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Aminopeptidase inhibitor
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Ubenimex(Bestatin) is a specific inhibitor of aminopeptidase B and leucine aminopeptidase. It did not show any inhibition of aminopeptidase A, trypsin, chymotrypsin, elastase, papain, pepsin or thermolysin. Bestatin at 100 pg/ml showed no antibacterial and no antifungal activities. It has low toxicity with no death after intraperitoneal injection of 300 mg/kg to mice1.

Bestatin isolated from the culture filtrate of Streptomyces olivoreticuli MD976-C72. The structure of bestatin was elucidated to be (2S, 3R)-3-amino-2-hydroxy-4- phenylbutanoyll-(S)-leucine3, 4. Bestatin itself was not hydrolyzed by either of the enzymes, when bestatin was incubated as substrate, L-leucine was not detected by thin-layer chromatography.

Unlike the case of orthophenanthroline, the inhibitory activity of bestatin on aminopeptidase B was not reversed by addition of zinc ion. Bestatin has a pair of adjacent amino and hydroxyl groups, which shows metal-complexing activity5-7. If the inhibitory activity of bestatin is attributable to five-membered chelate ring formation by a pair of adjacent amino and hydroxyl groups of bestatin and a metal ion of the enzyme, the isomers having erythro AHPA, which is difficult to form a chelate ring, are expected not to show inhibitory activity. However, the isomers having erythro-AHPA or (2S, 3S)-AHPA showed marked inhibitory activity. Bestatin and its active isomers are effective due to a mechanism other than a chelating action at the active center8.

1. Umezawa H, Aoyagi T, Suda H, Hamada M, Takeuchi T, Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes, J Antibiot (Tokyo). 1976 Jan; 29(1):97-9.
2. Umezawa, H., Aoyagi, T., Suda, H., Hamada, M., And Takeuchi, T. 197615. Antibiotics 29, 97.
3. Suda, H., Takita, T., Aoyagi, T., And Umezawa, H. (1976) J. Antibiotics 29, 100.
4. Nakamura, H., Suda, H., Takita, T., Aoyagi, T., Umezawa, H., And Iitaka, Y. (1976) J. Antibiotics 29, 102.
5. Umezawa, S., Tsuchiya, T., And Tatsuta, K. (1966) Bull. Chem. Sot. Japan 39, 1235.
6. Barlow, C. B., And Gijthrie, R. D. (1967) J. Chem. Sot. (C) 1194.
7. Bukhari, S. T. K., Guthrie, R. D., Scott, A. I., And Wrixon, A. D. (1970) Tetrahedron 26, 3653.
8. Suda et al. Inhibition of aminopeptidase B and leucine aminopeptidase by bestatin and its stereoisomer, Archives of Biochemistry and Biophysics, 77, 196-200 (1976)

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
Cas No.58970-76-6
Solubility≥12.34mg/mL in DMSO
Chemical Name(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid
SDFDownload SDF
Shipping ConditionEvaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request
General tipsFor obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.


Cell experiment [1]:

Cell lines

K562 and K562/ADR cells

Preparation method

The solubility of this compound in DMSO is ≥12.34mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reaction Conditions

24 h; 100 μM


To determine the interaction and the possible role of APN in MDR, RT–PCR was performed to detect the mRNA levels of APN and MDR1 in K562 and K562/ADR cells. After incubation with various concentration of bestatin for 24 h, the expression of APN mRNA was almost unchanged in K562 and K562/ADR cells. However, K562/ADR cells exhibited a significant lower level of APN mRNA than K562 cells. On the other hand, high dose of bestatin (100 μM) induced MDR1 upregulation by 49.4% and 18.0% in K562 and K562/ADR cells, respectively. The result confirmed that bestatin was a substrate of P-gp in mRNA level.

Animal experiment [1]:

Animal models

Male Wistar rat

Dosage form

4 mg/kg, dis-solved in normal saline; oral taken


When bestatin and CsA were co-administered orally, the plasma concentrations of bestatin were increased significantly compared to that of control group. 1.97- and 1.92-fold increases were observed in Cmax (4.8±0.8 μg/ml vs. 2.4±0.6 μg/ml) and AUC (1.06±0.14 mg min/ml vs. 0.55±0.04 mg min/ml) of bestatin after combination with CsA, respectively. The results suggested concomitantly administered CsA increased the intestinal absorption of bestatin.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.


[1] Huo X, Liu Q, Wang C, et al. Enhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferative activity of bestatin[J]. European Journal of Pharmaceutical Sciences, 2013, 50(3): 420-428.

Biological Activity

Description Bestatin is a potent aminopeptidase inhibitor with IC50 values of 0.5 nM, 5 nM, 0.28 µM and 1-10 µM for cytosol aminopeptidase, aminopeptidase N, zinc aminopeptidase and amino peptidase B, respectively.
Targets cytosol aminopeptidase aminopeptidase N zinc aminopeptidase amino peptidase B    
IC50 0.5 nM 5 nM 0.28 µM 1-10 µM    

Quality Control

Research Update

1. The effects of bestatin on humoral response to sheep erythrocytes in non-treated and cyclophosphamide-immunocompromised mice. Immunopharmacol Immunotoxicol. 2013 Feb;35(1):133-8. doi: 10.3109/08923973.2012.719524. Epub 2012 Sep 7.
Bestatin potentiated the humoral response to SRBC in mice increasing numbers of PFC AND 2-ME-resistant anti-SRBC antibodies and decreasing total anti-SRBC hemagglutinins; while it partially restored cyclophosphamide-induced immunosuppression in a dose-and-schedule-dependent manner.
2. Methotrexate-bestatin interaction: Involvement of P-glycoprotein and organic anion transporters in rats. Int J Pharm. 2014 Feb 13. pii: S0378-5173(14)00102-1. doi: 10.1016/j.ijpharm.2014.02.020. [Epub ahead of print]
The intravenous co-administration of bestatin and MTX resulted in increased uptake of them in intestines and decreased uptake in kidney and hOAT1- or hOAT3-HEK 293 cells, which indicates that the interaction of these two drugs occurs through co-transport by P-gp in the intestinal mucosa and OATs in kidney.
3. Enhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferative activity of bestatin. Eur J Pharm Sci. 2013 Nov 20;50(3-4):420-8. doi: 10.1016/j.ejps.2013.08.010. Epub 2013 Aug 25.
Reduced intestinal absorption and accumulation of bestatin was caused by P-gp-mediated efflux and could be restored by the addition of P-gp inhibitors (verapamil or Cyclosporin A) or P-gp substrates (doxorubicin) leading to decreased IC50 value and increased level of bestatin.
4. [Inhibition of tumor cell invasion and induction of apoptosis by ubenimex]. Yao Xue Xue Bao. 2012 Dec;47(12):1593-8.
Bestatin (Ubenimex) at high concentration inhibited proliferation of tumor cells (HT-1080) and induced apoptosis and cell arrest at G1 phase; while it at low concentration inhibited the aminopeptidase activity and invasion of tumor cells.
5. Organic anion transporters involved in the excretion of bestatin in the kidney. Peptides. 2012 Feb;33(2):265-71. doi: 10.1016/j.peptides.2012.01.007. Epub 2012 Jan 18.
OAT1 and OAT3 have been found to be involved in the renal excretion of bestatin, since reduced uptake of bestatin in hOAT1-HEK and hOAT3-HEK 293 cells were observed in the presence of OAT substrates including PAH, PCG and JBP485.