5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases (original) (raw)
Related papers
2014
Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl] benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IRb phosphorylation and 2-deoxyglucose cellular uptake.
Diabetes is a metabolic disorder wherein blood glucose level is increased along with some other abnormal conditions like polyuria, polydipsia and polyphagia. As per WHO estimation, 380 million people will become diabetic by 2025. Tyrosine residues are selectively dephosphorylated by Protein tyrosine phosphatases (PTPs) and thus a wide variety of cellular processes are regulated by their action. Protein tyrosine phosphatase 1B (PTP1 B) has shown to be a negative regulator in the insulin signaling pathways. Recent gene knockout studies carried out on mice portrays PTP1B as an effective target for drug discovery process related to anti-diabetic and anti-obese agents. PTPs are also involved in several other disorders like cancer. The structure of compounds synthesized by the present method were confirmed by TLC, IR, NMR and Mass spectroscopy. The anti-diabetic activity of the synthesized compounds were tested against PTP1B enzyme by using Calbiochem® PTP1B colorimetric assay kit. Among all synthesized compounds 4c, 4d, 4e, 4f had shown promising anti-diabetic activity, while other compounds have shown lesser potency as anti-diabetic agent.
Cellular Inhibition of Protein Tyrosine Phosphatase 1B by Uncharged Thioxothiazolidinone Derivatives
ChemBioChem, 2007
The control of cellular tyrosine phosphorylation levels requires the precise balance of protein tyrosine kinase (PTK) and phosphatase (PTP) activities. Similar to the expression of oncogenic PTKs, [1] nonspecific inhibition of PTPs results in a massive increase in cellular phosphotyrosine content. [2] The human PTP superfamily consists of over 100 cysteine-dependent enzymes. [3] They contain a range of noncatalytic motifs and domains that typically mediate protein-protein interactions or target PTPs to particular subcellular compartments. [3] Individual PTPs play specific roles in cellular signal transduction, including the regulation of metabolic and mitogenic signaling, cell A C H T U N G T R E N N U N G adhesion and migration, and gene transcription. The mutation or genetic ablation of PTPs in mice causes generally adverse phenotypes, often involving immune [4, 5] or neuronal development [6, 7] effects. However, one notable exception is PTP1B (EC 3.1.3.48). Mice lacking this enzyme are healthy and display resistance to diet-induced diabetes and obesity, [8, 9] this is likely to be due to its function as a negative modulator of insulin [10] and leptin [11] signaling. This phenotype generated interest in PTP1B as a drug target for type II diabetes. Indeed, numerous small-molecule PTP1B inhibitors with varying specificity and cell-permeability have been reported. [12, 13] The PTP catalytic mechanism involves nucleophilic attack by an anionic cysteine residue on the phosphotyrosyl phosphate group. [14] This cysteine, part of the PTP signature motif, HC(X)5R, is situated at the base of a flexible active site pocket. By crystallography, similar binding interactions have been reported for PTP1B in complex with phosphotyrosine and peptide substrates. [15-17] Specifically, the phenyl ring of the substrate phosphotyrosine forms aromatic-aromatic interactions with Y46, at one side of the pocket, and F182, which is part of [a] M. Stuible, I.
Bioorganic & Medicinal Chemistry, 2006
The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure-activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation.
Diabetes is a group of metabolic diseases which characterized by increased blood glucose level along with polyuria, polydipsia and polyphagia. Protein tyrosine phosphatases (PTPs) are responsible for selective dephosphorylation of tyrosine residues and regulate a wide variety of cellular processes. Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin and leptin signal-transduction pathways. PTP1B inhibitors have emerged as attractive and potent pharmaceutical agents for the treatment of type-2 diabetes, obesity as well as in cancer therapy. As per literature survey and referred patients, the various derivatives of 4-carboxy benzamide were prepared and confirmed by Mass, NMR, IR and by their physiochemical data. The anti diabetic activity of the synthesized compounds was tested against streptozotocin induce diabetic model. Among them 4-(3-(4-methyl phenyl)-2-(piperazine-1-yl) acrylamido) benzoic acid and 4-(3-(4-methyl phenyl)-2-(piperidine-1-yl) acrylamido) benzoic acid was more active due to presence of methyl group presence in para position and increase compound stability by lipophilic binding with enzyme while other methoxy derivatives of 4-carboxy benzamide shows moderate active due to less liphophilic binding with PTP 1B enzymes.
European Journal of Medicinal Chemistry, 2012
The ethyl 2-(6-substituted benzo[d]thiazol-2-ylamino)-2-oxoacetate derivatives (OX 1e9) were prepared using a one-step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds OX-(1, 6 and 7) were rapid reversible (mixed-type) inhibitors of PTP-1B with IC 50 values in the low micro-molar range. The most active compounds OX-(1, 6 and 7) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the oxamate group in all compounds and the catalytic amino acid residues Arg221 and Ser216. The compounds were evaluated for their in vivo hypoglycemic activity, showing significant lowering of plasma glucose concentration in acute normoglycemic model and oral glucose tolerance test similarly at the effect exerted for hypoglycemic drug glibenclamide.
Bioorganic & Medicinal Chemistry, 2009
The 2-arylsulfonylaminobenzothiazole derivatives 1-27 were prepared using a one step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds 4 and 16 are rapid reversible (mixed-type) inhibitors of PTP-1B with IC 50 values in the low micromolar range. The most active compounds (4 and 16) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the nitro group in both compounds and the catalytic amino acid residues Arg 221 and Ser 216. Both compounds were evaluated for their in vivo antihyperglycemic activity in a type 2 diabetes mellitus rat model, showing significant lowering of plasma glucose concentration, during the 7 h post-intragastric administration.
International journal of molecular sciences, 2013
Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 μΜ. Its IC50 values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine th...