Synthesis and In Silico and In Vitro Antitumor Potential of Novel Organochalcogens Derived from Azidothymidine and 2,4,6-Trichloro-1,3,5-triazine

Abstract

The preparation of a new class of organochalcogen compounds derived from arylchalcogeno aminothymidine (ACAT) and 2,4,6-trichloro-1,3,5-triazine is described. The compounds were obtained in good yields via aromatic nucleophilic substitution reactions between ACAT derivatives and the triazine ring. The developed protocol selectively afforded monosubstituted derivatives, avoiding the formation of di- and trisubstituted isomers. Antitumor activity was evaluated against HT-29 (human colorectal adenocarcinoma) and NCI/ADR-RES (multidrug-resistant human ovarian carcinoma) cell lines using the MTT assay. Sulfur- and selenium-containing derivatives showed only moderate cytotoxic effects, reducing cell viability mainly at the highest tested concentration (100 μM). In contrast, tellurium-containing derivatives exhibited pronounced cytotoxic activity, with minimum IC50 values of 9.90 μM in HT-29 cells and 12.18 μM in NCI/ADR-RES cells, demonstrating notable efficacy against multidrug-resistant tumor cells. In addition, the antioxidant properties of the compounds were investigated in vitro. Tellurium derivatives displayed significant antioxidant activity, as demonstrated by inhibition of lipid peroxidation in the TBARS assay and by thiol-peroxidase (GPx-like) activity. A possible mechanism of action based on tubulin polymerization inhibition was investigated by means of a molecular docking study. The results demonstrate the potential of these novel organochalcogen compounds as antitumor agents, highlighting tellurium incorporation as a promising strategy to overcome multiple drug resistance (MDR) in cancer.