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 is an aminopeptidase inhibitor originally isolated from S. olivoreticuli. It inhibits aminopeptidase B (IC50 = 0.05 μg/ml), aminopeptidase N (IC50 = 16.9 μM), leucine aminopeptidase (IC50 = 0.01 μg/ml), and the aminopeptidase activity of leukotriene A4 (LTA4) hydrolase (Kapp = 172 nM). It is selective for these aminopeptidases over aminopeptidase A, trypsin, chymotrypsin, elastase, papain, pepsin, and thermolysin. Bestatin inhibits the production of LTB4 in erythrocytes when used at a concentration of 70 μM. It increases the expression of Akt, inhibits proliferation, migration, and invasion, and induces autophagy and apoptosis in 5637 bladder cancer cells. Bestatin (5 and 15 mg/kg) decreases serum levels of LTB4 and reduces tumor growth in a patient-derived xenograft (PDX) mouse model of colorectal cancer.

Chemical Properties

white powder, soluble in methanol, ethanol, DMSO and other organic solvents, from Streptomyces olivoreticuli.

Originator

Inst. of Microbial Chem (Japan)

Uses

Different sources of media describe the Uses of 58970-76-6 differently. You can refer to the following data:
1. Ubenimex (also known as bestatin) is a competitive aminopeptidase B inhibitor with an IC50 of 100 mg/ml for K562 cells. Proliferation of all the cell lines except KG1 was inhibited by bestatin. P39/TSU, HL60 and U937 were highly sensitive, with 50% growth inhibitory concentration. It is useful in the treatment of non-lymphocytic leukemia. In other types of cancers ubenimex added to radiotherapy or chemotherapy following surgery significantly inmases survival time through immunopotentiation. It is being studied for use in the treatment of acute myelocytic leukemia.
2. Bestatin is "pseudo"-dipeptide isolated from Strepotmyces olivreticuli in 1976. Bestatin is a potent aminopeptidase B inhibitor with no carboxypeptidase activity. Bestatin acts as an immunomodulator by activating macrophages and T lymphocytes. Bestatin also exhibits good antitumour activity and is has been investigated in clinical trials.

Application

Bestatin can indirectly act on monocytes by inhibiting Aminopeptidase B, which in turn inhibits the catabolism of tuftsin. Bestatin has also been shown to inhibit Leukotriene A4 hydrolase. It can directly stimulate lymphocytes through its fixation on the cell surface. The agent has been used in multiple leukemia studies. Bestatin is an aminopeptidase inhibitor, inhibits enkephalin metabolism and leukotriene A4 hydrolase. Inhibits tumor cell proliferation.

Brand name

Bestatin

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

• 1738-69-8 L-Leucine benzyl ester 
• 172025-46-6 (S)-2-[((4S,5S)-5-Benzyl-2,2-dimethyl-[1,3]dioxolane-4-carbonyl)-amino]-4-methyl-pentanoic acid benzyl ester 
• 172025-48-8 (S)-2-((2S,3S)-2,3-Dihydroxy-4-phenyl-butyrylamino)-4-methyl-pentanoic acid benzyl ester 
• 172025-43-3 (R)-1-[(4R,5S)-5-(Hydroxy-phenyl-methyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-ethane-1,2-diol 
• 172025-45-5 (4S,5S)-5-Benzyl-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid 
• 176895-32-2 (3aS,6S,6aS)-2,2-dimethyl-6-phenyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one 
• 100-58-3 phenylmagnesium bromide 
• 246506-75-2 [1-benzyl-3-cyano-2-oxo-3-(triphenyl-λ⁵-phosphanylidene)-propyl]-carbamic acid tert-butyl ester 
• 246506-78-5 2-(3-tert-butoxycarbonylamino-2-oxo-4-phenylbutyrylamino)-4-methylpentanoic acid benzyl ester 
• 18942-49-9 Boc-D-Phe-OH 
• 301544-37-6 (S)-2-Isocyano-4-methyl-pentanoic acid benzyl ester 
• 2462-35-3 L-leucine benzyl ester hydrochloride 
• 63219-70-5 N-(benzyloxycarbonyl)-D-phenylalaninal 
• 2448-45-5 Cbz-D-Phe 

Downstream Products

• 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 
• 1225383-33-4 (S)-2-{(2S,3R)-3-[(9H-fluoren-9-yl)methoxy]carbonylamino-2-hydroxy-4-phenylbutanamido}-4-methylpentanoic acid 
• 62023-78-3 nitrobestatin 

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.