Products Cited in Publications Worldwide Substituted benzylamino-2′-deoxyadenosine a modified nucleoside with radiosensitizing properties

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

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

DOI: PMID:

Abstract

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.

Keywords

Radiosensitizing nucleosides ; Dissociative electron attachment ; Clonogenic assay ; MTT test ; Cell cycle

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8-Bromo-2'-deoxyadenosine

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8-Bromo-2'-deoxyadenosine

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