2. Academic Validation
  3. 8-(4-Trifluoromethylthio)benzylamino-2'-deoxyadenosine: a purine nucleoside as a potential radiosensitizer

8-(4-Trifluoromethylthio)benzylamino-2'-deoxyadenosine: a purine nucleoside as a potential radiosensitizer

  • Eur J Med Chem. 2025 Dec 5:299:118094. doi: 10.1016/j.ejmech.2025.118094.
Magdalena Datta 1,  Adrian Szczyrba 1,  Patryk Nowak 2,  Magdalena Zdrowowicz 1,  Michał Rychłowski 3,  Sebastian Demkowicz 4,  Artur Sikorski 2,  Janusz Rak 5
Affiliations

Affiliations

  • 1 Laboratory of Biological Sensitizers, Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308, Gdańsk, Poland.
  • 2 Laboratory of Crystallochemistry, Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308, Gdańsk, Poland.
  • 3 Laboratory of Recombinant Vaccines, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Abrahama 58, 80-307, Gdańsk, Poland.
  • 4 Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdańsk, Poland.
  • 5 Laboratory of Biological Sensitizers, Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308, Gdańsk, Poland. Electronic address: janusz.rak@ug.edu.pl.
PMID: 40876255 DOI: 10.1016/j.ejmech.2025.118094
Abstract

DNA damage induced by hydroxyl radicals may be insufficient to achieve optimal radiotherapy outcomes in solid tumors. To counteract this limitation, radiosensitizers are used in conjunction with ionizing radiation. In this study, we identify 8-(4-Trifluoromethylthio)benzylamino-2'-deoxyadenosine (dA-NHbenzylSCF3) as a potential radiosensitizer through computational modeling. Its efficacy is further substantiated by stationary radiolysis experiments and in vitro studies using prostate (PC3) and breast Cancer (MCF-7) cell lines. Importantly, the compound exhibits no cytotoxic effects on these Cancer cells or human mammary fibroblasts (HMF). Clonogenic assay demonstrates a significant reduction in cell survival following irradiation. Flow cytometry analyses indicate that dA-NHbenzylSCF3 enhances DNA double-strand break formation (DSBs) and induces Apoptosis without perturbing cell cycle progression. Cellular uptake studies reveal its predominant cytoplasmic localization, with partial nuclear distribution. Furthermore, the compound is neither phosphorylated by cellular kinases nor incorporated into genomic DNA. These findings underscore dA-NHbenzylSCF3 as a promising radiosensitizer for improving radiotherapy outcomes.

Keywords

Apoptosis; Clonogenic assay; DEA; DSBs; MTT test; Radiosensitizing nucleosides; Stationary radiolysis.

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