5-Selenocyanato and 5-trifluoromethanesulfonyl derivatives of 2′-deoxyuridine: synthesis, radiation and computational chemistry as well as cytotoxicity

Abstract

5-Selenocyanato-20 -deoxyuridine (SeCNdU) and 5-trifluoromethanesulfonyl-2 0 -deoxyuridine (OTfdU) have been synthesized and their structures have been confirmed with NMR and MS methods. Both compounds undergo dissociative electron attachment (DEA) when irradiated with X-rays in an aqueous solution containing a hydroxyl radical scavenger. The DEA yield of SeCNdU significantly exceeds that of 5-bromo-2 0 -deoxyuridine (BrdU), remaining in good agreement with the computationally revealed profile of electron-induced degradation. The radiolysis products indicate, in line with theoretical predictions, Se-CN bond dissociation as the main reaction channel. On the other hand, the DEA yield for OTfdU is slightly lower than the degradation yield measured for BrdU, despite the fact that the calculated driving force for the electron-induced OTfdU dissociation substantially overpasses the thermodynamic stimulus for BrdU degradation. Moreover, the calculated DEA profile suggests that the electron attachment induced formation of 5-hydroxy-2 0 -deoxyuridine (OHdU) from OTfdU, while 2 0 -deoxyuridine (dU) is mainly observed experimentally. We explained this discrepancy in terms of the increased acidity of OTfdU resulting in efficient deprotonation of the N3 atom, which brings about the domination of the OTfdU(N3-H) À anion in the equilibrium mixture. As a consequence, electron addition chiefly leads to the radical dianion, OTfdU(N3-H)c 2À, which easily protonates at the C5 site. As a result, the C5-O rather than O-S bond undergoes dissociation, leading to dU, observed experimentally. A negligible cytotoxicity of the studied compounds toward the MCF-7 cell line at the concentrations used for cell labelling calls for further studies aiming at the clinical use of the proposed derivatives.

Low-energy electron-induced decomposition of 5-trifluoromethanesulfonyl-uracil: A potential radiosensitizer

“…This discrepancy was finally explained by protonation of the compound at the C 5 position in solution which promotes the cleavage of the C 5 -O bond rather than the O-S bond. 22 The present calculations for the gas phase also predict that the cleavage of the O-S bond should be more favorable (see Table I); however, the total ion yields for cleavage of the C 5 -O bond vs. the O-S bond are approximately equal. In this context, we note that under single collision conditions, the yield of a particular anion formed by DEA is associated to the DEA cross section σ DEA , which is influenced by autodetachment.…”

“…These findings can be compared with the outcomes obtained by Makurat et al upon electron attachment in an aqueous 5-trifluoromethanesulfonyl-2 -deoxyuridine (OTfdU) solution. 22 Briefly, this study was carried out in a deoxygenated aqueous OTfdU solution containing an OH • radical scavenger and phosphate buffer (pH = 7.0). Solvated electrons were generated in the solution through irradiation with X-rays.…”

“…21 In the light of such findings, a novel compound was proposed-5-trifluoromethanesulfonyl-2 -deoxyuridine (OTfdU). It possesses a substantial adiabatic electron affinity (AEA) and appears to be prone to undergo effective electron-induced dissociation, 22 thereby can be treated as a pseudohalouracil. Its fragmentation induced by solvated electrons was studied by steady-state radiolysis combined with theoretical methods.…”

“…Its fragmentation induced by solvated electrons was studied by steady-state radiolysis combined with theoretical methods. 22 However, no DEA study in the gas-phase has been reported so far. Therefore, we have investigated DEA to 5trifluoromethanesulfonyl-uracil (OTfU), shown in Fig.…”

Uracil-5-yl O-Sulfamate: An Illusive Radiosensitizer. Pitfalls in Modeling the Radiosensitizing Derivatives of Nucleobases

“… 15 The mechanism that utilizes electrons unreactive toward native DNA and is operative under hypoxia when the damaging properties of hydroxyl radical are significantly impaired prompted us to propose several new uridine radiosensitizers. To this end, 5-selenocyanato-2′-deoxyuridine (SeCNdU), 16 5-trifluoromethanesulfonyl-2′-deoxyuridine (OTfdU), 16 5-iodo-4-thio-2′-deoxyuridine (ISdU), 17 or 5-thiocyanato-2′-deoxyuridine (SCNdU) 18 can be mentioned as representative examples. In the heart of our approach lies the quantum chemically calculated DEA profile obtained for a verified nucleoside/nucleobase.…”