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

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

Volume: 13 Issue: 3

Author(s): Balazs Balogh*, Anna Carbone, Virginia Spanò, Alessandra Montalbano, Paola Barraja, Stella Cascioferro, Patrizia Diana and Barbara Parrino*

Affiliation:

• Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7, H-1092 Budapest,Hungary

• Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo,Italy

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

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.

Cite this article as:

Balogh Balazs*, Carbone Anna, Spanò Virginia, Montalbano Alessandra, Barraja Paola, Cascioferro Stella, Diana Patrizia and Parrino Barbara*, Investigation of Isoindolo[2,1-a]quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods, Current Computer-Aided Drug Design 2017; 13 (3) . https://dx.doi.org/10.2174/1573409913666170124100334

DOI https://dx.doi.org/10.2174/1573409913666170124100334	Print ISSN 1573-4099
Publisher Name Bentham Science Publisher	Online ISSN 1875-6697