Synthesis and Pharmacological Evaluation of 4-Iminothiazolidinones for Inhibition of PI3 Kinase

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doi:10.1071/CH12140

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Chemical Institute

Synthesis and Pharmacological Evaluation of 4-Iminothiazolidinones for Inhibition of PI3 Kinase

Jo-Anne Pinson ^A, Oleg Schmidt-Kittler ^B, Mark Frazzetto ^A, Zhaohua Zheng ^A, Ian G. Jennings ^A, Kenneth W. Kinzler ^B, Bert Vogelstein ^B, David K. Chalmers ^A and Philip E. Thompson ^A ^C

^A Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Vic. 3052, Australia.
^B The Ludwig Center for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute and The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
^C Corresponding author. Email: philip.thompson@monash.edu

Australian Journal of Chemistry 65(10) 1396-1404 http://dx.doi.org/10.1071/CH12140
Submitted: 7 March 2012 Accepted: 18 April 2012 Published: 10 July 2012





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Abstract

The thiazolidinedione, compound 1, has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound 1 could 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.

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