Phosphonoformic acid

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. 

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. 

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. 

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... 

Yusufi ANK, Szczepanska-Konkel M, Kempson SA, McAteer JA, DousaTP. Inhibition of human renal epithelial NaVP cotransport by phosphonoformic acid. Biochem Biophys Res Comm 1986 139 679-686. 

Acyclovir (nucleoside analogue Foscarnet (phosphate analogue of guanosine) trisodium salt of phosphonoformic acid)... 

Non-dNTP inhibitors aphidicolin (10 mg/mL in water), phosphonoformic acid (10 mg/mL in water), actinomycin D (10 mg/mL in ethanol). Store frozen, protected from light, in small aliquots. Make up 400 pg/mL solutions just before use. 

Dry the disks and count in a liquid scintillation counter (see Note 1). The plot of radioactivity incorporated vs reaction time should be linear for at least 1.5-2 h and plateau after 3 1 h. Actinomycin D at a concentration of 100 pg/mL should inhibit DDDP activity by >80% and RDDP by <20% phosphonoformic acid at 100 pg/mL should strongly inhibit both DDDP and RDDP activities, but neither should be affected by 100 pg/mL of aphidicolin. 

The literature on antiviral screening for HHV-6 and HHV-7 is sparse and has been reviewed elsewhere (1,3-5). Cell systems for viral propagation have included primary human peripheral blood and cord blood lymphocytes (CBL), and T-cell lines. Methods for monitoring viral replication have included examining infected cultures for cytopathic effect, immunofluorescence analysis, quantitation of viral DNA, and focus-forming assays. Phosphonoformic acid (foscarnet), phosphonoacetic acid, and ganciclovir inhibit HHV-6 and HHV-7... 

In attempts to improve the delivery of phosphonoformate, the kinetics and products of hydrolysis of various triesters of phosphonoformic acid (PEA) in MeCN-HjO mixtures at -1 < pH < 14 have been studied. Phosphonoformate triesters are hydrolyzed to give mixtures of phosphites, phosphonoformate esters, and free acids. The rates and product distribution are dependent on pH and ester leaving group abilities. ... 

Lambert, R.W., Martin, J.A., Thomas, G.J., Duncan, I.B., Hall, M.J., and Heimer. E.P., Synthesis and antiviral activity of phosphonoacetic and phosphonoformic acid esters of 5-bromo-2 -deoxyuridine and related pyrimidine nucleosides and acyclonucleosides, J. Med. Chem., 32. 367, 1989. 

Phosphonoformic acid undergoes acid-catalysed decarboxylation to phosphorous acid under relatively drastic conditions (equation 73). ... 

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