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

[ Vol. 13 , Issue. 3 ]

Author(s):

Balazs Balogh, Anna Carbone, Virginia Spanò, Alessandra Montalbano, Paola Barraja, Stella Cascioferro, Patrizia Diana and Barbara Parrino   Pages 208 - 221 ( 14 )

Abstract:


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.

Keywords:

Topoisomerase I, quinoxaline, antiproliferative, topotecan, aromatechin, indenoisoquinoline, docking, pharmacophore model.

Affiliation:

Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7, H-1092 Budapest, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo

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