Solvent-Free Synthesis, DNA-Topoisomerase II Activity and Molecular Docking Study of New Asymmetrically N,N'-Substituted Ureas

Abstract

A new series of asymmetrically N,N'-substituted ureas 20–25 was prepared using solvent free conditions, which is an eco-friendly methodology, starting with Schiff bases derived from cinnamaldehyde and p-substituted anilines, which are subsequently submitted to reduction reactions that afford the corresponding asymmetric secondary amines. All of the intermediates were prepared using solvent free reactions, which were compared to traditional methodologies. All of the reactions required a remarkably short amount of time and provided good yields when solvent free conditions were employed compared to other methodologies. The DNA-topoisomerase II-α (topo II-α) activity was evaluated in relaxation assays, which showed that all of the compounds inhibited the enzyme activity at 10 μM, except for urea 24. Furthermore, a molecular docking study indicated that the compounds 20–25 binding to the topo II-α are able to interact with the same binding site as the anticancer drug etoposide, suggesting that the ureas could inhibit the enzyme by the same mechanism of action observed for etoposide, which prevents re-ligation of the DNA strands.

New 1,3,4-Thiadiazole Derivatives with Anticancer Activity

“…Thiadiazole derivatives act through various molecular targets, for example, CA IX carbonic anhydrase, Src and Abl kinases, and topoisomerase II [ 30 , 31 , 32 ].…”

Synthesis, Cytotoxicity and Mechanistic Evaluation of 4-Oxoquinoline-3-carboxamide Derivatives: Finding New Potential Anticancer Drugs

“…This interaction seems to contribute to the stabilization of the complex formed by this ligand and the topoisomerase II. Similar to etoposide [24], these derivatives bind between the base pairs showed, possibly preventing their stacking and consequently blocking the re-ligation of the cleaved phosphodiester bond between the nucleotides. However, 17b showed no parallel position interactions when compared with 16b , probable due to the effect of ortho-chlorine substitution.…”

Untitled

“…Docking study: Docking studies were performed by means of Glide v5.6 21 . It performs grid-based ligand docking with energetics and searches for favourable interactions between one or more typically small ligand molecules and a typically larger receptor molecule, usually a protein 22 .…”