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Chemical Compound Review

Bicyclam     1-[[4-(1,4,8,11- tetrazacyclotetradec-1...

Synonyms: SDZ-SID-791, AMD-3100, CHEMBL2311028, CS-0321, JM-3100, ...
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Disease relevance of SID791


High impact information on SID791

  • This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration [3].
  • Medical interest has centred on clinical trials of a bicyclam for the treatment of AIDS and for stem cell mobilization, and on adducts with Tc and Cu radionuclides for diagnosis and therapy [5].
  • Autoimmune collagen-induced arthritis (CIA) in IFN-gammaR-deficient DBA/1 mice was shown to be reduced in severity by treatment with the bicyclam derivative AMD3100, a specific antagonist of the interaction between the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 [6].
  • These interactions are consistent with the known structure-activity relationships for bicyclam anti-HIV activity and receptor mutation [7].
  • Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4 [8].

Chemical compound and disease context of SID791

  • High expectations are vested in the acyclic nucleoside phosphonates PMEA and PMPA (which have proved clearly efficacious against HIV infections in phase II/III and phase I/II trials, respectively) and the bicyclam derivatives, which have recently been shown to block HIV infection through interference with the viral co-receptor CXCR4 (fusin) [9].

Biological context of SID791


Anatomical context of SID791


Associations of SID791 with other chemical compounds

  • AMD3100 is a symmetric bicyclam, prototype non-peptide antagonist of the CXCR4 chemokine receptor [18].
  • The most potent interaction with CXCR4 and thus anti-HIV activity was shown by bicyclam analogs with cyclam rings composed of fourteen members that are linked by an aromatic (phenyl) bridge [4].

Gene context of SID791

  • The specificity of T-22 and AMD-3100 was further confirmed by their ability to block entry of HIV-1 in GHOST-CXCR4 transfected cells with no effect on viral entry in the GHOST-CCR5 cells [19].
  • Inhibition of CXCR 4 by AMD 3100 abrogates the effect of gp120 on both p53 and Apaf-1 [20].
  • They expressed mRNA of CXCR4, and the FIV infection was blocked by stromal cell-derived factor 1alpha (SDF-1alpha), SDF-1beta, or the bicyclam AMD3100 in a dose-dependent manner [21].

Analytical, diagnostic and therapeutic context of SID791


  1. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Donzella, G.A., Schols, D., Lin, S.W., Esté, J.A., Nagashima, K.A., Maddon, P.J., Allaway, G.P., Sakmar, T.P., Henson, G., De Clercq, E., Moore, J.P. Nat. Med. (1998) [Pubmed]
  2. CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer. Saur, D., Seidler, B., Schneider, G., Algül, H., Beck, R., Senekowitsch-Schmidtke, R., Schwaiger, M., Schmid, R.M. Gastroenterology (2005) [Pubmed]
  3. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Rubin, J.B., Kung, A.L., Klein, R.S., Chan, J.A., Sun, Y., Schmidt, K., Kieran, M.W., Luster, A.D., Segal, R.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor. Esté, J.A., Cabrera, C., De Clercq, E., Struyf, S., Van Damme, J., Bridger, G., Skerlj, R.T., Abrams, M.J., Henson, G., Gutierrez, A., Clotet, B., Schols, D. Mol. Pharmacol. (1999) [Pubmed]
  5. Cyclam complexes and their applications in medicine. Liang, X., Sadler, P.J. Chemical Society reviews. (2004) [Pubmed]
  6. AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor-deficient mice. Matthys, P., Hatse, S., Vermeire, K., Wuyts, A., Bridger, G., Henson, G.W., De Clercq, E., Billiau, A., Schols, D. J. Immunol. (2001) [Pubmed]
  7. Structure and dynamics of metallomacrocycles: recognition of zinc xylyl-bicyclam by an HIV coreceptor. Liang, X., Parkinson, J.A., Weishäupl, M., Gould, R.O., Paisey, S.J., Park, H.S., Hunter, T.M., Blindauer, C.A., Parsons, S., Sadler, P.J. J. Am. Chem. Soc. (2002) [Pubmed]
  8. Overexpression of Both CXC Chemokine Receptor 4 and Vascular Endothelial Growth Factor Proteins Predicts Early Distant Relapse in Stage II-III Colorectal Cancer Patients. Ottaiano, A., Franco, R., Aiello Talamanca, A., Liguori, G., Tatangelo, F., Delrio, P., Nasti, G., Barletta, E., Facchini, G., Daniele, B., Di Blasi, A., Napolitano, M., Ieranò, C., Calemma, R., Leonardi, E., Albino, V., Angelis, V.D., Falanga, M., Boccia, V., Capuozzo, M., Parisi, V., Botti, G., Castello, G., Vincenzo Iaffaioli, R., Scala, S. Clin. Cancer Res. (2006) [Pubmed]
  9. New perspectives for the treatment of HIV infections. De Clercq, E. Verh. K. Acad. Geneeskd. Belg. (1998) [Pubmed]
  10. The molecular target of bicyclams, potent inhibitors of human immunodeficiency virus replication. de Vreese, K., Kofler-Mongold, V., Leutgeb, C., Weber, V., Vermeire, K., Schacht, S., Anné, J., de Clercq, E., Datema, R., Werner, G. J. Virol. (1996) [Pubmed]
  11. Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Hendrix, C.W., Flexner, C., MacFarland, R.T., Giandomenico, C., Fuchs, E.J., Redpath, E., Bridger, G., Henson, G.W. Antimicrob. Agents Chemother. (2000) [Pubmed]
  12. Strong in vitro synergy between the fusion inhibitor T-20 and the CXCR4 blocker AMD-3100. Tremblay, C.L., Kollmann, C., Giguel, F., Chou, T.C., Hirsch, M.S. J. Acquir. Immune Defic. Syndr. (2000) [Pubmed]
  13. The antiviral activity of the CXCR4 antagonist AMD3100 is independent of the cytokine-induced CXCR4/HIV coreceptor expression level. Princen, K., Hatse, S., Vermeire, K., Bridger, G.J., Skerlj, R.T., De Clercq, E., Schols, D. AIDS Res. Hum. Retroviruses (2003) [Pubmed]
  14. Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. Maeda, K., Yoshimura, K., Shibayama, S., Habashita, H., Tada, H., Sagawa, K., Miyakawa, T., Aoki, M., Fukushima, D., Mitsuya, H. J. Biol. Chem. (2001) [Pubmed]
  15. CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages. Simmons, G., Reeves, J.D., McKnight, A., Dejucq, N., Hibbitts, S., Power, C.A., Aarons, E., Schols, D., De Clercq, E., Proudfoot, A.E., Clapham, P.R. J. Virol. (1998) [Pubmed]
  16. Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms. Guyon, A., Skrzydelsi, D., Rovère, C., Rostène, W., Parsadaniantz, S.M., Nahon, J.L. J. Neurochem. (2006) [Pubmed]
  17. Characterization and functionality of CXCR4 chemokine receptor and SDF-1 in human corneal fibroblasts. Bourcier, T., Berbar, T., Paquet, S., Rondeau, N., Thomas, F., Borderie, V., Laroche, L., Rostène, W., Haour, F., Lombet, A. Mol. Vis. (2003) [Pubmed]
  18. Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. Rosenkilde, M.M., Gerlach, L.O., Jakobsen, J.S., Skerlj, R.T., Bridger, G.J., Schwartz, T.W. J. Biol. Chem. (2004) [Pubmed]
  19. Susceptibility of diverse primary HIV isolates with varying co-receptor specificity's to CXCR4 antagonistic compounds. Owen, S.M., Rudolph, D., Schols, D., Fujii, N., Yamamoto, N., Lal, R.B. J. Med. Virol. (2002) [Pubmed]
  20. Regulation of neuronal P53 activity by CXCR 4. Khan, M.Z., Shimizu, S., Patel, J.P., Nelson, A., Le, M.T., Mullen-Przeworski, A., Brandimarti, R., Fatatis, A., Meucci, O. Mol. Cell. Neurosci. (2005) [Pubmed]
  21. CXCR4 is the primary receptor for feline immunodeficiency virus in astrocytes. Nakagaki, K., Nakagaki, K., Takahashi, K., Schols, D., De Clercq, E., Tabira, T. J. Neurovirol. (2001) [Pubmed]
  22. Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120. De Vreese, K., Van Nerum, I., Vermeire, K., Anné, J., De Clercq, E. Antimicrob. Agents Chemother. (1997) [Pubmed]
  23. The emerging role of fusion inhibitors in HIV infection. De Clercq, E. Drugs in R&D. (1999) [Pubmed]
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