title: Synthesis and Pharmacological Evaluation of 4-Iminothiazolidinones for Inhibition of PI3 Kinase.
abstract: The thiazolidinedione, compound1, has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound1could introduce isoform selectivity. We report the synthesis, characterization, and inhibitory activity of a novel series of 4-iminothiazolidin-2-ones for inhibition of the class I PI3K isoforms. Their synthesis was successfully achieved by multiple pathways described in this paper. Initial in vitro data of 28 analogues demonstrated poor inhibition of all class I PI3K isoforms. However, we identified an alternate target, the phosphodiesterases, and present preliminary screening results showing improved inhibitory activity.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Vic. 3052, Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Pinson
authors.forename: Oleg
authors.initials: O
authors.lastname: Schmidt-Kittler
authors.forename: Mark
authors.initials: M
authors.lastname: Frazzetto
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ian G
authors.initials: IG
authors.lastname: Jennings
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson