Multicomponent synthesis of new 5‐thiourea‐4‐aza‐2,3 didehydropodophyllotoxins as potent cytotoxic agents

Abstract

In this report, we have described the concise elaboration of 12 novel 5‐thiourea‐4‐aza‐2,3‐didehydropodophyllotoxin‐derivatives by the unconventional multicomponent reaction was based on a catalyst‐free and atom‐economical method. The synthetic approach features methodology using sulfur element in thiourea synthesis. Cytotoxicity of compounds was evaluated for their inhibition rate of cell growth against two human tumor cell lines (MCF‐7 and Hep‐G2). Some new 5‐thiourea‐4‐aza‐2,3‐didehydropodophyllotoxin such as 15a, 15d, 15l exhibit very good cytotoxicity and much more stronger than their precursor 5 amino‐4‐aza‐2,3‐didehydropodophyllotoxin. The number and chemical characters of the Cα substituents of the thiourea group may have a decisive role in the activity of the molecules. Docking studies of the tested molecules proved that compound 15a, 15d, 15l exhibit high binding affinity toward human topoisomerase II beta in compare to the reference inhibitor, etoposide. Further dock pose analysis sugessted these molecules as potential inhibitors‐based on their key interaction with residues within binding site of the protein.