Barbituric Acid Derivatives as Protein Tyrosine Phosphatase Inhibitors

Abstract

Scheme 2. Synthesis of benzaldehyde derivatives. Reagents and conditions: (a) K2CO3, DMF, rt, 1 4 h, > 85%, (b) morpholine, Et3N, THF, rt, 3 h, 95%, (c) N-bromosuccinimide, CCl4, reflux, 4 h, 56%, (d) CH3OCH2Cl, K2CO3, acetone, 0 oC → rt, 4 h, 53%, (e) 6 M HCl, THF, 50 oC, 2 h, >80%, (f) K2CO3, acetone, reflux, 2 h, 68%, (g) N,Ndiisopropylethylamine, DMF, 0 oC → rt, 2 h, > 95% Barbiturates infer derivatives of barbituric acid. Commonly used barbiturates like phenobarbital and secobarbital have substituents at the 5 position on this basic skeleton. Barbiturates slow down central nervous system (CNS) functions and have been used to treat medical conditions such as epileptic seizures and as anesthesia for surgical procedures. Beside the effects as CNS depressants, barbiturates have been shown to exhibit wide variety of other biological activities, including anti-tumor activities, immuno-modulating activities, herbicidal or insecticidal activities, PPARγ agonistic activities, and inhibitory activities against mucosal addressin cell adhesion molecule-1 interactions. Notably, barbiturates, including phenobarbital and secobarbital, were also found to inhibit the phosphatase activity of calcineurin, a protein Ser/Thr phosphatase. In view of this observation, we considered the barbituric acid moiety as a candidate scaffold for the design of protein tyrosine phosphatase (PTP) inhibitors. PTPs, together with protein tyrosine kinases, are key regulators of the phosphorylation of proteins involved in cellular signal transduction pathways. The importance of the regulated protein phosphorylation is evidenced by the recognition of a wide variety of diseases accompanied by the disturbances in the phosphorylation states of cellular proteins. Suggested as a strategy