Of phosphotriesters

A major problem in the development of phosphotriester syntheses has been the lack of appropriate condensing agents. DCC cannot be used, because it will not activate phosphodi-... 

Solodin I, Brown CS, Heath TD (1996) Synthesis of phosphotriester cationic phospholipids. Cationic lipids 2. Synlett 5 457-458... 

Fig. 3.29 31P-NMR (121 MHz) of phosphotriesters 5 and 6 in the absence (A) and presence (B) ofLUVs and after addition ofMn2+ ions. (Reprinted from Fig. 2 of ref. 116 with permission from the American Chemical Society.)...

Pirrung, M.C. and Shuey, S.W. (1994) Photoremovable protecting groups for phosphorylation of chiral alcohols. Asymmetric synthesis of phosphotriesters of (—)-3, 5 -dimethoxybenzoin. Journal of Organic Chemistry, 59, 3890-3897. 

Givens58 and Pirrung59 used photolabile 3 3 -dimethoxybenzoin esters for the protection of phosphotriesters. A complication attending the use of racemic 3 5 dimethoxybenzoin is the generation of four diastereoisomers if the phosphate is chiral. An asymmetric synthesis of 3, 5 -dimethoxybenzoin 303 [Scheme 7.30] via the 0-trimethylsilyl-3,5-dimethoxybenzaldehyde cyanohydrin 303 minimises the number of diastereoisomers created in the phosphorylation of chiral alcohols. Thus reaction of 303 with 2 - cyanoethoxy)(NPNf-diisopropy amino)-chlorophosphine afforded the phosphoramidite 30.4 which then reacted with Boc-Ser-OMe to give the two diastereoisomeric phosphotriesters 303, Photode-... 

The phosphotriesterase from the soil bacterium Pseudomonas diminuta is the only one that has been well characterized. The natural substrate for this enzyme is unknown it hydrolyzes a large number of phosphotriester substrates, but the best substrate is paraoxon.244 Phosphomonoesters are not substrates, and diesters are hydrolyzed only at greatly reduced rates.245... 

Perigaud has extended his work on the synthesis and biological activities of phosphotriester derivatives of AZT bearing a phenyl group or L-tyrosinyl residues. The novel AZT-derivatives (21a-d) also incorporating one S-pivaloyl-2-thioethyl residue were obtained via either P(III) or P(V) chemistry from the appropriate aryl precursors and evaluated for their in vitro anti-HIV activity. ECso values for their ability to inhibit HIV-1 replication in various cell culture experiments ranged between micro- and the nanomolar concentrations. S-Pivaloyl-2-thioethyl aryl phosphotriester derivatives of AZT were able to allow the efficient intracellular delivery of the parent nucleotide via their successive intracellular hydrolysis by an esterase and a phosphodiesterase. ... 

Sogorb, M.A., Vilanova, E., and Carrera, V., Future application of phosphotrieste-rases in the prophylaxis and treatment of organophosphorus insecticide and nerve agents poisonings, Toxicol. Lett., 151,219-233,2004. 

Pei, L., Omburo, G, McGuinn, W., D., et al., Encapsulation of phosphotrieste-rase within murine erythrocytes, Toxicol. Appl. Pharmacol., 124,296-301,1994. 

The hope that promiscuity is predictable is also supported by the identification of systematic patterns of promiscuity. For example, lactonases, and in particular lactonases that favor hydrophobic lactones, show a consistent tendency to promiscuously catalyze the hydrolysis of phosphotriesters. This pattern has now been seen in lactonases from three different superfamilies PLLs (TIM-barrels from the amidohydrolase superfamily Table 1, entry 11) PONs, or serum paraoxonases (calcium-dependent six-bladded /3-propellers Table 1, entry 13) and AHA (a lactonase from the metallo-/3-lactamase superfamily Table 1, entry 12). That very different scaffolds and active-sites configurations share the same promiscuity pattern suggests that these reactions share a key feature, probably in the geometry of their transition states. This feature must be distinct, also because many of these lactonases do not hydrolyze esters that are much closer to lactones than phosphotriesters, and should thus be amenable to structural analysis and prediction. 

The monomeric metaphosphate anion has also been directly observed in the gas phase by mass spectrometry (107). Ramirez and co-workers have utilized the negative ion chemical ionization technique to study the fragmentation of phosphotriesters. In many of these spectra, a prominent peak occurs at mie = 79 exact mass measurements of this peak confirm that it is P03. It is important to note, however, that all reactions where the metaphosphate anion has apparently been trapped have been conducted in nonaqueous media. 

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