Phenylalanine phosphonates

Early work on the use of phenylalanine phosphonates in synthetic peptides as SH2 domain ligands and phosphotyrosine phosphatase inhibitors proved the efficicacy of these agents in medicinal chemistry [20, 22], Incorporation of phosphonomethylene alanine (Pma) and phosphonomethylene phenylalanine (Pmp) using nonsense-mediated suppression has also been shown to be feasible using in vitro translation [5], but this has not been used for practical applications, perhaps because of scale-up challenges. Pma and Pmp have not yet been used in vivo in nonsense suppression, presumably because of the limited cell permeability of the amino acids. 

Synthesis of N-Protected Phenylalanine (Difluoromethyl)phosphonic Acids... 

Synthesis of Peptides Using Fmoc-Protected Phenylalanine (Difluoromethyl)phosphonate Dialkyl Ester Derivatives... 

DNBLeu (covalent).5 Chiral phases S-Asp-artyl-S-phenylalanine methyl ester, N.N- Di-propyl-S-alanine cupric acetate. Phosphonates, aryl-sulphoxides, nitrogen heterocycles, di-B-naphthols. 

One of the most investigated type of reaction in the field of catalytic imprinted polymers, as indicated by the large number of publications available, is certainly ester hydrolysis. In particular, a great deal of work has been carried out on systems inspired by hydrolytic enzymes since 1987. In 2000, Shea et al. [37] reported the preparation of enantioselective imprinted polymers for the hydrolysis of N-tert-butoxycarbonyl phenylalanine-p-nitrophenyl ester (55), using a system already developed by the same group in 1994 [19]. The system was inspired by the natural hydrolytic enzyme chymotrypsin and polymerisable imidazole units (27) were used as functional monomers coupled via ester linkages to a chiral phosphonate (56), analogue of (d)- or (L)-phenyl-alanine. After template removal, the imprinted polymers showed selectivity towards the hydrolysis of the enantiomer with which they were imprinted. The ratio of the rate constants, k /k, was 1.9 for the polymer imprinted with the D-enantiomer and kjku was 1.2 for that imprinted with the L-enantiomer. Moreover, the imprinted polymer showed a 2.5-fold increase in the rate of the reaction when compared with the control polymer, imprinted with a... 

Racemic haptens have the advantage of synthetic expedience, but they do not always yield (R)- and (S)-specific catalysts in a single experiment. The eighteen catalytic antibodies obtained with the tripeptide phosphonate 6,14 for example, only catalyzed the hydrolysis of substrates (7) containing D-phenylalanine at the cleavage site. Depsipeptides containing leucine or tryptophan in place of phenylalanine were not hydrolyzed. The selectivity for d- over... 

C Appert, J Zoh, N Amrhein (2003) Kinetic analysis of the inhibition of phenylalanine ammonia-lyase by 2-aminoindan-2-phosphonic acid and other phenylalanine analogues Phytochemistry 62(3) 415-422... 

Lamothe, M., et al. (1996). Inhibition of farnesyl protein transferase by new farnesyl phosphonate derivatives of phenylalanine. Bioorg Med Chem Lett 6 1291-1296. 

Zont, J. and Amrhein, N. (1992) Inhibitors of phenylalanine ammonia-lyase 2-aminoindan-2-phosphonic acid and related compormds. Liebigs Ann. Chem., 625-8. 

Af-Fmoc L-F2Pmp(OEt)2-OH (5) is indexed within the ACS system under registry number 160751-44-0 bearing the chemical name, 4-(difluoro-di-ethyl-phosphono-methyl)-Af-[(9H-9-ylmethoxy)carbonyl]-L-phenylalanine. The associated chemical structure is currently incorrectiy given as the free phosphonic acid, A-Fmoc l-F2Pmp-OH (6). 

Figure 3 Phosphonomethyl phenylalanine (Pmp) and phosphonodifluoromethyl phenylalanine (F2Pmp) are nonhydrolyzable phosphotyrosyl (pTyr) mimetics. Flexameric peptide sequences that incorporate either Pmp or F2Pmp inhibit protein tyrosine phosphatase 1B. The difluoro- analogs are most potent, presumably because of their reduced pKa relative to the phosphonate.

A variety of phosphonate analogues of tyrosine phosphate and related structures have been reported. These include L-2,3,5,6-tetrafluoro-4-(phosphono-methyl)phenylalanine (236) which was obtained through alkylation of the... 

Lamothe, M., Perrin, D.. Blotieres, D., Leborgne, M., Gras, S., Bonnet. D., Hill, B.T., and Halazy, S., Inhibition of famesyl protein ti ansferase by new farnesyl phosphonate derivatives of phenylalanine, Bioorg. Med. Chem. Lett.. 6. 1291, 1996. 

The importance of SA in the activation of resistance was further underscored by the demonstration that otherwise resistant Arabidopsis plants become susceptible to Peronospora parasitica when phenylalanine ammonia lyase (PAL) activity is specifically inhibited by 2-aminoindan-2-phosphonic acid [77]. Since PAL catalyzes the first step in the SA biosynthetic pathway and resistance was restored in these PAL-suppressed plants by exogenous application of SA, increased susceptibility is presumably caused by a block in SA synthesis. Likewise, tobacco plants exhibiting epigenetic suppression of PAL gene expression due to cosuppression do not develop SAR in response to TMV infection [78]. In addition, these plants fail to systemically express the PR-la gene after TMV infection. 

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