Biosafety assessment of novel organoselenium zidovudine derivatives in the Caenorhabditis elegans model

Antiretrovirals have improved considerably since the introduction of 3′-azido-3′-deoxythymidine (zidovudine or AZT), a molecule with also anticancer effects. Subsequently, a variety of other nucleosides have been synthesized. However, these medications are often associated with serious adverse events and the onset or exacerbation of degenerative processes, diseases, and syndromes, affecting mainly the mitochondria. In this study, we used Caenorhabditis elegans to investigate the toxicity potential of AZT and three new organoselenium derivatives with modifications in the 5′ position of the sugar ring in place of the 5′-OH group, with the insertion of a neutral, an electron-withdrawing and an electron-donating group attached to the aryl selenol moiety: 5′-seleno-(4-chloro-phenyl)-3-(amino)-thymidine (ASAT-4-Cl), 5′-seleno-(phenyl)-3-(amino)-thymidine (ASAT-Ph), and 5′-seleno-(4-methoxyphenyl)-3-(amino)- thymidine (ASAT-4-OMe). Analyzes included worm survival, behavior parameters, high-resolution respirometry, citrate synthase activity, and ATP levels. Although all compounds negatively affected C. elegans, ASAT-4-Cl and ASAT-Ph showed lower toxicity compared to AZT, especially in mitochondrial viability and ATP production. Therefore, more studies must be carried out on the use of these new compounds as pharmacological interventions.