Phosphonoformates

One of the simplest molecules found to inhibit the repHcation of DNA vimses in animals is phosphonoformic acid [4428-95-9] (PEA, 1) CH O P. Both PEA (as the trisodium salt CNa O P, foscamet [63585-09-1] audits homologue phosphono acetic acid [4408-78-0] (PAA, 2) C2H O P, were developed by Astra Pharmaceuticals (6) and show selective inhibition of DNA polymerase in various herpes vimses. 

Phosphonoformic acid (85) decarboxylated in acid solution, and it was proposed that the uncatalysed reaction involved a simple decarboxylation of the zwitterion. The acid-catalysed reaction showed some kinetic similarity to that of mesitoic acid and an elimination of carbon dioxide as trihydroxymethylcarbonium ion was preferred. Participation of the trans vicinal phosphonyl group in the solvolysis of the halides (86) and (87) has been deduced from rate measurements. In the norbornene derivatives, the relative rates of loss of chloride from (87a) and (87b) were 5 x 10 1. 

Preparation of trisodium phosphonoformate — Reaction of a chloroformate with a trialkyl phosphite and cleavage of the ester linkages... 

Triethyl phosphonoformate was prepared by the dropwise addition of ethyl chloroformate (10.85 g, 0.1 mol) to triethyl phosphite (16.6 g, 0.1 mol) with vigorous stirring at ambient temperature. After the... 

To the resultant triethyl phosphonoformate (105 g, 0.5 mol) was added sodium hydroxide solution (250 ml, 10 M) over a period of 15 min at ambient temperature. The solution became hot, and ethanol by-product boiled off from the reaction mixture. Upon cooling, a precipitate formed, which was recrystallized from water to give colorless crystals of the pure trisodium phosphonoformate hexahydrate (27.5 g, 19%), which exhibited IR and NMR spectra and x-ray crystal analysis in accord with the proposed structure. 

Helgstrand, A.J.E., Johansson, K.N.G., Misiorny, A., Noren, J.O., and Stening, G.B., Aliphatic Derivatives of Phosphonoformic Acid, Pharmaceutical Compositions and Methods for Combating Virus Infections, European Patent 3,007, 1979. 

Issleib, K., Balszuweit, A., Moegelin, W., and Bertram, D., Phosphonoformates and thiophosphonoformates by conversion of bistrimethylsilyl hypophos-phite, East German Patent 219,198, 1985. 

Of interest in this section are phosphonates (R-P(=0)(-OR )(-OR")), including bisphosphonates (R-CH(P03H2)2) and phosphonoformates ((R0-)(R 0-)P(=0)(C00R")) phosphinates (RR P(=0)(-OR")) will also be mentioned briefly. In contrast to phosphates, alkyl phosphonates are not likely to be hydrolyzed by esterases due to lower acidity, a different shape, and, in some cases, the inability to undergo pseudorotation [118]. This increases the probability of alternative cleavage pathways, in particular oxidative ones, as documented below. 

A. G. Mitchell, D. Nicholls, W. J. Irwin, S. Freeman, Prodrugs of Phosphonoformate The Effect of para-Substituents on the Products, Kinetics and Mechanism of Hydrolysis of Dibenzyl Methoxycarbonylphosphonate , J. Chem. Soc., Perkin Trans. 2 1992, 1145-1150. 

R. P. Iyer, J. H. Boal, L. R. Phillips, D. R. Thakker, W. Egan, Synthesis, Hydrolytic Behavior, and Anti-HIV Activity of Selected Acyloxyalkyl Esters of Trisodium Phosphonoformate (Foscarnet Sodium) , J. Pharm. Sci. 1994, 83, 1269- 1273. 

Phosphonoformate derivative 66 is a useful reagent for the synthesis of 1,4,2-dioxaphosphorin derivatives. 5 -Acetyluridine derivative 67 was prepared in this way, albeit in low yield (Equation 17) <2000JOC1218>. 

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog (Figure 49-2) that inhibits viral DNA polymerase, RNA polymerase, and HIVreverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV-1. 

Additional information <3, 11> (<3> N-acetyl-L-glutamate and L-glutamine have no influence on activity [3] <11,13> not inhibitory adenosine-5 -tri-phospho(5 )adenosine, phosphate, phosphonoformate [14]) [3, 14]... 

Phosphonoformate is a pyrophosphate analog and inhibits both DNA polymerases and reverse transcriptase. However, toxicity may prevent longterm treatment of AIDS patients. Amantadine has a narrow antiviral specificity. It specifically inhibits initiation of the replication of influenza virus RNA of type A (but not of type B). Active only against retroviruses, 3 -azidothymidine is a reverse transcriptase inhibitor, which acts by a chain termination mechanism. It was synthesized in the early 1960s but only recently has been used in treatment of AIDS victims. More recently a series of 2, 3 -dideoxynucleosides, such as dideoxyinosine, have also been used.d Acyclic phosphonates, such as phosphonylmethoxypropyladenine, avoid the need for metabolic phosphorylation of the drug.6... 

Phosphonoformic acid (Foscarnet), an antiviral drug, which consists of carboxylic acid and phosphate linked together, was shown to be absorbed in the small intestine by the phosphate carrier-mediated mechanism [154], The transport of folic acid was investigated in biopsy specimens of intestinal mucosa from healthy volunteers. A pH-dependent, active transport of folic acid was found in the proximal small intestine, whereas in the mucosa of the colon, folic acid uptake was driven by a facilitated diffusion, mediated by a low-affinity carrier [155]. The existence of folate receptors in the human colonic mucosa is logical due to the large amounts of folic acid produced by the colonic flora [145],... 

In many cases nucleic acid polymerases are zinc-dependent enzymes. Hutchinson et al.45 have drawn upon the use of phosphonoacetic acid and phosphonoformic acid and introduced mono- and bis-thiopyrophosphate. They propose that the inhibition of influenza virus occurs by inhibition of RNA transcriptase45. By using 31P-NMR they... 

The use of 2-5A as an antiviral agent in animals does not seem to be feasible at present as the highly charged oligonucleotide is not taken up by cells to any extent and is broken down rapidly in interferon treated cells. We are looking at the mode of action of another class of stable phosphorus-containing antivirals which appear to be readily taken up by cells. These antiviral compounds are phosphonoacetic (PAA) and phosphonoformic (PFA) acids, analogues of pyrophosphoric acid. 

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