20350-15-6

Basic information

• Product Name: Brefeldin A
• Synonyms: NECTROLIDE;SYNERGISIDIN;4h-cyclopent(f)oxacyclotridecin-4-one,1,6,7,8,9,11a-beta,12,13,14,14a-alpha-de;cahydro-1-beta-13-alpha-dihydroxy-6-beta-methyl-;cyanaein;CYANEIN;DECUMBIN;GAMMA-4-DIHDYROXY-2-(6-HYDROXY-1-HEPTENYL)-4-CYCLOPENTANECROTONIC ACID LAMBDA-LACTONE
• CAS NO: 20350-15-6
• Molecular Formula: C₁₆H₂₄O₄
• Molecular Weight: 280.36
• EINECS: 247-104-4
• Product Categories: All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Signalling;antibiotic
• Mol File: 20350-15-6.mol

Chemical Properties

• Melting Point: 200-205 °C
• Boiling Point: 492.7 °C at 760 mmHg
• Flash Point: 87 °C
• Appearance: White to almost white/Crystalline Powder
• Density: 1.108 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.513
• Storage Temp.: 2-8°C
• Solubility: methanol: 10 mg/mL, clear, colorless to faintly yellow
• PKA: 12.92±0.60(Predicted)
• Water Solubility: Soluble in dimethylsulfoxide, dichloromethane and ethanol. Slightly soluble in water.
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.
• Merck: 13,1355
• BRN: 25191
• CAS DataBase Reference: Brefeldin A(CAS DataBase Reference)
• NIST Chemistry Reference: Brefeldin A(20350-15-6)
• EPA Substance Registry System: Brefeldin A(20350-15-6)

Safety Data

• Hazard Codes: Xn,T
• Statements: 22-25-36/37/38-20/21/22
• Safety Statements: 24/25-45-36-26
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: GY8410000
• Hazardous Substances Data: 20350-15-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Brefeldin A is used as an antibiotic, antiviral, antifungal, and antitumor agent due to its broad range of bioactivity. It modulates various cellular processes, making it a valuable tool in the development of therapeutics for various diseases.
Used in Research and Development:
Brefeldin A is used as a research tool to study intracellular transport by vesicles or endosomes, as it reversibly interferes with protein trafficking and secretion mediated by the Golgi apparatus and endoplasmic reticulum. It is also used to study endosomal trafficking and function in cells of plants, fungi, invertebrates, and vertebrates.
Used in Drug Delivery Systems:
Brefeldin A can be employed in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles can be used as carriers for Brefeldin A delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.
Used in Chemical Synthesis:
Brefeldin A, as a metabolite from Penicillium brefeldianum, can be used in chemical synthesis for the development of new compounds with potential applications in various industries, including pharmaceuticals and agriculture.

Biological Activity

Reversible inhibitor of protein translocation from the endoplasmic reticulum (ER) to the Golgi apparatus. Blocks binding of ADP-ribosylation factor to the Golgi apparatus and inhibits GDP-GTP exchange.

Biochem/physiol Actions

Primary TargetBlocks translocation of proteins from the endoplasmic reticulum (ER) to the Golgi apparatus

Purification Methods

Brefeldin A was isolated from Penicillium brefeldianum and recrystallised from aqueous MeOH/EtOAc or MeOH. Its solubility in H2O is 0.6mg/mL, 10mg/mL in MeOH and 24.9mg/mL in EtOH. The O-acetate recrystallises from Et2O/pentane and has m 130-131o, [] D +17o (c 0.95, MeOH). [Sigg Helv Chim Acta 47 1401 1964, UV and IR: H.rri et al. Helv Chim Acta 46 1235 1963, total synthesis: Kitahara et al. Tetrahedron 3021 1979, X-ray : Weber et al. Helv Chim Acta 54 2763 1971, Beilstein 18 III/IV 1220.]

References

1) Fujiwara et al. (1988) Brefeldin A causes disassembly of the Golgi complex and accumulation of secretory proteins in the endoplasmic reticulum; J. Biol. Chem., 263 18545 2) Shao et al. (1996), Brefeldin A is a potent inducer of apoptosis in human cancer cells independently of p53; Exp. Cell Res., 227 190 3) Linardic et al. (1996), Brefeldin A promotes hydrolysis of sphingomyelin; Cell Growth Differ., 7 765

InChI:InChI=1/C16H24O4/c1-11-5-3-2-4-6-12-9-13(17)10-14(12)15(18)7-8-16(19)20-11/h4,6-8,11-15,17-18H,2-3,5,9-10H2,1H3/b6-4-,8-7-/t11-,12-,13-,14+,15+/m0/s1

Upstream product

• 29129-37-1 brefeldin A 4,7-O-diacetate 
• 62990-62-9 (E)-(R)-4-[(1R,2S,4S)-2-((E)-(S)-6-Hydroxy-hept-1-enyl)-4-(2-methoxy-ethoxymethoxy)-cyclopentyl]-4-(2-methoxy-ethoxymethoxy)-but-2-enoic acid 
• 54202-13-0 4-oxo-brefeldin-A 
• 177960-81-5 (1R,2E,6S,10E,11aS,13S,14aR)-1,13-bis[(tert-butyldimethylsilyl)oxy]-6-methyl-1,6,7,8,9,11a,12,13,14,14a-decahydro-4H-cyclopenta[f][1]oxacyclotridecin-4-one 
• 82729-81-5 (+)-n-butyl (<1S>-4-oxo-2-cyclopentenyl)acetate 
• 83692-17-5 4-O-acetyl-7-epi-brefeldin A 
• 74500-56-4 (S)-5-Trityloxy-pentan-2-ol 
• 71155-05-0 (1R,5S)-bicyclo[3.2.0]hept-2-en-6-one 
• 135191-56-9 (E)-4-[(1R,2S,4S)-2-((E)-(S)-6-Hydroxy-hept-1-enyl)-4-(2-methoxy-ethoxymethoxy)-cyclopentyl]-4-(2-methoxy-ethoxymethoxy)-but-2-enoic acid methyl ester 
• 1173198-67-8 C₂₃H₃₀O₅ 
• 4841-84-3 dimethyl cis-1,2,3,6-tetrahydrophthalate 
• 31139-02-3 (1R,6S)-6-methoxycarbonyl-3-cyclohexene-1-carboxylic acid 
• 88586-06-5 (3aS,7aR)-3a,4,7,7a-tetrahydroisobenzofuran-1(3H)-one 
• 104265-93-2 2,2'-[(3R,4S)-2-oxotetrahydrofuran-3,4-diyl]diacetic acid 

Downstream Products

• 956748-63-3 C₃₀H₃₇BrO₆ 
• 956748-64-4 C₄₄H₅₀Br₂O₈ 

Relevant articles and documents

A trans-vinylogous ester anion equivalent and its application to the synthesis of (+)-brefeldin A

A new trans-vinylogous ester anion equivalent which reacts with a variety of carbonyl systems has been developed. In addition, the concise total synthesis of (+)-brefeldin A utilizing facile acylation of this new variant of vinylogous acyl anion equivalent has been accomplished.

An olefin disconnection strategy for the practical synthesis of (+)-brefeldin A: olefin cross metathesis and intramolecular Horner-Wadsworth-Emmons olefination

The practical and convergent total synthesis of (+)-brefeldin A has been achieved by an olefin disconnection strategy. Key features of the total synthesis include the efficient formation of C2 and C10 olefins, employing an olefin cross metathesis (CM) reaction and an intramolecular HWE olefination, respectively.

Application of Ru(II)-Catalyzed Enyne Cyclization in the Synthesis of Brefeldin A

The approach to brefeldin A described herein hinges on Ru(II)-catalyzed cycloisomerization of an enyne obtained by the reaction of an alkynylzinc reagent with an α-chloro sulfide. Other key steps include Mislow-Evans rearrangement, cross-metathesis, and macrocyclization using a Roush-Masamune protocol.

Total synthesis of the antitumor macrolides, (+)-brefeldin A and 4-epi-brefeldin A from d-glucose: Use of the Padwa anionic allenylsulfone [3 + 2]-cycloadditive elimination to construct trans-configured chiral cyclopentane systems

A new synthesis of (+)-brefeldin A is reported via Padwa allenylsulfone [3 + 2]-cycloadditive elimination. Cycloadduct 13 was initially elaborated into iodide 27, which, following treatment with Zn, gave aldehyde 28 whose C(9) stereocenter was epimerized. Further elaboration into enoate 38 and Julia-Kocienski olefination with 5 subsequently afforded 39, which was deprotected at C(1) and O(15). Yamaguchi macrolactonization of the seco-acid thereafter afforded a macrocycle that underwent O-desilylation and inversion at C(4) to give (+)-brefeldin A following deprotection.

Synthesis and cytotoxic evaluation of acylated brefeldin a derivatives as potential anticancer agents

Brefeldin A has attracted considerable attention because of its potential function in cancer prevention. However, its therapeutic use is limited by its poor bioavailability. The modifications on brefeldin A were difficult because of its low stability and selectivity toward two hydroxyl groups within the same molecule. In this study, we report the selective acylation of brefeldin A under mild conditions and the preparation of a series of monoacylated and diacylated brefeldin A derivatives. Their cytotoxicity, antitumor activity against TE-1 cell, and molecular properties of adsorption, distribution, metabolism, and elimination were evaluated. Brefeldin A 7-O-benzoate, brefeldin A 4,7-O-dibenzoate, and brefeldin A 7-O-biotin carboxylate showed the most potent cytotoxic activity, with GI50 values of 0.39, 0.46, and 0.50 μm, respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. Our results may serve as a basis for the development of novel potential anticancer agents from brefeldin A derivatives.

Elucidation of strict structural requirements of Brefeldin A as an inducer of differentiation and apoptosis

Brefeldin A (BFA) can induce a wide variety of human cancer cells to differentiation and apoptosis and is in development as an anticancer agent. To elucidate structural requirements for cytotoxicity and induction of differentiation and apoptosis, BFA was structurally modified into various derivatives including 4-epi-BFA in this study. Their inducing activities of apoptosis were evaluated with their cytotoxicities, DNA fragmentation and morphological changes in human colon cancer cell HCT 116. The cytotoxicity of 4-epi-BFA (TX-1923) (IC50 = 60 μM) was 300 times lower than that of BFA (IC50= 0.2 μM). Furthermore, 4-epi-BFA induced DNA fragmentation and apoptotic morphological changes at much higher concentrations (70 and 50 μM, respectively) than BFA (0.11 and 0.36 μM, respectively). These results indicated that the configuration of 4-hydroxyl group of brefeldin A plays a key role in the cytotoxicity and induction of apoptosis. On the other hand, 7-O-acetyl-BFA, 4-O-acetyl-BFA, and 4,7-di-O-acetyl-BFA exhibited potential activities in cytotoxicity and inducibility of apoptosis. We suggested that the structural determinants for BFA include the moiety of the Michael acceptor, the conformational rigidity of the 13-membered ring, and the configuration of 4-hydroxyl group. (C) 2000 Elsevier Science Ltd.

Synthesis of (+)-Brefeldin-A

Two routes to (+)-brefeldin A have been investigated.In one the bicyclic ketone 2 was transformed into the hydroxy lactone 7.Subsequent reduction, opening of the heterocyclic ring and epimerization furnished the aldehyde 13.Further steps towards the natural product from this late stage intermediate 13 were not investigated.In the second route, the readily available hydroxy lactone 17 was converted into the enone 22.Conjugate addition of the requisite cuprate reagent to this afforded the 3,4-disubstituted cyclopentanone 24 which was converted into brefeldin-A 29 in five steps.

Trans-hydrogenation: Application to a concise and scalable synthesis of brefeldin a

The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium-catalyzed trans-hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch-type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron-catalyzed reductive formation of a non-terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring-closing alkyne metathesis catalyzed by a molybdenum alkylidyne.

Asymmetric total synthesis of (+)-brefeldin A: Intramolecular epoxide-opening/RCM strategy

A highly efficient asymmetric total synthesis of (+)-brefeldin A was accomplished by using intramolecular epoxide opening of an epoxy allylsilane and RCM reaction for the constructions of the cyclopentane and macrocyclic lactone rings of (+)-brefeldin A,

Total synthesis of (+)-brefeldin a

(+)-Brefeldin A was synthesized through an efficient route, which features (1) construction of the five-membered ring from a Crimmins aldol via tandem Li-I exchange and carbanion-mediated cyclization with concurrent removal of the chiral auxiliary, (2) introduction of the lower side chain (C10 to C16) via a Rh-catalyzed Michael addition of a vinyl boronic acid, (3) stereoselective reduction of the C7 ketone with Sml2, and (4) a 2-methyl-6- nitrobenzoic anhydride-mediated (Shiina) lactonization.