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

Abstract

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 IC 50 = 12.4 μM against lung cancer A549 cells.