Investigation of Isoindolo[2,1-a]quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods.

Background: Isoindolo[2,1-a]quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning.

Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-a]quinoxalin-6-imines, by comparing them with known inhibitors.

Methods: Different X-ray crystallographic structures with co-crystallized inhibitors were investigated and their binding modes were analyzed. The structures of the inhibitors were also compared through a pharmacophore analysis. As a validation of our docking method, the co-crystallized inhibitors were re-docked.

Conclusion: Our docking studies performed on Isoindolo[2,1-a]quinoxalines and other inhibitors revealed very important common features responsible for topoisomerase I inhibition that can improve the design of new inhibitors.