Phosphonic acids metabolism

Wackett LP, SL Shames, CP Venditti, CT Walsh (1987a) Bacterial carbon-phosphorus lyase products, rates and regulation of phosphonic and phosphinic acid metabolism. J Bacterial 169 710-717. 

Bisphosphonates are drugs of great interest in a number of metabolic bone diseases [119]. This therapeutic class comprises bis(phosphonic acids) and, more recently, bis(phosphonic acid) esters. The former are hydrophilic and poorly bioavailable, and they are generally not metabolized. In contrast, bis(phosphonic acid) esters may be more prone to biotransformation, as exemplified with the lead compound known as U-91502 (9.51 in Fig. 9.11). 

Fosetyl readily degrades to phosphonic acid (H3PO3) and carbon dioxide in aqueous solution, soil and plant tissue and phosphonic acid is considered to be the active and systemic principle through the disruption of phospholipid metabolism. 

Hydrolytic enzymes can also catalyzed the esterification of alcohols or acids with hetero atoms.1617 Some examples for the reactions of phosphorous and sulfur compounds by lipases are shown in Figure 16. By the repeated enantioselective acylation and hydrolysis of a hydroxyl phosphonate and its acetate with lipase AH, phosphonic acid analogue of carnitine (essential cofactor of fatty acid metabolism), (A)-phosphocarniiine, and its enantiomer were synthesized as shown in Figure 16 (b). 

FIGURE 52.1. Metabolic detoxification of warfare nerve agents tabun, sarin, soman, and VX in mammals in vivo. Chemical names of metabolites are EDMPA - ethyl dimethylaminophosphoric acid, IMPA - isopropyl methylphosphonic acid, PMPA - pinacolyl methyl-phosphonic acid, EMPA - ethyl methylphosphonic acid, and MPA - methylphosphonic acid. 

The range of phosphonic acids which can be utilized enzymically (at least by those enzymes present in Pseudomonas fluorescens) has recently been extended to include aminoalkyl-, hydroxyalkyl- and oxoalkyl-phosphonic acids, as well as phosphonodipep-tides only slight growth was seen with the herbicide glyphosate (A-phosphonomethyl-glycine (83), which is metabolized to (aminomethyl)phosphonic acid, and neither phos-phinothricin (84) nor its dialanyl tripeptide bialaphos supports growth in contrast to the behaviour of other bacterial extracts isolated from soil ". ... 

The phosphonic aeid moiety has been shown to be inhibitors of numerous metabolic processes [99,100], In recent years, S-adenosyl-L-homocystein hydrolase(AdoHcy) has become an attractive target for drug design since its inhibitors have been shown to exhibit antiviral [101], antiparasitic [102], antiarthritic [103], and immunosuppressive effects [104], Importantly, a-aminophosphonate diesters are more attractive as intermediates for multistep synthesis than the corresponding phosphonic acids. The insolubility of the latter in both organic and neutral aqueous media complicates derivation of both the amine and acid functionalities. 

Hildebrand, R.L., The Role of Phosphonates in Living Systems, CRC Press, Boca Raton, 1983. Hildebrand, R.L., Curley-Joseph, J, Lubansky, H.J., and Henderson, T.O., Biology of alkylphosphonic acids. A review of the distribution, metabolism, and structure of naturally occurring alkylphosphonic acids, in Topics in Phosphorus Chemistry, Vol. 11, John Wiley Sons, New York, 1983, pp. 297-338. Hudson, H.R., Quasi-phosphonium intermediates and compounds, in Topics in Phosphorus Chemistry, Vol. 11, John Wiley Sons, New York, 1983, pp. 339-436. 

Aminoethylphosphonic acid (P-ciliatine, ALP) HjN CH2 CHj P(0)(0H)2, is of particular interest because of its occasional occurrence in biological materials (Chapter 11.7). In the organism tetrahymena , 15% of the total phosphorus is present as ALP. It is also found in Japanese sea anemones and in some shellfish. Its biosynthesis and function are not at present completely understood, but phosphonates are currently of much interest in connection with possible alternative systems of metabolism (Chapter 11.7). 

H-Phosphonates of nucleosides are only weakly acidic and they may diffuse through cell membranes before oxidation to the 5 -monophosphate. The H-phosphonate of AZT (98) has been evaluated by two groups. Imbach and coworkers [111] have shown that (98) was metabolized to AZT in both cell culture medium and CEM cell extract. Consistent with this observation. 

We proposed a metabohc pathway of phosphonates with structure lo in plants when these compounds lo were initially designed. lo might be metabolized to substituted phenoxyacetic acids (lo-a) as auxin-type herbicide and acylphospho-nates (lo-c) as PDHc El inhibitors after the hydrolysis and oxidation by esterases and oxidases took place in plants (Scheme 1.21). 

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