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Chemical Compound Review

AzddTMP     [(2R,3S,5R)-3-azido-5-(5- methyl-2,4-dioxo...

Synonyms: AZTMP, ZDVMP, AZT-MP, CHEMBL257695, AG-A-46645, ...
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Disease relevance of AZT-MP


High impact information on AZT-MP


Biological context of AZT-MP

  • The findings described here raise the concern that the capability of the two major host DNA polymerases to incorporate AZT-MP or ddCMP into DNA might cause adverse side effects on human DNA metabolism and mutation in the genomes of patients under long term continuous treatment with AZT and ddC [9].
  • The drug-design rationale on which these approaches are based is that the ester conjugate will be converted by hydrolysis and/or enzymatic cleavage to AZT or its 5′-monophosphate (AZT-MP) [10].
  • The bottleneck in the conversion of AZT to AZTTP is the phosphorylation of AZT monophosphate (AZTMP) by cellular thymidylate kinase [11].
  • The present study also raises the question of whether AZT-MP inhibition of this activity may lead to potential mutagenic effects due to inhibition of 3' to 5' exonuclease-mediated proofreading functions involved in DNA replication [12].
  • There were no significant differences after 6 or 12 hours of incubation with AZT between AZT phosphate levels in maternal and fetal PBMCs isolated at term or at 17-21 weeks of gestation: AZT monophosphate was found to be the major metabolite (about 95%) [13].

Anatomical context of AZT-MP

  • However, replication was inhibited by AZT monophosphate at concentrations previously reported to accumulate in human cells cultured in the presence of AZT, suggesting that AZT monophosphate may contribute to cytotoxicity by inhibiting chromosomal replication [14].
  • Upon incubation of double-labeled [14C]AZT-P-[3H]ddI in freshly isolated rat hepatocytes in suspension at a final concentration of 10 microM, the dimer was taken up intact by cells and then rapidly cleaved to AZT, AZT monophosphate, ddI, and ddI monophosphate [15].
  • After 3 hr of incubation in the presence of 0.5 mM AZT, both AZT and its monophosphorylated form (AZT-MP) could be detected in the sensitive cell line in concentrations above the NMR detection levels [16].
  • In the present study, AZT-MP inhibited 3' to 5' exonuclease activity of calf thymus DNA polymerase delta at pharmacological relevant intracellular concentrations [12].
  • Although the active triphosphorylated metabolite was not detected in the fetus, the AZT-monophosphate was detected in almost all fetal tissues examined [17].

Associations of AZT-MP with other chemical compounds


Gene context of AZT-MP

  • The mechanism of AZT resistance implies an increased ability of the multidrug-resistant (SS) RT to remove AZT-monophosphate (AZTMP) from blocked primers through a nucleotide-dependent reaction [22].
  • Moreover, the findings indicate that retention of AZT-MP and AZP-TP was prolonged significantly (P less than 0.05 and P less than 0.01 respectively) in association with GM-CSF treatment [23].
  • We observed very high levels of AZT-MP in stimulated (PHA + IL2) PBMCs (> 100 pmol/10(6) cells) while, as expected, much lower concentrations were measured in resting PBMCs or MDMs (0.1 to 2 pmol/10(6) cells) [24].

Analytical, diagnostic and therapeutic context of AZT-MP


  1. Mutations E44D and V118I in the reverse transcriptase of HIV-1 play distinct mechanistic roles in dual resistance to AZT and 3TC. Girouard, M., Diallo, K., Marchand, B., McCormick, S., Götte, M. J. Biol. Chem. (2003) [Pubmed]
  2. Synthesis of a photoaffinity analog of 3'-azidothymidine, 5-azido-3'-azido-2',3'-dideoxyuridine. Interactions with herpesvirus thymidine kinase and cellular enzymes. Mao, F., Rechtin, T.M., Jones, R., Cantu, A.A., Anderson, L.S., Radominska, A., Moyer, M.P., Drake, R.R. J. Biol. Chem. (1995) [Pubmed]
  3. Azidothymidine induces apoptosis and inhibits cell growth and telomerase activity of human parathyroid cancer cells in culture. Falchetti, A., Franchi, A., Bordi, C., Mavilia, C., Masi, L., Cioppi, F., Recenti, R., Picariello, L., Marini, F., Del Monte, F., Ghinoi, V., Martineti, V., Tanini, A., Brandi, M.L. J. Bone Miner. Res. (2005) [Pubmed]
  4. Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2'-deoxynucleoside triphosphates. Meyer, P.R., Matsuura, S.E., Schinazi, R.F., So, A.G., Scott, W.A. Antimicrob. Agents Chemother. (2000) [Pubmed]
  5. Crystal structure of yeast thymidylate kinase complexed with the bisubstrate inhibitor P1-(5'-adenosyl) P5-(5'-thymidyl) pentaphosphate (TP5A) at 2.0 A resolution: implications for catalysis and AZT activation. Lavie, A., Konrad, M., Brundiers, R., Goody, R.S., Schlichting, I., Reinstein, J. Biochemistry (1998) [Pubmed]
  6. Structural basis for efficient phosphorylation of 3'-azidothymidine monophosphate by Escherichia coli thymidylate kinase. Lavie, A., Ostermann, N., Brundiers, R., Goody, R.S., Reinstein, J., Konrad, M., Schlichting, I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. AZT monophosphate knocks thymidylate kinase for a loop. Kenyon, G.L. Nat. Struct. Biol. (1997) [Pubmed]
  8. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. Lim, S.E., Copeland, W.C. J. Biol. Chem. (2001) [Pubmed]
  9. Human DNA polymerases alpha and beta are able to incorporate anti-HIV deoxynucleotides into DNA. Copeland, W.C., Chen, M.S., Wang, T.S. J. Biol. Chem. (1992) [Pubmed]
  10. Novel approaches for designing 5'-O-ester prodrugs of 3'-azido-2', 3'-dideoxythymidine (AZT). Parang, K., Wiebe, L.I., Knaus, E.E. Current medicinal chemistry. (2000) [Pubmed]
  11. Expressing engineered thymidylate kinase variants in human cells to improve AZT phosphorylation and human immunodeficiency virus inhibition. Wöhrl, B.M., Loubière, L., Brundiers, R., Goody, R.S., Klatzmann, D., Konrad, M. J. Gen. Virol. (2005) [Pubmed]
  12. Inhibition of mammalian DNA polymerase-associated 3' to 5' exonuclease activity by 5'-monophosphates of 3'-azido-3'-deoxythymidine and 3'-amino-3'-deoxythymidine. Bridges, E.G., Faraj, A., Sommadossi, J.P. Biochem. Pharmacol. (1993) [Pubmed]
  13. Phosphorylation of 3'-azidothymidine in maternal and fetal peripheral blood mononuclear cells during gestation and at term. Agbaria, R., Manor, E., Barak, J., Balzarini, J. J. Acquir. Immune Defic. Syndr. (2003) [Pubmed]
  14. Effects of 3'-azido-3'-deoxythymidine metabolites on simian virus 40 origin-dependent replication and heteroduplex repair in HeLa cell extracts. Bebenek, K., Thomas, D.C., Roberts, J.D., Eckstein, F., Kunkel, T.A. Mol. Pharmacol. (1993) [Pubmed]
  15. Comparative metabolism of the antiviral dimer 3'-azido-3'-deoxythymidine-P-2',3'-dideoxyinosine and the monomers zidovudine and didanosine by rat, monkey, and human hepatocytes. Pan-Zhou, X.R., Cretton-Scott, E., Zhou, X.J., Xie, M.Y., Rahmani, R., Schinazi, R.F., Duchin, K., Sommadossi, J.P. Antimicrob. Agents Chemother. (1997) [Pubmed]
  16. Intracellular metabolism of 3'-azido-3'-deoxythymidine (AZT): a nuclear magnetic resonance study on T-lymphoblastoid cell lines with different resistance to AZT. Di Vito, M., Bozzi, A., Ferretti, A., Cianfriglia, M., Barca, S., Signoretti, C., Lenti, L., d'Agostino, F., Strom, R., Podo, F. Biochem. Pharmacol. (1997) [Pubmed]
  17. Transplacental pharmacokinetics and fetal distribution of azidothymidine, its glucuronide, and phosphorylated metabolites in late-term rhesus macaques after maternal infusion. Patterson, T.A., Binienda, Z.K., Lipe, G.W., Gillam, M.P., Slikker, W., Sandberg, J.A. Drug Metab. Dispos. (1997) [Pubmed]
  18. Characterization of Streptococcus pneumoniae thymidylate kinase: steady-state kinetics of the forward reaction and isothermal titration calorimetry. Petit, C.M., Koretke, K.K. Biochem. J. (2002) [Pubmed]
  19. Disposition and oral bioavailability in rats of an antiviral and antitumor amino acid phosphoramidate prodrug of AZT-monophosphate. Song, H., Johns, R., Griesgraber, G.W., Wagner, C.R., Zimmerman, C.L. Pharm. Res. (2003) [Pubmed]
  20. Pro-oxidant properties and cytotoxicity of AZT-monophosphate and AZT. Mak, I.T., Nedelec, L.F., Weglicki, W.B. Cardiovasc. Toxicol. (2004) [Pubmed]
  21. Low-dose, sublingual AZT-monophosphate therapy for HIV+ patients? Johnson, S. Med. Hypotheses (2001) [Pubmed]
  22. Multidrug-resistant HIV-1 reverse transcriptase: involvement of ribonucleotide-dependent phosphorolysis in cross-resistance to nucleoside analogue inhibitors. Mas, A., Vázquez-Alvarez, B.M., Domingo, E., Menéndez-Arias, L. J. Mol. Biol. (2002) [Pubmed]
  23. Effects of granulocyte-macrophage colony-stimulating factor on 3'-azido-3'-deoxythymidine uptake, phosphorylation and nucleotide retention in human U-937 cells. Dhawan, R.K., Kharbanda, S., Nakamura, M., Ohno, T., Kufe, D. Biochem. Pharmacol. (1990) [Pubmed]
  24. Monitoring of intracellular levels of 5'-monophosphate-AZT using an enzyme immunoassay. Goujon, L., Brossette, T., Dereudre-Bosquet, N., Creminon, C., Clayette, P., Dormont, D., Mioskowski, C., Lebeau, L., Grassi, J. J. Immunol. Methods (1998) [Pubmed]
  25. Zidovudine inhibits thymidine phosphorylation in the isolated perfused rat heart. Susan-Resiga, D., Bentley, A.T., Lynx, M.D., Laclair, D.D., McKee, E.E. Antimicrob. Agents Chemother. (2007) [Pubmed]
  26. Preparative-scale high-performance liquid chromatographic separation and purification of 3'-azido-3'-deoxythymidine-5'-phosphate. Turcotte, J.G., Pivarnik, P.E., Shirali, S.S., Singh, H.K., Sehgal, R.K., Macbride, D., Jang, N.I., Brown, P.R. J. Chromatogr. (1990) [Pubmed]
  27. AZT and AZT-monophosphate prodrugs incorporating HIV-protease substrate fragment: synthesis and evaluation as specific drug delivery systems. Liotard, J.F., Mehiri, M., Di Giorgio, A., Boggetto, N., Reboud-Ravaux, M., Aubertin, A.M., Condom, R., Patino, N. Antivir. Chem. Chemother. (2006) [Pubmed]
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