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

Abstract

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-β-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 μM against lung cancer A549 cells.