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 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●).
Highlights
The recording times are selected at the maximum intensity of the absorption signal after electron pulse for the specified concentration of 2-TU, which corresponds to the steady-state concentrations of transient species
N3 radicals is an assignment of the experimental transient spectra observed at low and high concentration of 2-TU to appropriate intermediates based on theoretical calculations and possible specific reactions of
2, Br2 ) with 2-TU reported the formation of only one intermediate, namely, dimeric radical cation (2-TU)+ characterized by an absorption band with λmax = 430 nm and which exists in an equilibrium shown on Scheme 2 [58]
Summary
Their research in the 1950-s on the therapeutic properties of sulfur-substituted nucleobases (thiobases) resulted in two new chemotherapeutic drugs, thioguanine and 6-mercaptopurine, which were approved by US Food and Drug Administration (FDA). For treatment of acute leukemia and are still used for this purpose. Their revolutionary work was based on the fact, that substitution of carbonyl oxygen atom in canonical nucleobase by sulfur atom affects cell metabolism and leads to their death [1]. The aforementioned studies were devoted mostly to purine based thiobases but thiopyrimidines have their place on the wide spectrum of biologically active compounds.
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