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

• Published in: Toxicology and applied pharmacology Vol. 491; p. 117045
• Main Authors: Baptista, Fabiane Bicca Obetine, da Silva, Aline Franzen, Cordeiro, Larissa Marafiga, de Souza, Larissa Ilha, da Silveira, Tássia Limana, Soares, Marcell Valandro, Michelotti, Paula, Corte, Cristiane Lenz Dalla, da Silva, Rafael Santos, Rodrigues, Oscar Endrigo Dorneles, Arantes, Leticia Priscilla, Soares, Félix Alexandre Antunes
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2024
• Subjects: Animals; Anti-HIV Agents - toxicity; C. elegans; Caenorhabditis elegans - drug effects; Chalcogen derivatives; Mitochondria; Mitochondria - drug effects; Organoselenium Compounds - pharmacology; Organoselenium Compounds - toxicity; Zidovudine; Zidovudine - toxicity; Chalcogen derivatives; C. elegans; Mitochondria; Zidovudine
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2024.117045

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.
•Investigations have been carried out into the toxicity of new chalcogen derivatives of AZT.•AZT was observed to reduce mitochondrial oxygen flux at the OXPHOS stage in C.elegans.•The derivatives with benzeneselenol insertion, ASAT-4-Cl and ASAT-Ph, were the least toxic.•ASAT-4-OMe was the most harmful derivative notably, the derivative containing the p-methoxyl group was found to be more toxic to mitochondria compared to AZT.