58970-76-6

Basic information

• Product Name: Bestatin
• Synonyms: N-[(2S,3R)-3-AMINO-2-HYDROXY-1-OXO-4-PHENYLBUTYL]-L-LEUCINE;N-((2S,3R)-3-AMINO-2-HYDROXY-4-PHENYLBUTYRYL)-L-LEUCINE;[(2S,3R)-3-AMINO-2-HYDROXY-4-PHENYLBUTYRYL]-L-LEUCINE;[(2S,3R)-3-AMINO-2-HYDROXY-4-PHENYLBUTANOYL]-LEU;[(2S,3R)-3-AMINO-2-HYDROXY-4-PHENYLBUTANOYL]-LEU-OH;[(2S, 3R)-3-AMINO-2-HYDROXY-4-PHENYLBUTANOYL]-L-LEUCINE;BESTATIN;[S-(R*,S*)]-N-(3-amino-2-hydroxy-4-phenylbutyroyl)-L-leucine
• CAS NO: 58970-76-6
• Molecular Formula: C₁₆H₂₄N₂O₄
• Molecular Weight: 308.37
• EINECS: 261-529-2
• Product Categories: Active Pharmaceutical Ingredients;Ubenimex;Pepetides;ProteaseInhibitors;peptides;Bestatin
• Mol File: 58970-76-6.mol
• Article Data: 20

Chemical Properties

• Melting Point: 245 °C (dec.)(lit.)
• Boiling Point: 448.76°C (rough estimate)
• Flash Point: 319.5 °C
• Appearance: White/Powder
• Density: 1.0917 (rough estimate)
• Vapor Pressure: 1.8E-15mmHg at 25°C
• Refractive Index: 1.5800 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Aqueous Acid (Slightly, Sonicated), DMSO (Slightly, Heated), Methanol (Slightly,
• PKA: 8.1, 3.1(at 25℃)
• Water Solubility: Soluble in water (<1 25), DMSO (2 mg/ml), methanol (5 mg/ml), 1eq. NaOH (50 mM), ethanol (<1 mg/ml at 25°C), acetic acid,
• Merck: 13,9910
• CAS DataBase Reference: Bestatin(CAS DataBase Reference)
• NIST Chemistry Reference: Bestatin(58970-76-6)
• EPA Substance Registry System: Bestatin(58970-76-6)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• RTECS: OH2915000
• Hazardous Substances Data: 58970-76-6(Hazardous Substances Data)

Usage

Description

Bestatin, also known as Ubenimex, is a potent aminopeptidase inhibitor originally isolated from Streptomyces olivoreticuli. It is a white powder that is soluble in various organic solvents such as methanol, ethanol, and DMSO. Bestatin selectively inhibits aminopeptidase B, aminopeptidase N, leucine aminopeptidase, and the aminopeptidase activity of leukotriene A4 hydrolase. It has been found to have immunomodulatory properties, antitumor activity, and has been investigated in clinical trials for its potential therapeutic applications.

Uses

Used in Oncology:
Bestatin is used as an anticancer agent for the treatment of non-lymphocytic leukemia. It has been shown to inhibit the proliferation of various cancer cell lines and is particularly effective in treating acute myelocytic leukemia. When added to radiotherapy or chemotherapy following surgery, Bestatin significantly increases survival time through immunopotentiation.
Used in Immunomodulation:
Bestatin acts as an immunomodulator by activating macrophages and T lymphocytes, enhancing the immune response against cancer cells.
Used in Enzyme Inhibition:
Bestatin is used as an inhibitor of aminopeptidase B, aminopeptidase N, leucine aminopeptidase, and leukotriene A4 hydrolase. It inhibits the production of leukotriene B4 in erythrocytes and has been shown to decrease serum levels of leukotriene B4, reducing tumor growth in colorectal cancer.
Used in Drug Development:
Bestatin has been investigated for its potential use in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells. It can indirectly act on monocytes by inhibiting aminopeptidase B, which in turn inhibits the catabolism of tuftsin. Bestatin can also directly stimulate lymphocytes through its fixation on the cell surface.
Used in Pharmaceutical Industry:
Bestatin is used as a pharmaceutical agent for the development of treatments targeting various types of cancers, including leukemia and colorectal cancer. Its immunomodulatory and antitumor properties make it a promising candidate for further research and potential therapeutic applications in oncology.

Originator

Inst. of Microbial Chem (Japan)

Biological Activity

Aminopeptidase inhibitor (K i = 0.001-90 mM); inhibits enkephalin metabolism and leukotriene A 4 hydrolase. Inhibits tumor cell proliferation.

Safety Profile

Poison by intraperitoneal route.Moderately toxic by subcutaneous route. Experimentalreproductive effects. When heated to decomposition itemits toxic fumes of NOx.

Clinical claims and research

Bestatin (ubenimex) is a potent inhibitor of aminopeptidase N and aminopeptidase B, which was isolated from a culture filtrate of Streptomyces olivoreticuli during the search for specific inhibitors of enzymes present on the membrane of eukaryotic cells. Inhibitors of aminopeptidase activity are associated with macrophage activation and differentiation, and Bestatin has shown significant therapeutic effects in several clinical trials. In one multi-institutional study, patients with acute non-lymphocytic leukemia (ANLL) were randomized to receive either Bestatin or control orally after completion of induction and consolidation therapy, and concomitant with maintenance chemotherapy. Remission duration was prolonged in the Bestatin group, although this difference did not reach statistical significance. However, OS was prolonged in the Bestatin group. Recently, a confirmatory phase III trial in ANLL was reported that extended the observation to a significant prolongation of remission. Bestatin has also shown adjuvant activity when administered to acute leukemia and CML patients who did not develop graft-versus-host disease (GVHD) within 30 days following BMT. Bestatin-treated acute leukemia patients had an increased incidence of chronic low-grade GVHD compared with the control arm and a lower relapse rate. Recently, a phase III study of resected stage 1 squamous cell lung cancer patients treated orally with either Bestatin or placebo daily for 2 years revealed that 5-year cancer-free survival was significantly greater in the Bestatin group (71%) as compared to the placebo group (62%). OS was also significantly improved, as was cancer-free survival. Recent studies in patients with nonsmall cell lung cancer (NSCLCs) suggest that it also has anti-angiogenic activity.

Mode of action

Bestatin acts as an immunomodulator by activating macrophages and T lymphocytes.

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)

InChI:InChI=1/C16H24N2O4/c1-10(2)8-13(16(21)22)18-15(20)14(19)12(17)9-11-6-4-3-5-7-11/h3-7,10,12-14,19H,8-9,17H2,1-2H3,(H,18,20)(H,21,22)/t12-,13?,14+/m1/s1

Upstream product

• 577979-03-4 methyl N-{(2S,3R)-2-O-benzyl-4-phenyl-3-[9-phenyl-9-fluorenyl-amino]-butanoyl}-L-leucine 
• 87304-15-2 (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid 
• 62023-23-8 [(R)-1-Benzyl-2-(3,5-dimethyl-pyrazol-1-yl)-2-oxo-ethyl]-carbamic acid benzyl ester 
• 1089733-96-9 C₃₀H₃₂N₂O₄ 
• 180922-42-3 ethyl (2S,3R)-2-hydroxy-4-phenyl-3-(tosylamino)butanoate 
• 180922-44-5 (2S,3R)-2-hydroxy-4-phenyl-3-(tosylamino)butanoic acid 
• 6125-24-2 2-Phenylnitroethane 
• 1738-77-8 L-leucine benzyl ester p-toluenesulfonate 
• 62023-65-8 (2S,3R)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-4-phenyl-butanoic acid 
• 18942-49-9 Boc-D-Phe-OH 
• 869115-78-6 (2S,3R)-2-Acetoxy-3-tert-butoxycarbonylamino-4-phenyl-butyric acid 
• 301544-46-7 (S)-2-((R)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenyl-butyrylamino)-4-methyl-pentanoic acid benzyl ester 
• 308238-66-6 (S-(R*,S*))-N-(3-amino-2-hydroxy-4-phenylbutyroyl)-L-leucine 
• 121445-53-2 N-<(2S,3S)-3-azido-2-hydroxy-4-phenylbutanoyl>-L-leucine benzyl ester 

Downstream Products

• 62023-78-3 nitrobestatin 
• 1225383-33-4 (S)-2-{(2S,3R)-3-[(9H-fluoren-9-yl)methoxy]carbonylamino-2-hydroxy-4-phenylbutanamido}-4-methylpentanoic acid 
• 65322-89-6 methyl (2S)-2-(((2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl)amino)-4-methylpentanoate 
• 1459703-81-1 (S)-methyl 2-((2S,3R)-3-acetamido-2-acetoxy-4-(4-bromophenyl)butanamido)-4-methylpentanoate 
• 1459703-80-0 (S)-methyl 2-((2S,3R)-3-acetamido-4-(4-bromophenyl)-2-hydroxybutanamido)-4-methylpentanoate 
• 1459703-79-7 (S)-methyl 2-((2S,3R)-3-acetamido-2-acetoxy-4-phenylbutanamido)-4-methylpentanoate 
• 82008-81-9 (S)-methyl 2-((2S,3R)-3-acetamido-2-hydroxy-4-phenylbutanamido)-4-methylpentanoate 
• 1333111-61-7 Boc-LYP₂ 
• 1312302-10-5 tert-butyl (2R,3S)-3-hydroxy-4-[(S)-4-methyl-1-(methylamino)-1-oxopentan-2-ylamino]-4-oxo-1-phenylbutan-2-ylcarbamate 
• 1041865-45-5 (S)-2-[1-(dimethylamino)naphthalene-5-sulfonamido]ethyl 2-[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanamido]-4-methylpentanoate 
• 87304-15-2 (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid 

Relevant articles and documents

A route to dipeptides containing β-amino-α-hydroxy acid fragments by coupling of N-boc-β-lactams with α-amino esters. Application to the synthesis of (-)-bestatin

α-Amino esters are smoothly acylated by N-Boc-3-alkoxy-4-alkyl-β-lactams in DMF under the influence of sodium azide, giving a novel dipeptide coupling reaction.

Preparation method of ubenimex

The invention provides a preparation method of ubenimex. The preparation method comprises that L-leucine benzyl ester p-toluenesulfonate and HOBt undergo a condensation reaction to produce an activated ester solution, (2S, 3R)-3-benzyloxyformamido-2-hydroxy-4- phenylbutyric acid and a weak acid strong alkali inorganic salt are mixed, the activated ester solution is added into the mixture drop by drop and undergoes a reaction to produce N-[(2S, 3R)-3-benzoylformamido-2-hydroxy-4-phenylbutyryl]-L-leucine, and N-[(2S, 3R)-3-benzoylformamido-2-hydroxy-4-phenylbutyryl]-L-leucine is reduced into ubenimex through hydrogen gas. The preparation method utilizes ethyl acetate as an organic solvent, saves tetrahydrofuran-caused potential safety hazard, utilizes the weak acid strong alkali inorganic salt as a base catalyst, saves a cost, is free of an organic solvent and is easy to operate.

A Ubenimex the asymmetric synthesis of the method of

The invention relates to an ubenimex synthesis method which is simple and convenient in operation. The method comprises the steps: (S1) catalyzing nitrobenzene ethane and glyoxylic acid, which serve as raw materials, by a catalyst, so as to obtain (2S,3R)-2-hydroxy-3-nitro-4-phenyl-butyric acid; (S2) catalyzing (2S,3R)-2-hydroxy-3-nitro-4-phenyl-butyric acid and L-leucine, which serve as raw materials, by a condensation agent and an activator, so as to obtain N-[(2S,3R)-4-phenyl-3-nitro-2-hydroxy butyryl]-L-leucine; (S3) reducing nitro of N-[(2S,3R)-4-phenyl-3-nitro-2-hydroxy butyryl]-L-leucine, which serves as a raw material, into amino, thereby obtaining ubenimex. By adopting the method to asymmetrically synthesize ubenimex, the steps are simple, subsequent resolution is avoided, the utilization ratio of atoms is high, and the production cost is low.