title: Cytotoxicity of thiazolidinedione-, oxazolidinedione- and pyrrolidinedione-ring containing compounds in HepG2 cells.
abstract: Liver damage occurred in some patients who took troglitazone (TGZ) for type II diabetes. The 2,4-thiazolidinedione (TZD) ring in TGZ's structure has been implicated in its hepatotoxicity. To further examine the potential role of a TZD ring in toxicity we used HepG2 cells to evaluate two series of compounds containing different cyclic imides. N-phenyl analogues comprised 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT); 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO) and N-(3,5-dichlorophenyl)succinimide (NDPS). Benzylic compounds, which closely resemble TGZ, included 5-(3,5-dichlorophenylmethyl)-2,4-thiazolidinedione (DCPMT); 5-(4-methoxyphenylmethyl)-2,4-thiazolidinedione (MPMT); 5-(4-methoxyphenylmethylene)-2,4-thiazolidinedione (MPMT-I); 5-(4-methoxyphenylmethyl)-2,4-oxazolidinedione (MPMO); 3-(4-methoxyphenylmethyl)succinimide (MPMS) and 3-(4-methoxyphenylmethylene)succinimide (MPMS-I). Cytotoxicity was assessed using the MTS assay after incubating the compounds (0-250μM) with HepG2 cells for 24h. Only certain TZD derivatives (TGZ, DCPT, DCPMT and MPMT-I) markedly decreased cell viability, whereas MPMT had low toxicity. In contrast, analogues without a TZD ring (DCPO, NDPS, MPMO, MPMS and MPMS-I) were not cytotoxic. These findings suggest that a TZD ring may be an important determinant of toxicity, although different structural features, chemical stability, cellular uptake or metabolism, etc., may also be involved. A simple clustering approach, using chemical fingerprints, assigned each compound to one of three classes (each containing one active compound and close homologues), and provided a framework for rationalizing the activity in terms of structure.
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Keil
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Frederick
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Erina Y
authors.initials: EY
authors.lastname: Jacinto
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Kennedy
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, USA; West Center for Computational Chemistry and Drug Design, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Zauhar
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: West
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Ruy
authors.initials: R
authors.lastname: Tchao
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, USA. Electronic address: p.harvis@usciences.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Harvison
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D010080:Oxazoles / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000633:toxicity*; D045162:Thiazolidinediones / Q000737:chemistry / Q000633:toxicity*
chemical_list: D010080:Oxazoles; D013388:Succinimides; D045162:Thiazolidinediones
keywords: Clustering; Cytotoxicity; HepG2 cells; Molecular fingerprints; Oxazolidinedione; Pyrrolidinedione; Succinimide; Thiazolidinedione; Troglitazone