133407-82-6

Basic information

• Product Name: MG-132
• Synonyms: PROTEASOME INHIBITOR MG-132;N-[(PHENYLMETHOXY)CARBONYL]-L-LEUCYL-N-[(1S)-1-FORMYL-3-METHYLBUTYL]-L-LEUCINAMIDE;N-CBZ-LEU-LEU-LEUCINAL;MG-132;Z-LLL-CHO;Z-LL-CHO;Z-LEU-LEU-LEU-CHO;Z-LEU-LEU-LEU-H
• CAS NO: 133407-82-6
• Molecular Formula: C26H41N3O5
• Molecular Weight: 475.62
• Product Categories: Cytokine signaling;Apoptosis Inducers;API;Aldehydes;and Substrates;Application Index;Bioactive Small Molecules;Biochemicals and Reagents;Building Blocks;C13-C60;Calpain and Lysosomal Proteases;Calpain and Proteasome Inhibitors;Carbonyl Compounds;Cell Biology;Cell Signaling and Neuroscience;Cell Signaling Enzymes;Chemical Synthesis;Enzymes;Inhibitors;Intracellular Protein Degradation;Nitric Oxide and Cell Stress;Organic Building Blocks;Proteasome;Proteasomes;Z;ProteasomeInhibitors;peptides;inhibitor
• Mol File: 133407-82-6.mol

Chemical Properties

• Melting Point: 80-84℃ (DEC.)
• Boiling Point: 682 °C at 760 mmHg
• Flash Point: 366℃
• Appearance: White/solid film
• Density: 1.073
• Vapor Pressure: 1.86E-18mmHg at 25°C
• Refractive Index: 1.506
• Storage Temp.: −20°C
• Solubility: methanol: 1 mg/mL
• PKA: 11.14±0.46(Predicted)
• Water Solubility: Soluble in ethanol, chloroform, methanol, water.
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO, DMF or ethanol may be stored at -20° for up to 1 week.
• CAS DataBase Reference: MG-132(CAS DataBase Reference)
• NIST Chemistry Reference: MG-132(133407-82-6)
• EPA Substance Registry System: MG-132(133407-82-6)

Safety Data

• Statements: 36/37/38
• Safety Statements: 24/25
• WGK Germany: 3
• Hazardous Substances Data: 133407-82-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
MG-132 is used as a proteasome and NF-κB inhibitor for its ability to suppress gastric cancer cell proliferation, induce macro-autophagy, and activate stress kinases.
Used in Neuroprotection:
MG-132 is used as a neuroprotective product due to its ability to induce neurite outgrowth in PC12 cells and block NFκB activation, which can be beneficial in treating neurodegenerative diseases.
Used in Research Applications:
MG-132 is used as a research tool to study the role of proteasomes and NF-κB in various cellular processes, as well as to investigate the effects of proteasome inhibition on protein degradation and cellular signaling pathways.

Biological Activity

Potent cell-permeable inhibitor of proteasome (IC 50 = 100 nM) and calpain (IC 50 = 1.2 μ M). Inhibits TNF- α -induced NF- κ B activation and I κ B α degradation. Induces neurite outgrowth in PC12 cells and has anticancer properties in vitro .

Biochem/physiol Actions

Cell permeable: yes

References

1) Tsubuki et al. (1996), Differential inhibition of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine; J. Biochem.,? 119 572 2) Wu? et al. (2010), Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells; Autophagy, 6 228 3) Meriin? et al. (1998), Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis; J. Biol. Chem., 273 6373 4) Fiedler et al. (1998), Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132; Am. J. Respir. Cell Mol. Biol., 19 259

InChI:InChI=1/C26H41N3O5/c1-17(2)12-21(15-30)27-24(31)22(13-18(3)4)28-25(32)23(14-19(5)6)29-26(33)34-16-20-10-8-7-9-11-20/h7-11,15,17-19,21-23H,12-14,16H2,1-6H3,(H,27,31)(H,28,32)(H,29,33)/t21-,22-,23-/m0/s1

Upstream product

• 7801-71-0 N-benzyloxycarbonyl-L-leucyl-L-leucine 
• 13139-15-6 N-tert-butoxycarbonyl-L-leucine 
• 82010-31-9 (S)-(1-hydroxymethyl-3-methylbutyl)carbamic acid tert-butyl ester 
• 1161015-91-3 {1-[1-(1-hydroxymethyl-3-methylbutylcarbamoyl)-3-methylbutylcarbamoyl]-3-methylbutyl}carbamic acid benzyl ester 
• 1228687-82-8 C₂₆H₄₃N₃O₅ 
• 1211877-30-3 C₂₆H₄₃N₃O₅ 
• 7517-19-3 methyl (L)-leucinate hydrochloride 
• 3504-37-8 Cbz-L-Leu-L-Leu-OMe 
• 2018-66-8 Z-Leu-OH 
• 61-90-5 L-leucine 
• 7533-40-6 (S)-2-amino-4-methylpentan-1-ol 
• 1334176-70-3 C₂HF₃O₂*C₁₂H₂₆N₂O₂ 
• 1334176-68-9 Boc-L-leucine-L-leucinol 
• 1211877-22-3 ((S)-1-(((S)-1-(((S)-1-hydroxy-4-methylpentan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamic acid benzyl ester 

Relevant articles and documents

Application of proteasome inhibitor in inhibition of novel coronavirus

The invention provides application of a proteasome inhibitor in inhibition of a novel coronavirus or preparation of novel coronavirus inhibitors. The proteasome inhibitor has a structure represented by a formula (I) or isomers, pharmaceutically acceptable salts thereof and prodrugs thereof. According to the application, by applying the proteasome inhibitor to inhibition of the novel coronavirus, good inhibiting activity is obtained, and a novel treatment way of think is provided for diseases such as pneumonia caused by the novel coronavirus.

A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.

Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif

The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophi

α-Keto Phenylamides as P1′-Extended Proteasome Inhibitors

The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off-target-related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA-approved proteasome inhibitors bortezomib (1) or carfilzomib (2). A systematic comparison of electrophilic headgroups recently identified the class of α-keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure-activity relationship (SAR)-based approach for rational ligand design using an electronic parameter (Hammett's σ) and in silico molecular modeling. This resulted in the tripeptidic α-keto phenylamide BSc4999 [(S)-3-(benzyloxycarbonyl-(S)-leucyl-(S)-leucylamino)-5-methyl-2-oxo-N-(2,4-dimethylphenyl)hexanamide, 6a], a highly potent (IC50=38 nM), cell-permeable, and slowly reversible covalent inhibitor which targets both the primed and non-primed sites of the proteasome's substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α-keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies.

Synthesis and SAR study of novel peptide aldehydes as inhibitors of 20S proteasome

Based on the analysis of the crystal structure of MG101 (1) and 20S proteasomes, a new series of peptide aldehyde derivatives were designed and synthesized. Their ability to inhibit 20S proteasome was assayed. Among them, Cbz-Glu(OtBu)-Phe-Leucinal (3c), Cbz-Glu(OtBu)-Leu-Leucinal (3d), and Boc-Ser(OBzl)-Leu-Leucinal (3o) exhibited the most activity, which represented an order of magnitude enhancement compared with MG132 (2). The covalent docking protocol was used to explore the binding mode. The structure-activity relationship of the peptide aldehyde inhibitors is discussed.

Studies of the synthesis of all stereoisomers of MG-132 proteasome inhibitors in the tumor targeting approach

MG-132 is a tripeptide aldehyde (Z-L-leu-L-leu-L-leu-H, 2) proteasome inhibitor that exerts antitumor activity and enhances cytostatic/cytotoxic effects of chemo- and radiotherapy. Because of a troublesome synthesis of tripeptides with a non-natural configuration and modified side chains of amino acids, only two stereoisomers of MG-132 have been reported. Here, we propose a new approach to the synthesis of tripeptide aldehydes based on the Ugi reaction. Chiral, enantiomerically stable 2-isocyano-4-methylpentyl acetates were used as substrates for Ugi reaction resulting in a formation of tripeptide skeletons. Further functionalization of the obtained products led to a synthesis of tripeptide aldehydes. All stereoisomers of MG-132 were synthesized and studied as potential inhibitors of chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide hydrolyzing activities of proteasome. These studies demonstrated the influence of absolute configuration of chiral aldehydes on the cytostatic/cytotoxic effects of the synthesized compounds and revealed that only (S,R,S)-(-)-2 stereoisomer is a more potent. proteasome inhibitor than MG-132.

A new and general method for the synthesis of tripeptide aldehydes based on the multi-component Ugi reaction

Tripeptide aldehydes, such as Z-Leu-Leu-Leu-H (MG-132), are an important class of compounds due to their biological activity. A new, general method for the synthesis of tripeptide aldehydes based on the multi-component Ugi reaction was developed. A careful choice of isocyanides makes it possible to obtain tripeptide precursors whose functionalization led to target structures. This method can be used for the preparation of tripeptide aldehydes with non-natural amino acid side chains.

Proteasome regulation of NF-KB activity

Disclosed herein is a method for regulating the activity of NF-κB in an animal comprising contacting cells of the animal with certain proteasome inhibitors.

Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein

Disclosed herein is a method for reducing the rate of degradation of proteins in an animal comprising contacting cells of the animal with certain proteasome inhibitors. The structure of the inhibitors are also disclosed.