Why does the type of halogen atom matter for the radiosensitizing properties of 5-halogen substituted 4-thio-2′-deoxyuridines?

Paulina Spisz , Magdalena Zdrowowicz , Samanta Makurat , Witold Kozak , Konrad Skotnicki , Krzysztof Bobrowski , Janusz Rak

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.
Author Paulina Spisz (FCh / DPCh / LBS)
Paulina Spisz,,
- Laboratory of Biological Sensitizers
, Magdalena Zdrowowicz (FCh / DPCh / LBS)
Magdalena Zdrowowicz,,
- Laboratory of Biological Sensitizers
, Samanta Makurat (FCh / DPCh / LBS)
Samanta Makurat,,
- Laboratory of Biological Sensitizers
, Witold Kozak (FCh / DPCh / LBS)
Witold Kozak,,
- Laboratory of Biological Sensitizers
, Konrad Skotnicki
Konrad Skotnicki,,
-
, Krzysztof Bobrowski
Krzysztof Bobrowski,,
-
, Janusz Rak (FCh / DPCh / LBS)
Janusz Rak,,
- Laboratory of Biological Sensitizers
Journal seriesMolecules, ISSN 1420-3049, (A 30 pkt)
Issue year2019
Vol24
No15
Pages1-17
Publication size in sheets0.8
Article number2819
Keywords in Englishradiosensitizers, stationary radiolysis, pulse radiolysis, modified nucleosides, cellular response
ASJC Classification1605 Organic Chemistry
DOIDOI:10.3390/molecules24152819
URL https://doi.org/10.3390/molecules24152819
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)30
ScoreMinisterial score = 30.0, 05-08-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 1.146; WoS Impact Factor: 2017 = 3.098 (2) - 2017=3.268 (5)
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