Perhaps the most extensively employed of all phosphotyrosine analogs is the difluorophosphonate derivative 20. The synthesis of this analog was first described by Burke and his colleagues (Smyth et al. 1992; Burke et al. 1993) and was subsequently introduced into peptides and evaluated as SH2 ligands in 1994 (Burke et al. 1994; Gilmer et al. 1994). The phosphonate moiety is not only resistant to hydrolysis by adventitious intracellular phosphatases, but the electron-withdrawing effect of the difluoro substituents ensures that the phosphonate is doubly ionized at physiological pH. In addition to the difluoromethylene moiety, a variety of other groups have been used to link the phosphoryl moiety to the aromatic nucleus, including methylene, hydroxymethylene, and fluoromethylene (Burke et al. 1994). The -OPO3H group on phosphotyrosine has also been replaced with -CH2COOH (Gilmer et al. 1994; Tong et al. 1998), -OCH2COOH (Burke et al. 1999), -CHOHCOOH (Beaulieu et al. 1999), -CF2COOH (Burke et al. 1999), -CH2SO3H (Gilmer et al. 1994), -CH2CH2COCOCH3 (Gilmer et al. 1994), and NO2 (Gilmer et al. 1994). In addition, the phosphoryl group has been directly attached to the aromatic ring (i.e., no bridging group) (Stankovic et al. 1997). A number of geminal analogs [e.g., 21 (Bohacek et al. 2001) and 22 (Kole et al. 1995; Ye et al. 1995)] have been prepared and examined as well. Although the general statement that peptides containing 20 in place of phosphotyrosine possess the greatest affinity for their intended targets may be true, there is sufficient variability among the protein-binding domains that any generalization concerning binding preferences is dangerous. For example, the monocarboxylic acid analogs of phosphotyrosine appear to have reasonable affinity for cer tain SH2 domains, but are poor inhibitors for the protein tyrosine phosphatase family member PTP1B (Gao et al. 2000).
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