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Chemical Compound Review

AGN-PC-00K77H     2-[(3-amino-2-hydroxy-4- phenyl...

Synonyms: CHEMBL1161364, SureCN8191715, NSC-265489, AC1L1FHH, AC1Q5SDE, ...
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Disease relevance of Bestatin

  • We observed significant therapeutic activity against preexisting experimental and spontaneous metastases when bestatin was administered at high doses per animal for 4 weeks [1].
  • The aminopeptidase inhibitor Bestatin [2S,3R-(3-amino-2-hydroxy-4-phenylbutanoyl)-L-leucine] was tested for both in vitro and in vivo macrophage activation and antitumor activity in various experimental tumor systems including the metastasizing ESb lymphoma system [2].
  • Cultures of resting macrophages were rendered nonspecifically tumoricidal for the two lymphoma sublines ESb and 721 (ESb-Cl 18.1), for the mastocytoma P815X, for LS lymphoma cells, and for proliferating lymphoblasts from DBA/2, C57BL/6J, and CBA mice by exposure to Bestatin at 50 micrograms/ml culture medium [2].
  • Bestatin reversibly inhibits Aeromonas aminopeptidase (EC in a process that is remarkable for its unusual degree of time dependence [3].
  • Inhibition by bestatin of a mouse ascites tumor dipeptidase. Reversal by certain substrates [4].

Psychiatry related information on Bestatin

  • As bestatin has no direct antibiotic effect on S. typhimurium, it must be concluded that the therapeutic effects of the drug on chronic infection must be solely contributed to elevation of the host's own defense mechanisms [5].
  • The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors [6].
  • The present study assesses the ability of bestatin to reduce chronic alcohol consumption in the genetically selected high alcohol-consuming P rats [7].
  • In addition, the novel finding of a carry-over inhibition of alcohol intake in the bestatin-free period adds further impetus to the recommendation that this drug, which has been safely used in humans, might be examined as a possible therapeutic agent for alcohol abuse [8].
  • Potentiation of phencyclidine-induced stereotyped behaviors in rats by thiorphan and bestatin [9].

High impact information on Bestatin


Chemical compound and disease context of Bestatin


Biological context of Bestatin

  • K562/CD13 cells cocultured with vascular endothelial cells did not undergo apoptosis, but the addition of bestatin resulted in the induction of apoptosis in K562/CD13 cells (2.70-fold difference [95% CI = 1.77-fold to 3.63-fold], P<.001) [10].
  • In the presence of bestatin (0.5 mg/ml), one-fourth of these products appeared to be dipeptides, tripeptides, or both: they were resistant to ninhydrin at acid pH (a treatment that decarboxylates only free amino acids) except after intensive acid hydrolysis, and they eluted from a Sephadex G-10 column with an apparent average size of 300 daltons [16].
  • Hydrogen bonds involving active site residues Lys-262, Asp-273, Gly-360, and Leu-362 are responsible for stabilizing the backbone nitrogen and oxygen atoms of bestatin [12].
  • The macrophage activation to lyse tumor cells was sharply dependent on the Bestatin dose and appeared about 24 hr after injection of the dipeptide [2].
  • Hydrolysis of the amide bond of arginyl-p-nitroanilide was inhibited by bestatin with an IC50 of 2.6 +/- 1.2 microM [17].

Anatomical context of Bestatin

  • Degradation of abnormal proteins in intact mouse reticulocytes: accumulation of intermediates in the presence of bestatin [16].
  • Bestatin also had T-cell adjuvant activity when it was admixed with a suboptimal vaccine composed of irradiated tumor cells [1].
  • Bestatin activates macrophages through a T-cell-independent process to lyse tumor target cells, inasmuch as macrophages from homozygous athymic nude (nu/nu) mice treated i.p. with the dipeptide were also stimulated and cytotoxic for tumor cells [2].
  • We present evidence that the macrophage is the prominent host cell responsible for tumor cell destruction in animals treated with Bestatin and rule out the possibility that natural killer cells play a major role in the experiments described [2].
  • Ability of the immunomodulating dipeptide bestatin to activate cytotoxic mononuclear phagocytes [2].

Associations of Bestatin with other chemical compounds


Gene context of Bestatin

  • Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC(50) of 25 microM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13 [23].
  • To further examine the role of LTB4 in oral carcinogenesis, two LTA4H inhibitors, bestatin and SA6541, were evaluated in a long-term chemoprevention experiment [24].
  • The behavioural response to SP was significantly increased by 2.0 nmol of bestatin, an aminopeptidase inhibitor, but not by 1.0 nmol [25].
  • Verapamil significantly increased the inhibitory activity of bestatin on K562 cells, indicating that the intracellular concentration of bestatin can be mediated also by P-glycoprotein [26].
  • When phosphoramidon was injected together with bestatin and captopril which have no significant effect alone, SP- or NK A-induced behavioral response was significantly increased [25].

Analytical, diagnostic and therapeutic context of Bestatin


  1. Immunomodulatory and therapeutic properties of bestatin in mice. Talmadge, J.E., Lenz, B.F., Pennington, R., Long, C., Phillips, H., Schneider, M., Tribble, H. Cancer Res. (1986) [Pubmed]
  2. Ability of the immunomodulating dipeptide bestatin to activate cytotoxic mononuclear phagocytes. Schorlemmer, H.U., Bosslet, K., Sedlacek, H.H. Cancer Res. (1983) [Pubmed]
  3. The slow, tight binding of bestatin and amastatin to aminopeptidases. Wilkes, S.H., Prescott, J.M. J. Biol. Chem. (1985) [Pubmed]
  4. Inhibition by bestatin of a mouse ascites tumor dipeptidase. Reversal by certain substrates. Patterson, E.K. J. Biol. Chem. (1989) [Pubmed]
  5. Stimulation of cell-mediated immunity by bestatin correlates with reduction of bacterial persistence in experimental chronic Salmonella typhimurium infection. Dickneite, G., Kaspereit, F., Sedlacek, H.H. Infect. Immun. (1984) [Pubmed]
  6. Effect of inhibition of neuropeptidases on the pain threshold of mice and rats. Carenzi, A., Frigeni, V., Reggiani, A., Della Bella, D. Neuropharmacology (1983) [Pubmed]
  7. Effect of bestatin, an aminopeptidase inhibitor, on alcohol intake in alcohol-preferring P rats. Szczepanska, R., Harding, S., Grupp, L.A. Alcohol. Clin. Exp. Res. (1996) [Pubmed]
  8. Characterization of the decline in alcohol consumption by aminopeptidase inhibition. Szczepanska, R., Harding, S., Grupp, L.A. Drug and alcohol dependence. (1996) [Pubmed]
  9. Potentiation of phencyclidine-induced stereotyped behaviors in rats by thiorphan and bestatin. Hiramatsu, M., Nabeshima, T., Fukaya, H., Furukawa, H., Kameyama, T. Eur. J. Pharmacol. (1986) [Pubmed]
  10. Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells. Mishima, Y., Matsumoto-Mishima, Y., Terui, Y., Katsuyama, M., Yamada, M., Mori, M., Ishizaka, Y., Ikeda, K., Watanabe, J., Mizunuma, N., Hayasawa, H., Hatake, K. J. Natl. Cancer Inst. (2002) [Pubmed]
  11. Leukotriene A4 hydrolase: mapping of a henicosapeptide involved in mechanism-based inactivation. Mueller, M.J., Wetterholm, A., Blomster, M., Jörnvall, H., Samuelsson, B., Haeggström, J.Z. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  12. Leucine aminopeptidase: bestatin inhibition and a model for enzyme-catalyzed peptide hydrolysis. Burley, S.K., David, P.R., Lipscomb, W.N. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  13. Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against Plasmodium falciparum In Vitro. Skinner-Adams, T.S., Andrews, K.T., Melville, L., McCarthy, J., Gardiner, D.L. Antimicrob. Agents Chemother. (2007) [Pubmed]
  14. The antitumor effect of bleomycin combined with bestatin against Ehrlich ascites carcinoma in mice. Kaya, G., Akin, C., Altuğ, T., Devrim, S. Proc. Soc. Exp. Biol. Med. (1988) [Pubmed]
  15. Successful chemoimmunotherapy of murine L1210 lymphatic leukemia with cyclophosphamide and mafosfamide-treated leukemia cells. Kawalec, M., Skórski, T., Kawiak, J. Investigational new drugs. (1988) [Pubmed]
  16. Degradation of abnormal proteins in intact mouse reticulocytes: accumulation of intermediates in the presence of bestatin. Botbol, V., Scornik, O.A. Proc. Natl. Acad. Sci. U.S.A. (1979) [Pubmed]
  17. Molecular cloning and functional expression of a Caenorhabditis elegans aminopeptidase structurally related to mammalian leukotriene A4 hydrolases. Baset, H.A., Ford-Hutchinson, A.W., O'Neill, G.P. J. Biol. Chem. (1998) [Pubmed]
  18. An oligopeptide transporter is expressed at high levels in the pancreatic carcinoma cell lines AsPc-1 and Capan-2. Gonzalez, D.E., Covitz, K.M., Sadée, W., Mrsny, R.J. Cancer Res. (1998) [Pubmed]
  19. Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-L-glutamate. Identification and characterization of a novel N-acetylated alpha-linked acidic dipeptidase activity from rat brain. Robinson, M.B., Blakely, R.D., Couto, R., Coyle, J.T. J. Biol. Chem. (1987) [Pubmed]
  20. A Ca2+-dependent autoregulation of lipopolysaccharide-induced IL-8 receptor expression in human polymorphonuclear neutrophils. Bhattacharya, C., Samanta, S., Gupta, S., Samanta, A.K. J. Immunol. (1997) [Pubmed]
  21. Glucagon-(19-29), a Ca2+ pump inhibitory peptide, is processed from glucagon in the rat liver plasma membrane by a thiol endopeptidase. Blache, P., Kervran, A., Dufour, M., Martinez, J., Le-Nguyen, D., Lotersztajn, S., Pavoine, C., Pecker, F., Bataille, D. J. Biol. Chem. (1990) [Pubmed]
  22. Mechanism-based inactivation of leukotriene A4 hydrolase/aminopeptidase by leukotriene A4. Mass spectrometric and kinetic characterization. Orning, L., Gierse, J., Duffin, K., Bild, G., Krivi, G., Fitzpatrick, F.A. J. Biol. Chem. (1992) [Pubmed]
  23. Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. Bauvois, B., Puiffe, M.L., Bongui, J.B., Paillat, S., Monneret, C., Dauzonne, D. J. Med. Chem. (2003) [Pubmed]
  24. Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors. Sun, Z., Sood, S., Li, N., Ramji, D., Yang, P., Newman, R.A., Yang, C.S., Chen, X. Carcinogenesis (2006) [Pubmed]
  25. Phosphoramidon potentiates mammalian tachykinin-induced biting, licking and scratching behaviour in mice. Sakurada, T., Tan-No, K., Yamada, T., Sakurada, S., Kisara, K. Pharmacol. Biochem. Behav. (1990) [Pubmed]
  26. Aminopeptidase inhibitors bestatin and actinonin inhibit cell proliferation of myeloma cells predominantly by intracellular interactions. Grujić, M., Renko, M. Cancer Lett. (2002) [Pubmed]
  27. Bestatin, an inhibitor of aminopeptidases, provides a chemical genetics approach to dissect jasmonate signaling in Arabidopsis. Zheng, W., Zhai, Q., Sun, J., Li, C.B., Zhang, L., Li, H., Zhang, X., Li, S., Xu, Y., Jiang, H., Wu, X., Li, C. Plant Physiol. (2006) [Pubmed]
  28. Aminopeptidase activity in human nasal mucosa. Ohkubo, K., Baraniuk, J.N., Hohman, R., Merida, M., Hersh, L.B., Kaliner, M.A. J. Allergy Clin. Immunol. (1998) [Pubmed]
  29. Crystallization and preliminary X-ray crystallographic studies of recombinant human leukotriene A4 hydrolase complexed with bestatin. Tsuge, H., Ago, H., Aoki, M., Furuno, M., Noma, M., Miyano, M., Minami, M., Izumi, T., Shimizu, T. J. Mol. Biol. (1994) [Pubmed]
  30. Cancer cell-targeted drug delivery utilizing oligopeptide transport activity. Nakanishi, T., Tamai, I., Takaki, A., Tsuji, A. Int. J. Cancer (2000) [Pubmed]
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