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<p>To verify whether the recently synthesized nucleoside, 8-(4-Trifluoromethoxy)benzylamino-2′-deoxyadenosine, can sensitize tumorous cells to X-rays, radiolytic and in vitro studies have been conducted. Molecular modeling demonstrated that excess electrons should lead to efficient dissociative electron attachment (DEA) to dA-NHbenzylOCF<sub>3</sub> resulting in a radical product that can potentially damage DNA. The computationally predicted DEA process was confirmed via stationary radiolysis of a dA-NHbenzylOCF<sub>3</sub> water solution followed by LC-MS analysis of the obtained radiolytes. Moreover, dA-NHbenzylOCF<sub>3</sub> was tested against its cytotoxicity and clonogenicity. We showed that the modified nucleoside is not cytotoxic to PC3, MCF-7, and HaCaT cell lines. Additionally, the clonogenic test exhibited a statistically significant radiosensitization of PC3 and MCF-7 cells to X-rays. On the other hand, flow cytometry assays demonstrated that the action of dA-NHbenzylOCF<sub>3</sub> is related to its influence on the cell cycle rather than the level of DNA double-strand breaks induced by ionizing radiation. Our findings indicate that the compound enters the cell and predominantly localizes in the cytoplasm, with a notable amount also detected in the nucleus. Moreover, we established that the compound is not phosphorylated by cellular kinases nor integrated into genomic DNA by the replication machinery.</p>

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Substituted benzylamino-2′-deoxyadenosine a modified nucleoside with radiosensitizing properties

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月20日

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  • Magdalena Datta,
  • Adrian Szczyrba,
  • Anna Czaja,
  • Magdalena Zdrowowicz,
  • Sebastian Demkowicz,
  • Janusz Rak

摘要

To verify whether the recently synthesized nucleoside, 8-(4-Trifluoromethoxy)benzylamino-2′-deoxyadenosine, can sensitize tumorous cells to X-rays, radiolytic and in vitro studies have been conducted. Molecular modeling demonstrated that excess electrons should lead to efficient dissociative electron attachment (DEA) to dA-NHbenzylOCF3 resulting in a radical product that can potentially damage DNA. The computationally predicted DEA process was confirmed via stationary radiolysis of a dA-NHbenzylOCF3 water solution followed by LC-MS analysis of the obtained radiolytes. Moreover, dA-NHbenzylOCF3 was tested against its cytotoxicity and clonogenicity. We showed that the modified nucleoside is not cytotoxic to PC3, MCF-7, and HaCaT cell lines. Additionally, the clonogenic test exhibited a statistically significant radiosensitization of PC3 and MCF-7 cells to X-rays. On the other hand, flow cytometry assays demonstrated that the action of dA-NHbenzylOCF3 is related to its influence on the cell cycle rather than the level of DNA double-strand breaks induced by ionizing radiation. Our findings indicate that the compound enters the cell and predominantly localizes in the cytoplasm, with a notable amount also detected in the nucleus. Moreover, we established that the compound is not phosphorylated by cellular kinases nor integrated into genomic DNA by the replication machinery.