Phosphotyrosine Mimetics

Hajduk PJ, Zhou MM, Fesik SW, NMR-based discovery of phosphotyrosine mimetics that bind to the Lck SH2 domain, Bioorg. Med. Chem. Lett., 9 2403-2406, 1999. 

Qabar, M. N., Urban, J., and Kahn, M. (1997) A facile solution and solid phase synthesis of phosphotyrosine mimetic L-4-[diethylphosphono(difluoromethyl)]phe-nylalanine (F2Pmp(EtO)2 derivatives. Tetrahedron 53, 11,171-11,178. 

Lu, W., Gong, D., Bar-Sagi, D., and Cole, P. A. (2001) Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling. Mol. Cell 8, 759-769. 

Liu, W.-Q., Roques, B.R, and Garbay, C., Synthesis of L-2,3,5,6-tetrafluoro-4-(phosphonomethyl)phe-nylalanine, a novel non-hydrolyzable phosphotyrosine mimetic and L-4-(phosphonodifluorome-thyl)phenylalanine. Tetrahedron Lett., 38, 1389, 1997. 

Chu CY, Chang CP, Chou YT, Handoko HYL, Lo LC, Lin JJ (2013) Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein. J Med Chem 56 2841-2849... 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

M.R. Groves, Z.J. Yao, P.P. Roller, T.R. Burke Jr, D. Barford, Structural basis for inhibition of the protein tyrosine phosphatase IB by phosphotyrosine peptide mimetics. Biochemistry 37 (1998) 17773-17783. 

Smyth, M. S., Ford, H. Jr., and Burke, T. R. Jr. (1992) A general method for the preparation of benzylic alpha, alpha-difluorophosphonic acids non-hydrolyzable mimetics of phosphotyrosine. Tetrahedron Lett. 33, 4137-4140. 

Wrobel, J. and Dietrich, A. (1993) Preparation of L-(phosphonodifluoromethyl) phenylalanine derivatives as non-hydrolyzable mimetics of O-phosphotyrosine. Tetrahedron Lett. 34, 3543-3546. 

Vanadate (VOj or H2VO4 ) was first recognized in 1979 as having insulin mimetic properties [258]. Since then, vanadate and vanadyl (V ) have been shown to mimic most but not all biological actions of insulin in vitro and to lower blood glucose in streptozotocin-treated rats [259, 260]. Vanadate is a potent inhibitor of phosphotyrosine phosphatases, an interesting activity since the insulin receptor is a tyrosine kinase, and some of the actions of insulin have been proposed to take place via autophosphorylation of the insulin receptor and phosphorylation of cellular substrates on tyrosine residues [261]. Some recent developments on the mechanism and the in vivo activity of vanadate and its derivatives are presented here. 

The cellular and in vivo use of natural phosphoamino acid-containing peptides has severe limitations because, in addition to the poor chemical stability of the 0-phosphate group, they are subjected to dephosphorylation by phosphatases and are poorly absorbed into cells. These circumstances and the potential therapeutic use of compounds containing enzymatically and chemically stable phosphoamino acid isosteres have motivated the synthesis of phosphoamino mimetics. Figure 20 shows some selected examples of phosphotyrosine (44 [175-177], 45 [176], 46 [178], 47 [179], 48-49 [177], 50 [180], 51 [177], 52 [181], 53 [182], 54 [183], 55-56 [184,185], 57 [186]), phosphoserine (58 [187], 59 [188], 60 [189,190], and phosphothreonine (61 [191]) mimetics. These building blocks have been incorporated into peptides and peptidomimetics by solid-phase synthesis using standard procedures [175,179,182,183,189,192-198]. 

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