Phosphate mimics

Phosphates are often poor drug candidates29 due to their instability in biological fluids and inability to penetrate cell membranes. As a result, we focused our efforts on the discovery of suitable phosphate mimics. In these studies we evaluated various analogs with well-known phosphate replacements (Figure 4), namely phosphonate (3), sulfate (4), carboxylate (5) and dicarboxylate (6). 

Lindell and Turner have subsequently applied the methodology to the synthesis of diflu-oromethylene phosphonates for evaluation as inhibitors of aspartate transcarbamoylase (equation 110)152. Similarly, Chambers and coworkers utilized this method in the preparation of 2-amino-l,l-difluoroethylphosphonic acid, a phosphate mimic (equation 111)153. 

Although these probes show potent, heat-sensitive labeling profiles with purified tyrosine phosphatases, suggestive of specific active site modification, their use in complex proteomes was not reported [109]. Zhang and coworkers introduced a more specific class of tyrosine phosphatase probe [110]. This probe consists of an a-bromobenzylphosphonate moiety that acts as a tyrosine phosphate mimic and a mechanism-based inhibitor of tyrosine phosphatases. The chemistry of the probe mode of action is shown in Scheme 7. 

Salts of the tetrafluoroaluminate (TFA) anion have been known for many years. Yet aqueous routes to pure materials have not been established despite the substantial amount of literature available on the subject. The present review will discuss the various synthetic methods that have been employed and will demonstrate a revised method for preparing pure TFA salts. These materials are important because TFA is able to stimulate various guanosine nucleotide-binding proteins (G-proteins) and inhibit P-type ATPases by serving as a nonhydrolyzing phosphate mimic. Additionally, various TFA salts serve as precursors to aluminum trifluoride, which is used as a catalyst for chlorofluorocarbon isomerizations and fluorinations. 

Figure 2 Traditional phosphorus-, sulfur-, and carboxylate-containing replacements for the phosphate group, along with the more recently discovered cyclic phosphate mimics.

Table 1 A comparison of bond angles, bond lengths, and Kia valnes for phosphates, phosphonates, and flnorinated analogs (9, 22) illnstrates the problems with using phosphonates as phosphate mimics ...

Cyclic phosphate mimics tetronic acid derivatives... 

Cyclic phosphate mimics squaric acid-based motifs... 

Cyclic phosphate mimics thiazolidinones and rhodanines (thioxothiazolidinones)... 

Cyclic phosphate mimics do they really mimic the phosphate group ... 

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