Why Does the Type of Halogen Atom Matter for the Radiosensitizing Properties of 5-Halogen Substituted 4-Thio-2′-Deoxyuridines?

Abstract

Radiosensitizing properties of substituted uridines are of great importance for radiotherapy. Very recently, we confirmed 5-iodo-4-thio-2′-deoxyuridine (ISdU) as an efficient agent, increasing the extent of tumor cell killing with ionizing radiation. To our surprise, a similar derivative of 4-thio-2’-deoxyuridine, 5-bromo-4-thio-2′-deoxyuridine (BrSdU), does not show radiosensitizing properties at all. In order to explain this remarkable difference, we carried out a radiolytic (stationary and pulse) and quantum chemical studies, which allowed the pathways to all radioproducts to be rationalized. In contrast to ISdU solutions, where radiolysis leads to 4-thio-2’-deoxyuridine and its dimer, no dissociative electron attachment (DEA) products were observed for BrSdU. This observation seems to explain the lack of radiosensitizing properties of BrSdU since the efficient formation of the uridine-5-yl radical, induced by electron attachment to the modified nucleoside, is suggested to be an indispensable attribute of radiosensitizing uridines. A larger activation barrier for DEA in BrSdU, as compared to ISdU, is probably responsible for the closure of DEA channel in the former system. Indeed, besides DEA, the XSdU anions may undergo competitive protonation, which makes the release of X− kinetically forbidden.

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

“…Thus, the activation barrier calculated with the high accuracy method explains the experimental observations. Indeed, as indicated in our recent studies on radiosensitizing properties of 5-iodo-4-thio-2′-deoxyuridine 17 and 5-bromo-4-thio-2′-deoxyuridine, 18 the activation energy of ca. 7 kcal/mol is sufficient to completely quench the electron-attachment-induced release of the halide anion from the above-mentioned thiouridines.…”

“… 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.…”

Application of Radiosensitizers in Cancer Radiotherapy

“…These agents are intrinsic inactive, their effect becomes evident only in the presence of ionizing radiation to “fix” or stabilize DNA radical lesions in oxygen-deficient cells. 32 Misonidazole, a 2-nitroimidazole, is one of the earliest developed nitroimidazoles. In preclinical studies, misonidazole showed better radiosensitizing effect than 5-nitro imidazole or metronidazole (Flagyl®) in the majority of solid murine tumors.…”

Radiation Induced One-Electron Oxidation of 2-Thiouracil in Aqueous Solutions

“…Surprisingly, much less attention was directed into studies of radicals derived from sulfur nucleobases exposed to reactions with one-electron reductants and oxidants in aqueous phase. Reactions of hydrated electrons eaq− with bis(1-substituted-uracil-4-yl) disulfide [53], 2-thio analogues of cytosine and uracil [54], 8-thioguanosine [55], 5-iodo-4-thio-2′-deoxyuridine [56] and 5-bromo-4-thio-2′-deoxyuridine [57], H atoms (H ● ) with 8-thioguanosine [55], formate (CO2●−) and 2-hydroxypropan-2-yl ((CH 3 ) 2 ● COH) radicals with 2-thio analogues of cytosine and uracil [54], hydroxyl radicals ( • OH), dichloride ( Cl2●−) and dibromide ( Br2●−) radical anions with 2-TU [58], 4-thiouracil [59] and 8-thioguanosine [55] and azide radicals ( ● N 3 ) with 4-thiouracil [59] and 8-thioguanosine [55] are all but a few examples.…”