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Brusatol.

ABSTRACT: The title compound, C(26)H(32)O(11), is composed of an ?,?-unsaturated cyclo-hexa-none ring (A), two cyclo-hexane rings (B and C), a six-membered lactone ring (D) and tetra-hydro-furan ring (E). Ring A exists in a half-chair conformation with a C atom displaced by 0.679?(2)?Å from the mean plane through the remaining five atoms. Ring B exists in a normal chair conformation. Both rings C and D exist in a twisted-chair conformation due to the O-atom bridge and the carbonyl group in rings C and D, respectively. Ring E shows an envelope conformation with a C atom displaced by 0.761?(1)?Å from the mean plane through the remaining five atoms. The ring junctions are A/B trans, B/C trans, C/D cis and D/E cis. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, O-H?O hydrogen bonds involving the hy-droxy, lactone and ester groups and C-H?O inter-actions are observed.

SUBMITTER: Hu SZ

PROVIDER: S-EPMC3379203 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Brusatol.

Hu Shu-Zhi SZ Jin Lu L Yu Tong T Tian Hai-Yan HY Jiang Ren-Wang RW

Acta crystallographica. Section E, Structure reports online 20120502 Pt 6

The title compound, C(26)H(32)O(11), is composed of an α,β-unsaturated cyclo-hexa-none ring (A), two cyclo-hexane rings (B and C), a six-membered lactone ring (D) and tetra-hydro-furan ring (E). Ring A exists in a half-chair conformation with a C atom displaced by 0.679 (2) Å from the mean plane through the remaining five atoms. Ring B exists in a normal chair conformation. Both rings C and D exist in a twisted-chair conformation due to the O-atom bridge and the carbonyl group in rings C and D, ...[more]

PMID: 22719401

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The toxic effects and possible mechanisms of Brusatol on mouse oocytes.

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Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.

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Brusatol, a Nrf2 Inhibitor Targets STAT3 Signaling Cascade in Head and Neck Squamous Cell Carcinoma.

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Application of Mass Spectrometry Profiling to Establish Brusatol as an Inhibitor of Global Protein Synthesis.

Project description:The KEAP1/Nrf2 pathway senses and responds to changes in intracellular oxidative stress. Mutations that result in constitutive activation of Nrf2 are present in several human tumors, especially non-small cell lung cancer. Therefore, compounds that inhibit Nrf2 activity might be beneficial in treating patients whose tumors show activation of this pathway. Recent reports suggest that the natural product brusatol can potently and selectively inhibit Nrf2 activity, resulting in cell cytotoxicity, and can be effectively combined with chemotherapeutic agents. Here, we analyzed the effects of brusatol on the cellular proteome in the KEAP1 mutant non-small cell lung cancer cell line A549. Brusatol was found to rapidly and potently decrease the expression of the majority of detected proteins, including Nrf2. The most dramatically decreased proteins are those that display a short half-life, like Nrf2. This effect was confirmed by restricting the analysis to newly synthesized proteins using a labeled methionine analogue. Moreover, brusatol increased the expression of multiple components of the ribosome, suggesting that it regulates the function of this macromolecular complex. Finally, we show that brusatol induces its potent cellular cytotoxicity effects on multiple cancer cell lines in a manner independent of KEAP1/Nrf2 activity and with a profile similar to the protein translation inhibitor silvestrol. In conclusion, our data show that the activity of brusatol is not restricted to Nrf2 but, rather, functions as a global protein synthesis inhibitor.

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The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers.

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Brusatol Derivative-34 Attenuates Allergic Airway Inflammation Via Inhibition of the Spleen Tyrosine Kinase Pathway.

Project description:Brusatol derivative-34 (Bru-34), a derivative of brusatol, has been shown significantly anti-inflammatory activity in mice in our previously work. However, to our knowledge, there were very limited studies on how Bru-34 affected airway inflammation. Thus, in this present study, the effects and potential mechanisms of Bru-34 on allergic airway inflammation were examined both in vivo and in vitro. The results showed that Bru-34 attenuated the allergic airway inflammation in mice, with significant decreasing of the inflammatory cells and mediators in bronchoalveolar lavage fluids and attenuation of the histopathological alterations in the lung tissues. In addition, Bru-34 significantly inhibited the release of inflammatory cytokines in antigen induced rat basophilic leukemia -2H3 (RBL-2H3) cells. What's more, Bru-34 significantly decreased the expression of spleen tyrosine kinase (Syk), p-Syk, cytoplasmic phospholipase A2 (cPLA2), p-cPLA2, nuclear factor-κB (NF-κB) and p-NF-κB both in allergic mice lung tissue and antigen induced RBL-2H3 cells. Furthermore, the collaborative effects of Bru-34 with inhibitors against Syk, cPLA2, and NF-κB, showed that Syk was an important target of Bru-34, and cPLA2 and NF-κB played important roles in the coordinated inflammatory response. In conclusion, Bru-34 could significantly modulate the allergic airway inflammation, and its potential mechanism was revealed at least partially via down-regulating of Syk-cPLA2 -NF-κB signaling.

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Redox-sensitive micelles composed of disulfide-linked Pluronic-linoleic acid for enhanced anticancer efficiency of brusatol.

Project description:Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic® F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by 1H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway.

| S-EPMC5815479 | biostudies-literature

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