title: Investigation of Isoindolo[2,1-a]quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7, H-1092 Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Balogh
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Spanò
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Montalbano
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: Cascioferro
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Parrino
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000494:pharmacology; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007097:Imines; D054833:Isoindoles; D011810:Quinoxalines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I
keywords: Topoisomerase I; antiproliferative; aromatechin; docking; indenoisoquinoline; pharmacophore
  model.; quinoxaline; topotecan