Tyrosine phosphatase inhibitors

Scheme 10.7 Protein tyrosine phosphatase inhibitor assay.

Umezawa K, Kawakami M, Watanabe T. Molecular design and biological activities of protein-tyrosine phosphatase inhibitors. Pharmacol Ther 2003 99 15-24. 

Already in 1982, it was suggested that the intermediate chromium(V) state is involved in the carcinogenic process.9 Reactive Cr(V) and Cr(IV) intermediates may be harmful in many ways acting as tyrosine phosphatase inhibitors, or by forming organic radicals upon reaction with cellular reductants, which in turn can react with O2 and lead to reactive oxygen species.10 Reaction of chromium(VI) with... 

In the search for novel orally active hypoglycemic agents, a team from Hoffmann-LaRoche used the readily available (see Section 10.20.9.2.3) chloromethylpyrimido[4,3-( ]-l,2,4-triazine 86 as a starting material for the synthesis of the protein tyrosine phosphatase inhibitors 87 (individual yields were not detailed), as shown in Equation (12) <2003BML2895>. 

The piperazine-substituted pyrimido[5,4-< ][l,2,4]triazine 103 undergoes selective reaction with benzylic halides to provide the benzylic piperazinyl analogues 104 <2003BML2895> as shown in Equation (15). The products are protein tyrosine phosphatase inhibitors. 

Support-bound, enantiomerically pure alcohols can be converted into phosphonates by Mitsunobu esterification, which results in complete inversion at the stereo-genic center. This strategy has been used to prepare peptidyl phosphonates on solid phase. These are interesting transition-state analogs with potential utility as peptidase inhibitors (Figure 11.3 [12,13]) or tyrosine phosphatase inhibitors [14]. Serine or threonine derivatives can be converted into phosphonates by direct phosphonylation with an activated monoalkyl phosphonate [15] or by treatment with phosphonamidites RP(OR)NR2 in the presence of tetrazole followed by oxidation [16]. 

Vazquez, J., Tautz, L., Ryan, J. J., Vuori, K., Mustelin, T., and Pellecchia, M. (2007). Development of molecular probes for second-site screening and design of protein tyrosine phosphatase inhibitors. Journal of Medicinal Chemistry 50, 2137-2143. 

Tsiani, E., E. Bogdanovic, A. Sorisky, L. Nagy, and I.G. Fantus. 1998. Tyrosine phosphatase inhibitors, vanadate and pervanadate, stimulate glucose transport and GLUT translocation in muscle cells by a mechanism independent of phosphatidyli-nositol 3-kinase and protein kinase C. Diabetes 47 1676-1686. 

Fleming, I., Bauersachs, J., Fisslthaler, B., and Busse, R. 1998. Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress. Circ. Res. 82 686-695. 

Chen YT, Seto CT. Parallel synthesis of a Ubrary of bidentate protein tyrosine phosphatase inhibitors based on tiie a-ketoacid motif. Bioorg. Med. Chem. 2004 12 3289-3298. 

Tautz L, Mustelin T (2007) Strategies for developing protein tyrosine phosphatase inhibitors. Methods 42 250-260... 

Taha MO, Bustanji Y, Al-Bakri AG et al (2007) Discovery of new potent human protein tyrosine phosphatase inhibitors via pharmacophore and QSAR. analysis followed by in sUico screening. J Mol Graph Model 25 870-884... 

Chen L, Sung SS, Yip ML et al (2006) Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Mol Pharmacol 70 562-570... 

Sobhia ME, Paul S, Shinde R et al (2012) Protein tyrosine phosphatase inhibitors a patent review (2002—2011). Expert Opin Ther Pat 22 125-153... 

Evaluating Effects of tyrosine Phosphatase Inhibitors on T Cell Receptor Signaling... 

Functionalisation of the isothiazol-3-one S,S-dioxide system at C-5 provided several interesting derivatives. An example regarding the synthesis of some protein tyrosine phosphatase inhibitors [56] is reported below in... 

In 2000, Otani et al. isolated two furano-o-naphthoquinones, (-)-nocardione A and (—)-nocardione B (142 and 143, Figure 5.27 and 5.28) as new tyrosine phosphatase inhibitors with moderate antifungal and cytotoxic activities. Due to the scarcity of the materials (only 8 mg of 142 and 0.3 mg of 143 were obtained from 4.5 L of the culture broth of Nocardia sp. TP-AO 248), their absolute configuration remained unknown. In order to solve this problem, we undertook a synthesis of optically active 142 and 143 with known absolute configuration.35... 

Protein tyrosine phosphatases play a crucial role in the control of the activity of receptor tyrosine kinases, nonreceptor tyrosine kinases, and the signaling pathways that they regulate. The importance of the tyrosine phosphatases for receptor tyrosine kinase signaling is illustrated by the observation that virtually all receptor tyrosine kinases can be activated, even in the absence of ligand, by treatment of cells with tyrosine phosphatase inhibitors, demonstrating that the activity of tyrosine kinases is continuously controlled by inhibitory tyrosine phosphatase action. As outlined above, the activity of most receptor tyrosine kinases is positively controlled by Tyr-phosphorylation in the activation loop. Protein tyrosine phosphatases that remove these stimulatory phosphate residues will inhibit receptor activity and the biological responses mediated by Tyr-phosphorylation-dependent signaling pathways. 

The pyrrole nucleus is commonly found in biologically active lead compounds and designed analogs, and two out of many recently published examples will be mentioned here. The pyrrole core structures of roseophilin and prodigiosin have been studied as protein tyrosine phosphatase inhibitors <04CBC1575>. A new class of 2-vinylpyrroles, 6-pyrrolyl-2,4-dioxo-5-hexenoic acids, were found to be active HIV-1 integrase inhibitors <04BMCL1745>. 

Inhibitors of serine/threonine phosphatases, such as okadaic acid or microcystin, can be used to investigate the effects of serine/threonine phosphorylation on kinase targeting. Tyrosine phosphatase inhibitors can be used to investigate the effect of tyrosine phosphorylation on kinase targeting in a specific cell type. For example, orthovanadate has been shown to induce translocation of the immunoreactivity of phospholipase C gamma from the cytosolic to the membrane fraction of mast cells (Atkinson et al, 1993). Conversely, in permeabilized preparations, the phosphatases themselves, if known, can be added to inhibit the putative pathway. 

Strategies for Designing Specific Protein Tyrosine Phosphatase inhibitors and Their intraceiiuiar Activation... 

Kim JH, Do HJ, Wang WH, Machaty Z, Han YM, Day BN, Prather RS. 1999a. A protein tyrosine phosphatase inhibitor, sodium orthovanadate, causes parthenogenetic activation of pig oocytes via an increase in protein tyrosine kinase activity. Biol Reprod 61(4) 900-905. 

He Y, Zeng L-F, Yu Z-H, He R, Liu S, Zhang Z-Y. Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors. Bioorg. Med. Chem. 2012 20 1940-1946. 

Elastin gene expression in rat lung fibroblasts was selectively inhibited by okadaic acid (Berk et al. 1996). In vitro, 5 nM had minimal effects (91 % control values) on elastin mRNA levels okadaic acid at 25 nm and 50 nm decreased elastin mRNA to 23 and 6 % of control levels, respectively. Inhibition of protein synthesis with cycloheximide did not block okadaic add-induced suppression of elastin mRNA levels. Okadaic acid had minimal effect of rat GTP-binding protein mRNA levels. Sodium orthovanadate, a tyrosine phosphatase inhibitor, induced minor decreases in elastin mRNA levels at micromolar concentration. Protein kinase C desensitisation by prolonged exposure to phorbol 12-myristate 13-acetate did not alter the effect of okadaic add on elestin mRNA levels. 

Diperoxovanadate, a synthetic diperoxovanadium compound and cell-permeable oxidant that acts as a protein tyrosine phosphatase inhibitor and insuli-... 

Antileishmanial activity Antimalarial activity Antitripanosomal activity Analgesic activity Antimicrobial activity Blockage of the dopaminergic receptors Spasmolitic activity Stimulant of the CNS Cytotoxic activity CD45 protein tyrosine phosphatase inhibitor... 

In situ click chemistry was used to assemble inhibitors for acetylcholinesterase derived from tacrine and phenylphenanthridinium azides. The in situ generated inhibitors were extremely potent acetylcholinesterase inhibitors and care should be observed in handling these neurotoxic compounds. A potent inhibitor of human o -l,3-fucosyltransferase was similarly identified from a 1,2,3-triazole library of 85 compounds prepared by the [3-1-2] cycloaddition reaction of azides with terminal alkynes . Also, protein tyrosine phosphatase inhibitors are synthesized in a similar manner. ... 

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