Design, synthesis, and computational explorations of novel 2-thiohydantoin nucleosides with cytotoxic activities

A novel series of S-alkylated, N-alkylated, and N-glycosylated 2-thiohydantoin derivatives were synthesized via the reaction of (E)-5-(arylidene)-1-phenyl-2-thiohydantoins 5a-d with alkyl halides/glycosyl bromides under aqueous, anhydrous alkaline/glycosylation conditions, respectively. The structures of the novel compounds were confirmed by elemental analyses and spectral data. Computational studies using DFT calculations with B3LYP/6-31 + G (d,p) level were performed to study the electronic and geometric properties obtained from the stable structure of the investigated compounds. A good correlation was found between the quantum chemical parameters and experimental observations. The synthesized derivatives exhibited good binding interactions towards the cyclin-dependent kinase 2, especially (E)-5-(chlorobenzylidene)-3-(2 ' 0.3 ' 0.4 ' 0.6 '-tetra-O-acetyl-beta-d-galactopyranosyl)-1-phenyl-2-thiohydantoin (11g), which have good key interactions such as the co-crystallized ligand. In addition, it had selective cytotoxic activities with IC50 = 12.4 mu M against lung cancer A549 cells.

Automated summary

A novel series of 2-thiohydantoin derivatives were synthesized and their structures were confirmed. Computational studies were conducted to investigate their properties, showing good correlation with experimental observations. These derivatives exhibited good binding interactions with cyclin-dependent kinase 2 and displayed selective cytotoxic activities against lung cancer cells.