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Chemical Compound Review

CHEMBL121754     aminophosphonic acid

Synonyms: AG-D-11561, CHEBI:15907, CTK1A2567, LS-186704, AC1L22LY, ...
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Disease relevance of aminophosphonic acid

  • To determine whether such compounds are also effective in vivo, severe combined immunodeficiency mice injected with HL-60 myeloid leukemia cells were treated systemically with equal doses of either phosphoramidate or phosphorothioate c-myc antisense or mismatched oligonucleotides [1].
  • No direct binding of the 2'- O -methyl, PNA or (N3'-P5') phosphoramidate anti-TAR oligonucleotides to the HIV-1 reverse transcriptase was observed [2].
  • Recent studies suggest that eukaryotic RNA viruses have evolved alternative pathways of cap metabolism catalysed by structurally unrelated enzymes that nonetheless employ a phosphoramidate intermediate [3].
  • Here we report biological properties of phosphoramidate oligonucleotides targeted against the human T cell leukemia virus type-I Tax protein, the major transcriptional transactivator of this human retrovirus [4].
  • The phosphoramidate triester prodrugs of anti-human HIV 2', 3'-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5'-monophosphate (ddNMP), resulting in an improved formation of ddN 5'-triphosphate and, hence, higher antiviral efficacy [5].

High impact information on aminophosphonic acid

  • Uniformly modified oligonucleotides containing N3'-P5' phosphoramidate linkages exhibit (NP) extremely high-affinity binding to single-stranded RNA, do not induce RNase H activity, and are resistant to cellular nucleases [6].
  • In the present work, we demonstrate that phosphoramidate oligonucleotides are effective at inhibiting gene expression at the mRNA level, by binding to their complementary target present in the 5'-untranslated region [6].
  • Antileukemia effect of c-myc N3'-->P5' phosphoramidate antisense oligonucleotides in vivo [1].
  • In addition to demonstrating that the active site of antibody 28B4 does indeed reflect the mechanistic information programmed in the aminophosphonic acid hapten, these high-resolution structures provide a basis for enhancing turnover rates through mutagenesis and improved hapten design [7].
  • Phosphorylation was achieved either by preincubating FixJ with FixL* and ATP or by exposing FixJ to the inorganic phospho donor ammonium hydrogen phosphoramidate [8].

Chemical compound and disease context of aminophosphonic acid

  • All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate [9].
  • A series of alkylating phosphoramidate analogs of 5-fluoro-2'-deoxyuridine has been prepared and their growth inhibitory activity evaluated against murine L1210 leukemia and B16 melanoma cells in vitro [10].
  • The anti-human immunodeficiency virus (HIV) activity of abacavir (ABC; 1-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro-ABC-MP) to virus-infected cell cultures [11].
  • The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains [12].
  • In a systematic search for developing a virucidal spermicide with potent anti-human immunodeficiency virus (HIV) and spermicidal activities, we synthesized and evaluated 14 phosphoramidate derivatives of 5-bromo-6-methoxy-zidovudine (PP-BMZ) with differing amino acid ester side chains and para substitutions on the phenyl moiety [13].

Biological context of aminophosphonic acid

  • The nuclease activity of 1,10-phenanthroline-copper ion can be targeted to specific DNA sequences by attachment of the ligand to the 5' end of complementary deoxyoligonucleotides via a phosphoramidate linkage [14].
  • We assessed the inhibitory potential of morpholino phosphoramidate antisense oligonucleotides (morpholinos) on HCV translation by codelivering them with reporter plasmids expressing firefly luciferase under the translational control of the HCV internal ribosome entry site (IRES) into the livers of mice [15].
  • Thus, cation-resistant bacterial cell growth may be dependent on the hydrolysis of adenylylated and/or guanylylated phosphoramidate substrates by hinT [16].
  • The reaction follows ping-pong kinetics with a covalent enzyme-guanylate intermediate containing a phosphoramidate linkage, probably phospholysine [17].
  • The higher T m obtained with 2'- O -methyl, (N3'-P5') phosphoramidate and PNA molecules concerning the annealing with the stem-loop structure of the TAR RNA, in comparison with the beta-phosphodiester oligonucleotides, is correlated with their high inhibitory effect on reverse transcription [2].

Anatomical context of aminophosphonic acid

  • Isosequential phosphorothioate oligodeoxynucleotides and uniformly modified and chimeric phosphoramidate oligodeoxynucleotides containing six central phosphodiester linkages are all quite stable in cell nuclei [4].
  • When introduced into tax-transformed fibroblasts ex vivo, only the uniformly modified anti-tax phosphoramidate oligodeoxynucleotide caused a sequence-dependent reduction in the Tax protein level [4].
  • In this study, we evaluated the permeability of a series of phosphoramidate triester prodrugs of the anti-HIV drug 2',3'-didehydro-2',3'-dideoxythymidine across monolayers of Caco-2, Madin-Darby canine kidney (MDCKII) epithelial cell line, and its recombinant clone containing the human MDR1/P-gp gene (MDR1-MDCKII) [18].
  • The irreversible activation of adenylate-cyclase by 5'guanylylimidodiphosphate, a phosphoramidate analog of 5'GTP, has been examined in toad (Bufus marinus) plasma membranes using the technique of preincubating the membranes with the nucleotide under various controlled conditions followed by washing and subsequent assay of enzyme activity [19].
  • Correlations with their anti-HIV activities in a thymidine kinase deficient (TK-) CEM cell line have been established with a rationale of designing phosphoramidate pronucleotides capable of delivering intracellularly their respective 5'-nucleoside monophosphate derivatives [20].

Associations of aminophosphonic acid with other chemical compounds


Gene context of aminophosphonic acid

  • Stereopure and stereorandom phosphorothioates containing a G-quartet (shown in other studies to form high-order tetrad structures), antisense to c-myc, exhibited considerable nonspecific binding to many proteins, as did the isosequential phosphoramidate [26].
  • Optimization of an aminophosphonic acid series of compounds for inhibition of endothelin-converting enzyme (ECE) has led to the discovery of CGS 31447 [27].
  • A phosphoramidate-modified oligonucleotide complementary to TGF beta 3 mRNA was capable of inhibiting normal epithelial-mesenchymal transformation by 80% [28].
  • The oligo-N3'-->P5' phosphoramidate inhibited telomerase activity in cells in the presence of the cellular up-take enhancer (FuGENE6) in a dose- and sequence-dependent manner, with IC(50) values of approximately 1 nM [29].
  • Structural RNA mimetics: N3'-->P5' phosphoramidate DNA analogs of HIV-1 RRE and TAR RNA form A-type helices that bind specifically to Rev and Tat-related peptides [30].

Analytical, diagnostic and therapeutic context of aminophosphonic acid

  • A nuclease-resistant N3' --> P5' phosphoramidate isosequential analog of this aptamer also folds as a hairpin and forms with TAR a loop-loop "kissing" complex with a binding constant in the low nanomolar range as demonstrated by electrophoretic mobility-shift assays and surface plasmon resonance experiments [31].
  • Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate 166Ho-EDTMP [32].
  • The reaction products are inorganic phosphate and adenyl-5-yl phosphoramidate (AMP-PN) as determined by HPLC analysis [33].
  • The solution conformations of the dinucleotide d(TT) and the modified duplex d(CGCGAATTCGCG)2 with N3'--> P5' phosphoramidate internucleoside linkages have been studied using circular dichroism (CD) and NMR spectroscopy [34].
  • Here, we have examined the ability of various 15-mer phosphoramidate TFOs targeted to the HIV-1 polypurine tract (PPT) sequence to prevent transcription elongation in cell cultures; the PPT sequence has been cloned in the transcribed region of a reporter firefly luciferase gene (luc) and transient expression experiments performed [35].


  1. Antileukemia effect of c-myc N3'-->P5' phosphoramidate antisense oligonucleotides in vivo. Skorski, T., Perrotti, D., Nieborowska-Skorska, M., Gryaznov, S., Calabretta, B. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  2. Modified (PNA, 2'-O-methyl and phosphoramidate) anti-TAR antisense oligonucleotides as strong and specific inhibitors of in vitro HIV-1 reverse transcription. Boulmé, F., Freund, F., Moreau, S., Nielsen, P.E., Gryaznov, S., Toulmé, J.J., Litvak, S. Nucleic Acids Res. (1998) [Pubmed]
  3. RNA capping enzyme and DNA ligase: a superfamily of covalent nucleotidyl transferases. Shuman, S., Schwer, B. Mol. Microbiol. (1995) [Pubmed]
  4. RNase H-independent antisense activity of oligonucleotide N3 '--> P5 ' phosphoramidates. Heidenreich, O., Gryaznov, S., Nerenberg, M. Nucleic Acids Res. (1997) [Pubmed]
  5. Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Saboulard, D., Naesens, L., Cahard, D., Salgado, A., Pathirana, R., Velazquez, S., McGuigan, C., De Clercq, E., Balzarini, J. Mol. Pharmacol. (1999) [Pubmed]
  6. Phosphoramidate oligonucleotides as potent antisense molecules in cells and in vivo. Faria, M., Spiller, D.G., Dubertret, C., Nelson, J.S., White, M.R., Scherman, D., Hélène, C., Giovannangeli, C. Nat. Biotechnol. (2001) [Pubmed]
  7. Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9-angstrom resolution. Hsieh-Wilson, L.C., Schultz, P.G., Stevens, R.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  8. Oxygen regulation of nifA transcription in vitro. Agron, P.G., Ditta, G.S., Helinski, D.R. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. Design and synthesis of lipophilic phosphoramidate d4T-MP prodrugs expressing high potency against HIV in cell culture: structural determinants for in vitro activity and QSAR. Siddiqui, A.Q., McGuigan, C., Ballatore, C., Zuccotto, F., Gilbert, I.H., De Clercq, E., Balzarini, J. J. Med. Chem. (1999) [Pubmed]
  10. Synthesis and biological evaluation of 5-fluoro-2'-deoxyuridine phosphoramidate analogs. Fries, K.M., Joswig, C., Borch, R.F. J. Med. Chem. (1995) [Pubmed]
  11. Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5'-triphosphate metabolite levels. Balzarini, J., Aquaro, S., Hassan-Abdallah, A., Daluge, S.M., Perno, C.F., McGuigan, C. FEBS Lett. (2004) [Pubmed]
  12. Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine. Harris, S.A., McGuigan, C., Andrei, G., Snoeck, R., De Clercq, E., Balzarini, J. Antivir. Chem. Chemother. (2001) [Pubmed]
  13. Importance of the alanine methyl ester side chain for the biological activity profile of dual-function phenyl phosphate derivatives of bromo-methoxy-zidovudine. Venkatachalam, T.K., D'Cruz, O.J., Uckun, F.M. Antivir. Chem. Chemother. (2000) [Pubmed]
  14. Nuclease activity of 1,10-phenanthroline-copper: sequence-specific targeting. Chen, C.H., Sigman, D.S. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  15. A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice. McCaffrey, A.P., Meuse, L., Karimi, M., Contag, C.H., Kay, M.A. Hepatology (2003) [Pubmed]
  16. 31P NMR and genetic analysis establish hinT as the only Escherchia coli purine nucleoside phosphoramidase and as essential for growth under high salt conditions. Chou, T.F., Bieganowski, P., Shilinski, K., Cheng, J., Brenner, C., Wagner, C.R. J. Biol. Chem. (2005) [Pubmed]
  17. Purification and properties of GTP:GTP guanylyltransferase from encysted embryos of the brine shrimp Artemia. Liu, J.J., McLennan, A.G. J. Biol. Chem. (1994) [Pubmed]
  18. Stereoselective and concentration-dependent polarized epithelial permeability of a series of phosphoramidate triester prodrugs of d4T: an in vitro study in Caco-2 and Madin-Darby canine kidney cell monolayers. Siccardi, D., Kandalaft, L.E., Gumbleton, M., McGuigan, C. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  19. Irreversible activation of adenylate cyclase of toad erythrocyte plasma membrane by 5'-guanylylimidodiphosphate. Bennett, V., Cuatrecasas, P. J. Membr. Biol. (1976) [Pubmed]
  20. Anti-HIV pronucleotides: decomposition pathways and correlation with biological activities. Egron, D., Lefebvre, I., Périgaud, C., Beltran, T., Pompon, A., Gosselin, G., Aubertin, A.M., Imbach, J.L. Bioorg. Med. Chem. Lett. (1998) [Pubmed]
  21. Inactivation of pea seed glutamine synthetase by the toxin, tabtoxinine-beta-lactam. Langston-Unkefer, P.J., Robinson, A.C., Knight, T.J., Durbin, R.D. J. Biol. Chem. (1987) [Pubmed]
  22. Enzymatic synthesis of duplex circular phiX174 DNA containing phosphoramidate bonds in the (-) strand. Letsinger, R.L., Hapke, B., Petersen, G.R., Dumas, L.B. Nucleic Acids Res. (1976) [Pubmed]
  23. A novel approach to thymidylate synthase as a target for cancer chemotherapy. Li, Q., Boyer, C., Lee, J.Y., Shepard, H.M. Mol. Pharmacol. (2001) [Pubmed]
  24. The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship. Siddiqui, A.Q., Ballatore, C., McGuigan, C., De Clercq, E., Balzarini, J. J. Med. Chem. (1999) [Pubmed]
  25. Pharmacokinetics of amino acid phosphoramidate monoesters of zidovudine in rats. Song, H., Griesgraber, G.W., Wagner, C.R., Zimmerman, C.L. Antimicrob. Agents Chemother. (2002) [Pubmed]
  26. Comparison of binding of N3'-->P5' phosphoramidate and phosphorothioate oligonucleotides to cell surface proteins of cultured cells. Hawley, P., Nelson, J.S., Fearon, K.L., Zon, G., Gibson, I. Antisense Nucleic Acid Drug Dev. (1999) [Pubmed]
  27. Characterization of CGS 31447, a potent and nonpeptidic endothelin-converting enzyme inhibitor. Shetty, S.S., Savage, P., DelGrande, D., De Lombaert, S., Jeng, A.Y. J. Cardiovasc. Pharmacol. (1998) [Pubmed]
  28. Epithelial-mesenchymal transformation of embryonic cardiac endothelial cells is inhibited by a modified antisense oligodeoxynucleotide to transforming growth factor beta 3. Potts, J.D., Dagle, J.M., Walder, J.A., Weeks, D.L., Runyan, R.B. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  29. Oligonucleotide N3'-->P5' phosphoramidates as efficient telomerase inhibitors. Herbert, B.S., Pongracz, K., Shay, J.W., Gryaznov, S.M., Shea-Herbert, B. Oncogene (2002) [Pubmed]
  30. Structural RNA mimetics: N3'-->P5' phosphoramidate DNA analogs of HIV-1 RRE and TAR RNA form A-type helices that bind specifically to Rev and Tat-related peptides. Rigl, C.T., Lloyd, D.H., Tsou, D.S., Gryaznov, S.M., Wilson, W.D. Biochemistry (1997) [Pubmed]
  31. Loop-loop interaction of HIV-1 TAR RNA with N3'-->P5' deoxyphosphoramidate aptamers inhibits in vitro Tat-mediated transcription. Darfeuille, F., Arzumanov, A., Gryaznov, S., Gait, M.J., Di Primo, C., Toulmé, J.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  32. Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate 166Ho-EDTMP. Appelbaum, F.R., Brown, P.A., Sandmaier, B.M., Storb, R., Fisher, D.R., Shulman, H.M., Graham, T.C., Schuening, F.G., Deeg, H.J., Bianco, J.A. Blood (1992) [Pubmed]
  33. Hydrolysis of adenyl-5-yl imidodiphosphate by beef heart mitochondrial ATPase. Tomaszek, T.A., Schuster, S.M. J. Biol. Chem. (1986) [Pubmed]
  34. An oligodeoxyribonucleotide N3'--> P5' phosphoramidate duplex forms an A-type helix in solution. Ding, D., Grayaznov, S.M., Lloyd, D.H., Chandrasekaran, S., Yao, S., Ratmeyer, L., Pan, Y., Wilson, W.D. Nucleic Acids Res. (1996) [Pubmed]
  35. Transcription inhibition induced by modified triple helix-forming oligonucleotides: a quantitative assay for evaluation in cells. Faria, M., Wood, C.D., White, M.R., Hélène, C., Giovannangeli, C. J. Mol. Biol. (2001) [Pubmed]
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