Thiazolidinone Derivatives as Competitive Inhibitors of Protein Tyrosine Phosphatase 1B (PTP1B)

Abstract

Phosphorylation of tyrosine residues is an important mode of cellular regulation of enzyme activities and proteinprotein interactions.1,2 Reversible phosphorylation-dephosphorylation processes are controlled by two counteracting enzyme families: protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs).3 These enzymes are involved in diverse cellular processes, including cell growth, proliferation, differentiation, apoptosis, aging, immune response, and metabolism.4 The critical roles played by PTKs and PTPs in cellular functions implicate them in various human diseases. 5,6 Given that a PTP controls the duration of the phosphorylation state of a protein, suppression of the activity of the PTP could be an effective way to prolong the signal induced by tyrosine phosphorylation. For example, inhibition of PTP1B, a major phosphatase for insulin and leptin receptors, could augment the signals provoked by insulin and leptin, thus increasing insulin and leptin sensitivity.7-10 These notions were confirmed via numerous biological experiments, including the deletion of the PTP1B-encoding gene in mice.11,12 In our ongoing interest in developing the inhibitors of PTP1B, which is a therapeutic target for diabetes and obesity, we synthesized a series of thiazolidinone derivatives containing a single carboxylate moiety as a phosphate mimic, hoping that the presence of a monocarboxylate moiety could compromise the solubility and cell permeability of the compounds. The thiazolidinone derivatives were evaluated for their in vitro activity of PTP1B inhibition and in vivo efficacy against diabetes and obesity in an animal model.Thiazolidinone derivatives (ITZ1-18) were synthesized by the methods outlined in Scheme 1. Knoevenagel condensation of methyl rhodanine (B) with a benzaldehyde derivative (D) in the absence of a catalyst yielded 5-arylidene rhodanine (H), which was obtained exclusively as a (Z)-isomer as determined by the 1 H-NMR spectrum. The arylidene rhodanine (H) was subsequently treated with a variety of arylamines (G1-18) to obtain ITZ1-18.13 Commercially available amines (G1-5) were purchased, while others (G6-18) were prepared stating from 3-or 4-nitrophenol as shown in Scheme 1.Compounds ITZ1-18 were evaluated for their inhibitory activity against PTP1B. To determine the half-maximal inhibitory concentrations (IC 50 ), p-nitrophenyl phosphate (pNPP) hydrolase activity of PTP1B was measured in the presence of an inhibitor at a series of different concentrations. The IC 50 values for the ITZ compounds are summarized in Table 1. Six of the compounds (ITZ9-10 and ITZ14-17) exhibited IC 50 values in low micromolar concentration ranges. ITZ15 was the most potent with an IC 50 of 1.4 μM. Kinetic analysis of the inhibitory action of ITZ15, using a Lineweaver-Burk plot, demonstrated that ITZ15 was a competitive inhibitor of PTP1B (Figure 1).To obtain the selectivity profile of ITZ15, the inhibitory activity was determined against the human PTPs, T cell protein tyrosine phosphatase (TCPTP) and Src homology-2 ...

Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo‐functionalised 4‐aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions

“…Inverting the order of the synthetic sequence was similarly productive (5!10 [21] !9 a), and this latter approach was also applicable to hydantoin 6. S-Methylation of the Knoevenagel product 11 [22] was followed by a regioselective N-alkylation prior to formation of the aminide 15 (Scheme 1). [23] The putative nitrenoids were then tested in goldcatalysed annulations against some standard ynamides.…”