58970-76-6

Usage

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

• 60016-66-2 benzyl N-[(2S,3R)-3-(N-benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-L-leucinate 
• 121445-53-2 N-<(2S,3S)-3-azido-2-hydroxy-4-phenylbutanoyl>-L-leucine benzyl ester 
• 308238-66-6 (S-(R*,S*))-N-(3-amino-2-hydroxy-4-phenylbutyroyl)-L-leucine 
• 301544-46-7 (S)-2-((R)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenyl-butyrylamino)-4-methyl-pentanoic acid benzyl ester 
• 87304-15-2 (2S)-2-[[(2S,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid 
• 95832-38-5 methyl (4R,5S)-2-oxo-4-phenylmethyl-1,3-oxazolidine-5-carboxylate 
• 1089733-96-9 C₃₀H₃₂N₂O₄ 
• 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 
• 172025-60-4 (2S,3R)-3-Azido-2-hydroxy-4-phenyl-butyric acid methyl ester 
• 612096-23-8 (2R,3S)-3-Bromo-2-hydroxy-4-phenyl-butyric acid methyl ester 
• 182699-39-4 (2S,3R)-methyl-2,3-epoxy-4-phenylbutanoic acid 

Downstream Products

• 1225383-33-4 (S)-2-{(2S,3R)-3-[(9H-fluoren-9-yl)methoxy]carbonylamino-2-hydroxy-4-phenylbutanamido}-4-methylpentanoic acid 
• 1333111-61-7 Boc-LYP₂ 
• 82008-81-9 (S)-methyl 2-((2S,3R)-3-acetamido-2-hydroxy-4-phenylbutanamido)-4-methylpentanoate 
• 1459703-79-7 (S)-methyl 2-((2S,3R)-3-acetamido-2-acetoxy-4-phenylbutanamido)-4-methylpentanoate 
• 1459703-80-0 (S)-methyl 2-((2S,3R)-3-acetamido-4-(4-bromophenyl)-2-hydroxybutanamido)-4-methylpentanoate 
• 1459703-81-1 (S)-methyl 2-((2S,3R)-3-acetamido-2-acetoxy-4-(4-bromophenyl)butanamido)-4-methylpentanoate 
• 65322-89-6 methyl (2S)-2-(((2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl)amino)-4-methylpentanoate 
• 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 
• 62023-78-3 nitrobestatin 

Relevant academic research and scientific papers

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.

A ubenimex in the synthesis of the impurity and its preparation method (by machine translation)

The invention provides a bestatin the impurities in the raw material, the impurity of the structure has been confirmed, is ubenimex quality control in order to obtain high-quality ubenimex bulk drug. The invention also provides a preparation method of the impurity, the preparation method of the high purity of the product, can be used as the raw materials of the bestatin quality research process impurities to the use of the reference substance. (by machine translation)

A synthesis method of ubenimex

The invention discloses a method for synthesizing ubenimex. The method comprises the following steps: by taking D-Boc-phenyl alaninal as a raw material, sequentially preparing hydroxynitrile, carrying out a nitrile hydrolysis reaction, performing amino protection, performing chiral resolution on (2RS,3R)-3-tert-butoxyacylamino-2-hydroxy-4-phenylbutyric acid, and synthesizing (S)-phenyl-2-((2S,3R)-3-(tert-butoxyacylamino)-2-hydroxy-4-phenylbutyramide)-4-mevalonate, thereby synthesizing the ubenimex. According to the synthetic method disclosed by the invention, the defect that the resolving agent used in the conventional synthetic method is high in toxicity (such as strychnine) or high in price (such as alpha-phenylethylamine) is overcome, the synthetic method is simple in steps and low in cost, and use of reagents such as strychnine is avoided; and moreover, a dextro-amino compound is taken as the chiral resolution agent, the price is low, the operation is simple, the stirring and recrystallization time is shortened, and the synthetic efficiency is greatly improved.

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.

Common precursor strategy for the synthesis of bestatin, amprenavir intermediate and syn-4-hydroxy-5-phenyl-γ-lactam

A common precursor strategy for the synthesis of bestatin hydrochloride, an anticancer agent, 1,3-diaminoalcohol, an amprenavir intermediate, and a syn-4-hydroxy-5-phenyl-γ-lactam intermediate of various bioactive molecules using an α,β-unsaturated ester as a common precursor is described. The protocol offers mild reaction conditions, good yields and excellent stereoselectivity.

Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase

The malarial PfA-M1 metallo-aminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-d-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the α-hydroxyβ-amino acid (P1) or the adjacent naturalα-amino acid (P1′). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBzl) 16 at the P1 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PfA-M1 pocket that interacts with the P1 side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria.

A short enantioselective synthesis of (-)-bestatin via l-proline-catalyzed α-amination of an aldehyde

A short and high yielding enantioselective synthesis of (-)-bestatin, a naturally occurring aminopeptidase inhibitor, is described via l-proline-catalyzed asymmetric α-amination of 3-phenylpropionaldehyde as the key reaction. The methodology also involves a Pd-catalyzed intramolecular cyclization of an allylic acetate giving a trans-oxazoline in a highly diastereoselective manner (dr > 14:1).

A total synthesis of (-)-bestatin using Shibasaki's asymmetric Henry reaction

A total synthesis of the potent aminopeptidase inhibitor (-)-bestatin has been achieved using Shibasaki's asymmetric Henry reaction catalyzed by an optically active rare earth lanthanum-(R)-binaphthol complex in 26% overall yield.

New stereoselective synthesis of the peptidic aminopeptidase inhibitors bestatin, phebestin and probestin

Peptidic aminopeptidase inhibitors, bestatin, phebestin and probestin have been prepared by stereo- and regiocontrolled reactions from a common α,β-epoxy ester precursor.