Generation of Thiyl Radicals by the Photolysis of 5-Iodo-4-thiouridine

Abstract

The photochemistry of 2',3',5'-tri-O-acetyl-5-iodo-4-thiouridine (3) in deoxygenated 1:1 CH(3)CN-H(2)O pH 5.8 (phosphate buffer) solution has been studied by means of steady-state and nanosecond laser flash photolysis methods. Under steady-state irradiation (lambda > or = 334 nm), the stable photoproducts were iodide ion, 2',3',5'-tri-O-acetyl-4-thiouridine (4), and two disulfides. The disulfides were the symmetrical bis-(2',3',5'-tri-O-acetyl-5-iodo-4-thiouridine) (5) and unsymmetrical 6, which contains both 4-thiouridine and 5-iodo-4-thiouridine residues. The formation of the dehalogenated photoproduct suggests that C(5)-I bond cleavage is a primary photochemical step. Attempts to scavenge the resulting C(5)-centered radical by suitable addends, bis-(N-alpha-acetyl)cystine-bis-N-ethylamide or benzene, were unsuccessful. Analysis of the photoproducts formed under these conditions showed that the S-atom is the reactive center. The photoproduct 4, obtained by irradiation of 3 in CD(3)CN-H(2)O, followed by reversed-phase HPLC isolation using nonlabeled eluents, did not contain deuterium. An analogous experiment performed in CH(3)CN-D(2)O gave deuterated product 4-d with 88% of the deuterium incorporated at C(5). Transient absorption observed upon laser excitation (lambda= 308 nm) of 3 was assigned to the 4-uridinylthiyl radical on the basis of the similarity of this spectrum with that obtained upon laser photolysis of the disulfide: bis-(2',3',5'-tri-O-acetyl-4-thiouridine) 14. On the basis of the results of steady-state and laser photolysis studies, a mechanism of the photochemical reaction of 3 is proposed. The key mechanistic step is a transformation of the C(5)-centered radical formed initially by C(5)-I bond cleavage into a long-lived S-centered radical via a 1,3-hydrogen shift. Theoretical calculations confirmed that the long-lived S-centered radical is the most stable radical derived from the 4-thiouracil residue.

5-Iodo-4-thio-2′-Deoxyuridine as a Sensitizer of X-ray Induced Cancer Cell Killing

“…The dimer, formed from two identical ISU fragments, was calculated to simply be the product of recombination of two S-centered ISU ● radicals after they were formed as a result of the reaction of t -BuO ● radicals with ISU. For the more complicated dimer, ISU–SU, the mechanism presented in Scheme 2 involved the DEA process where the SU ● radical was formed as discussed previously (see Section 2.2.1), followed by the N(3)H to C(5)H shift, as suggested by Wenska et al [42]. The two S-centered radicals, SU ● and ISU ● , may then react forming the observed ISU–SU dimer.…”

“…Moreover, it was additionally observed that if t -BuOH is absent, the dimer yield dramatically falls, which suggests the involvement of t -BuO ● radicals in the studied reactions (Supplementary Materials, Figure S11). Hence, the proposed pathway of dimer formation is based on the previous studies on 4-thiouridine disulfide [41,42] supplemented with the current observations.…”

NMR and UV Studies of 4-Thio-2′-deoxyuridine and Its Derivatives

“…Recently, much effort was directed to study the photophysical and photochemical properties of uridine derivatives that contain both C=O and C=S fragments. In the series of 4-thio-2’-deoxyuridines, it was found that the presence of the C=S function in the molecules dominated their photochemistry in aqueous solution [ 2 , 8 , 23 , 24 ]. According to the idea, 4-selenouridine derivatives that contain X groups (where X = halogen) will shift to much longer UV wavelengths than that of thiocarbonyl groups and could be particularly useful as potential UVA-induced anticancer agents.…”

Experimental and theoretical investigation of 5-para-nitro-benzylidene-thiazolidine-2-thione-4-one molecule

“…Despite the rather large calculated relative energies of the thiol and enol forms relative to the thione tautomer, as already reported in other studies [47,48,59,69,46], contributions from thiolic tautomers can not be excluded in liquid-phase [49][50][51][52][53][54]. Based on the above mentioned works and also on our results obtained on two other substituted benzylidene-thiazolidine derivatives [22] we assume the simultaneous presence of the thione and thiol tautomers of 5pN-BTT in DMSO solution.…”

“…The thione-thiol tautomeric equilibrium has a significant importance in biochemistry and it has attracted both, experimental and theoretical interest, different tautomers in solid and liquid phase being commonly reported [19,[46][47][48][49][50][51][52][53][54][55][56][57]. For this compound, the presence of thiol tautomers in both syn and anti conformers can be supposed because the barrier to rotation amounts to 0.96 kcal/mol at B3LYP/6-31G(d) level of theory, in gas-phase.…”