Bestatin
(Synonyms: 乌苯美司; Ubenimex) 目录号 : GC11780
An aminopeptidase inhibitor
Cas No.:58970-76-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
K562 and K562/ADR cells |
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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. |
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Reaction Conditions |
24 h; 100 μM |
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Applications |
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]: | |
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Animal models |
Male Wistar rat |
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Dosage form |
4 mg/kg, dis-solved in normal saline; oral taken |
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Applications |
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. |
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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. |
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References: [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. |
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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.
References:
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)
| Cas No. | 58970-76-6 | SDF | |
| 别名 | 乌苯美司; Ubenimex | ||
| 化学名 | (2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid | ||
| Canonical SMILES | CC(C)CC(C(=O)O)NC(=O)C(C(CC1=CC=CC=C1)N)O | ||
| 分子式 | C16H24N2O4 | 分子量 | 308.37 |
| 溶解度 | ≥ 12.34mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2429 mL | 16.2143 mL | 32.4286 mL |
| 5 mM | 0.6486 mL | 3.2429 mL | 6.4857 mL |
| 10 mM | 0.3243 mL | 1.6214 mL | 3.2429 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Bestatin as an experimental tool in mammals
Curr Drug Metab 2001 Mar;2(1):67-85.11465152 10.2174/1389200013338748
Bestatin, an antibiotic of microbial origin, is a potent inhibitor of some, but not all aminopeptidases. It can be administered, with low toxicity, to cultured cells, intact animals and humans. It has become a useful tool in elucidating the physiological role of some mammalian exopeptidases in the regulation of the immune system, in the growth of tumors and their invasion of surrounding tissues, and in the degradation of cellular proteins. Bestatin-sensitive enzymes play important roles in the digestion and absorption of peptides in the brush border of the intestine and the kidney, in the reproductive system, and in the metabolism of opioid peptides and leukotrienes. Aminopeptidase N emerges as the major target for the effects of Bestatin on the immune system and some of its effects on tumor growth and the endometrium. It is also the major bestatin-sensitive enzyme involved in the degradation of oligopeptides on the surface of intestine and kidney brush borders, and the inactivation of enkephalins in the brain. Bestatin-sensitive cytosolic exopeptidases are important in the degradation to amino acids of di- and tripeptides generated in most cells by cellular protein degradation, as well as those absorbed through the brush border of intestine and kidney. Inhibition of one of these exopeptidases, cytosol alanine aminopeptidase, results in apoptosis. Bestatin-sensitive cystinyl aminopeptidase is abundant in placenta. Two bestatin-sensitive enzymes, aminopeptidase B and nardilysin, are particularly abundant in late spermatids. Finally bestatin-sensitive LTA4 hydrolase generates the potent chemotactic agent, LTB4.
Bestatin, an aminopeptidase inhibitor with a multi-pharmacological function
Biomed Pharmacother 1991;45(2-3):49-54.1912369 10.1016/0753-3322(91)90122-a
Bestatin, the dipeptide N-((2S, 3R)-3-amino-2-hydroxy-4-phenyl butanyl) L-leucine is a leucine aminopeptidase and aminopeptidase-B inhibitor. It exerts a direct stimulating effect on lymphocytes (and monocytes) via its fixation on cell surface leucine-aminopeptidase, and an indirect effect on monocytes (and lymphocytes) via aminopeptidase B inhibition of tuftsin catabolism. Thus it is an immuno-modifier as shown by the Japanese and also our groups: a) immuno-modifier, especially stimulator, in normal young mice; b) immunorestorator and spontaneous tumor preventive agent in aged mice; c) immunorestorator in the elderly and in cancer patients and HIV infected subjects. It stimulates granulocytopoiesis and thrombocytopoiesis in vitro, and can restore them in vivo in myelo-hypoplastic man. The anti-aminopeptidase action of Bestatin also protects enkephalins against their catabolism, which encouraged us, with good preliminary results, to study its analgesic action and search for a preventive effect on "desaddicted" toxicomaniac relapses.
Review of ubenimex (Bestatin): clinical research
Biomed Pharmacother 1991;45(2-3):55-60.1912370 10.1016/0753-3322(91)90123-b
An immunomodulating agent, ubenimex (Bestatin) has low toxicity even after long-term oral administration and brings about significant modifications in immunological response. In a cooperative randomized controlled study of Bestatin immunotherapy for adult acute nonlymphocytic leukemia, prolongation of remission duration and survival was achieved with Bestatin immunotherapy combined with remission maintenance chemotherapy. The significant prolongation of remission duration and survival was seen in the Bestatin group, especially in the elderly patients. Randomized controlled studies of Bestatin immunotherapy were performed in solid tumors including malignant melanoma, carcinoma of the lung, stomach, bladder, head and neck and esophagus, and therapeutic benefits regarding disease free-interval or survival were observed in certain types of the above-mentioned cancers; however, Bestatin immunotherapy for these cancers should be further investigated in large-scale controlled studies to confirm its activity.
Bestatin Cream Impairs Solar Simulated Light鈥扗riven Skin Inflammation and Skin Carcinogenesis in Mice
J Invest Dermatol 2021 Nov;141(11):2699-2709.e2.34051272 10.1016/j.jid.2021.03.032
Leukotriene A4 hydrolase (LTA4H) is an enzyme that catalyzes the production of the inflammatory mediator leukotriene B4, which is involved in inflammatory responses mediated through the leukotriene B4/leukotriene B4 receptor type 1 (BLT1) signaling pathway. In this study, we investigated whether Bestatin, an LTA4H inhibitor, could suppress skin acute inflammation and carcinogenesis. In the clinical sample, BLT1 was significantly induced in human skin tissues after acute solar simulated light (SSL) exposure. BLT1 and NF-魏B p65 expressions were also increased in acute SSL鈥抜nduced mouse skin tissue. Furthermore, LTA4H and BLT1 were highly expressed in skin chronic inflammation and squamous cell carcinomas. More importantly, topical administration of Bestatin cream dramatically inhibited BLT1 expression in acute SSL鈥抜nduced human skin tissues. BLT1 and NF-魏B p65 expressions were also suppressed in acute SSL鈥抜nduced Lta4h-knockout and bestatin-treated mice skin tissues. Moreover, we conducted long-term prevention and therapeutic studies, which showed that Bestatin significantly attenuated SSL-induced skin carcinogenesis. Mechanistic studies showed that Bestatin inhibited skin carcinogenesis by suppressing cell proliferation and inducing cell apoptosis through LTA4H鈥払LT1鈥抪rotein kinase B鈥扤F-魏B p65 pathway. Overall, our results suggest that topical application of novel cream containing Bestatin might open a helpful avenue for SSL-induced skin carcinogenesis.
Clinical trials of Bestatin for leukemia and solid tumors
Biotherapy 1992;4(3):205-14.1599804 10.1007/BF02174207
A new immunomodulating agent, Bestatin (INN: ubenimex) has low toxicity after long-term oral administration and significantly modifies immunological responses. Prolongation of remission duration and survival was achieved in adult acute nonlymphocytic leukemia with Bestatin immunotherapy combined with remission maintenance chemotherapy. Patients with myelodysplatic syndrome (MDS) and chronic myelogenous leukemia (CML) responded to Bestatin, and it is noted that cytogenetic remission was obtained in CML. MDS and CML are thought to be a family of clonal malignant disorders in which malignant transformations occurs at the level of the pluripotent stem cell. Bestatin may be capable of modifying the biological-proliferative disequilibrium of the disease, and the therapy opens new and promising prospects in the treatment of both MDS and CML. Randomized controlled studies of Bestatin immunotherapy were performed in solid tumors including malignant melanoma, carcinoma of the lung, stomach, bladder, head and neck, and esophagus, and therapeutic benefits on disease free-interval or survival were observed in certain types of these cancers. However, the adjuvant activity of Bestatin immunotherapy for these cancers should be further investigated to confirm its activity.