracil 1b almost quantitatively in the radiolytic reduction. The pulse radiolysis studies suggested that the electron adducts are produced primarily at the thymine and 5-fluorouracil structural unit in the dimer hydrates 2a,b, respectively, in which the resulting dimer hydrate radical anion of 2b (2b*-) was more stable than that of 2a (2a*-). As characterized by pulse radiolysis and cyclic voltammetry, the 5-fluorouracil homodimer hydrate 2b bearing F-substituent at C(5') undergoes one-electron reduction to eliminate exclusively fluoride ion along with the formation of dimer hydrate C(5') radical (2b(-F)*) with oxidizing property. The formation of a possible dimer hydrate radical intermediate 2b(-F)* was also supported by the effect of amines as the reducing additives on the yields of 1b and 4b in the radiolytic reduction of 2b.

Communication: Electronic UV-Vis transient spectra of the ·OH reaction products of uracil, thymine, cytosine, and 5,6-dihydrouracil by using the complete active space self-consistent field second-order perturbation (CASPT2//CASSCF) theory

“…16,17 In addition, transient absorption spectroscopy has been widely used for the direct observation of the carbon-centered radicals formed in the reactions. 1,5,9,15,18,19 Regarding the latter technique, the spectra related to the pyrimidine nucleobases 1, 9 and some of their derivatives as 5,6-dihydrouracil or 1,3-dimethyluracil 9 in aqueous solution were reported early in 1970s. For uracil, a broadband centered at around 3.26 eV (380 nm) was observed at pH 3.15.…”

“…In this scenario, a systematic study on the · OH adducts of the pyrimidine nucleobases and the H-abstraction products of 5,6-dihydrouracil using accurate ab initio multiconfigurational methods that include dynamic correlation seems to be timely. Our motivation has also been enhanced by new experimental works in which transient absorption spectroscopy 19,24 has been employed to study nucleicacid damage. DNA/RNA oxidation by · OH radical remains a field of active research.…”

Current molecular design of intelligent drugs and imaging probes targeting tumor-specific microenvironments

“…Radiolytic reduction of the dimer hydrate 33 by e aq − regenerates 5FU, along with 1-(uracil-5 -yl)-5-fluorouracil (34). 66 The pulse radiolysis study demonstrated a one-electron reduction mechanism by which a radical anion in the form of an electronadduct at the 5FU moiety is generated as the initial intermediate during radiolytic reduction, followed by F − elimination from the radical anion and hydrolytic splitting of N1-C5 linkages to regenerate 5FU. 66 Further one-electron reduction can occur competitively from the radical [33(-F) • ] into a byproduct 34.…”

“…66 The pulse radiolysis study demonstrated a one-electron reduction mechanism by which a radical anion in the form of an electronadduct at the 5FU moiety is generated as the initial intermediate during radiolytic reduction, followed by F − elimination from the radical anion and hydrolytic splitting of N1-C5 linkages to regenerate 5FU. 66 Further one-electron reduction can occur competitively from the radical [33(-F) • ] into a byproduct 34. The reduction mechanism of pyrimidine dimer has provided a novel strategy of radiation-activated 5FU prodrugs for the treatment of malignant hypoxic solid tumors (Scheme 2).…”

Radiolytic one-electron reduction characteristics of tyrosine derivative caged by 2-oxopropyl group

“…Recently we have proposed caged drugs (prodrugs) that are activated by hypoxic X-irradiation. [7][8][9][10][11] Our studies illustrated that a 2-oxoalkyl group has an effective functionality for caging antitumor drugs such as 5-fluorouracil (5-FU) 8,9 and 5-fluorodeoxyuridine (5-FdUrd), 10 and for radiolytic activation of the resultant caged drugs. This class of radiation activated caged drugs release the 2-oxoalkyl group by reducing hydrated electrons, which are generated as the major active species along with hydrogen atoms and hydroxyl radicals upon radiolysis of an aqueous solution.…”