Total Synthesis of the NF-κB Inhibitor (−)-Cycloepoxydon:  Utilization of Tartrate-Mediated Nucleophilic Epoxidation

Li, Chaomin; Pace, Emily A.; Liang, Mei‐Chih; Lobkovsky, Emil; Gilmore, Thomas D.; Porco, John A.

doi:10.1021/ja0169769

Cited by 58 publications

(34 citation statements)

References 19 publications

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“…Natural and synthetic epoxyquinoids, such as cycloepoxydon, 84,85 dehydroxymethylepoxyquinomicin (DHMEQ), 86 epoxyquinol A, 87 Figure 4 Structures of SRC2 ((11S)-2a-bromo-3-oxoeudesmano-13,6a-lactone) and peperomins.…”

Section: Epoxyquinoidsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin-1, trigger the signal transduction pathway leading to the activation of the transcription factor, nuclear factor-jB (NF-jB). NF-jB induces a large number of target genes involved in many biological processes, such as inflammation, immunity, cell survival, cell death and carcinogenesis. As therapeutic agents for inflammatory diseases and cancer, as well as bioprobes for the characterization of intracellular biological response and cell function, a large number of natural and synthetic small molecules have been identified to inhibit the activation of the NF-jB signaling pathway. This review focuses on recent progress in the identification and biological properties of small molecules targeting the NF-jB signaling pathway induced by pro-inflammatory cytokines.

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Section: Epoxyquinoidsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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“…The preparation of jesterone, jesterone dimer, cycloepoxydon, torreyanic acid, and the related epoxyquinoids (Figs. 1 and 6A) have been described previously (Hu et al, 2001;Li et al, 2000Li et al, , 2001aLi et al, , 2002. All compounds were dissolved in 100% methanol before use.…”

Section: Methodsmentioning

confidence: 99%

“…Because a number of inhibitors of transcription factor NF-B have also been shown to inhibit tumor cell growth and because some epoxyquinoids have been shown to inhibit NF-B (Gehrt et al, 1998;Matsumoto et al, 2000;Hu et al, 2001;Li et al, 2001aLi et al, , 2002, we were interested in determining whether JD might affect the activity of NF-B. In this report, we demonstrate that JD is an efficient inhibitor of Rel/NF-B and acts by blocking the activity of IKK.…”

mentioning

confidence: 89%

“…In addition, we compared the activity of JD to a monomeric epoxyquinoid, cycloepoxydon, which we have shown previously can also inhibit NF-B (Li et al, 2001a). In these experiments, we first determined the concentration of JD and cycloepoxydon required to inhibit B-site DNA binding in SUDHL-4 cells by incubating the cells with increasing concentrations of the compounds for 3 h and then performing an EMSA.…”

Section: Synthetic Inhibitor Of Nf-bmentioning

confidence: 99%

“…We have been synthesizing and studying the bioactivity of several epoxyquinoids. For example, we have reported previously the total synthesis of the natural metabolites jesterone from Pestalotiopsis jesteri, cycloepoxydon from the Deuteromycetes strain 45-93, and epoxyquinol A from an uncharacterized fungus (Hu et al, 2001;Li et al, 2001aLi et al, , 2002.…”

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confidence: 99%

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Jesterone Dimer, a Synthetic Derivative of the Fungal Metabolite Jesterone, Blocks Activation of Transcription Factor Nuclear Factor κB by Inhibiting the Inhibitor of κB Kinase

Liang

Bardhan

et al. 2003

Molecular Pharmacology

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Rel/nuclear factor-B (NF-B) transcription factors control a variety of cellular processes, such as cell growth and apoptosis, and are continually activated in many human diseases, including chronic inflammatory diseases and cancer. Jesterone dimer (JD) is a synthetic derivative of the natural fungal metabolite jesterone, and JD has previously been shown to be cytotoxic in select tumor cell lines. In this report, we demonstrate that JD is a potent inhibitor of the activation of transcription factor NF-B. Namely, JD inhibits tumor necrosis factor-␣-induced activation of NF-B in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-B pathway by inhibiting the inhibitor of B kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IB␣, inhibits the activity of a constitutively active form of the IKK␤ catalytic subunit, and converts IKK␤ to stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-B at 20 M, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-B at this concentration. Finally, JD inhibits both proliferation and DNA binding by REL-containing complexes in the human lymphoma SUDHL-4 cell line, and JD activates caspase-3 activity in these cells. In summary, these results suggest that JD induces apoptosis in tumor cells through a mechanism that involves the inhibition of Rel/NF-B activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.

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Asymmetric Epoxidation of Electron‐Deficient Alkenes

Porter

Skidmore

2009

Organic Reactions

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Asymmetric epoxidation reactions have the distinction of being among the first enantioselective transformations to be widely sued in organic synthesis. The Sharpless asymmetric epoxidation is arguably one of the most important methods for the synthesis of enantiomerically enriched intermediates uses en route to a wide range of synthetic targets. To date most examples have employed electrophilic oxidizing agents and are thus applicable to electron‐neutral or electron‐rich double bonds. On the other hand alkenes substituted with electron‐withdrawing groups often react inefficiently with electrophilic oxidizing agents; such alkanes are more readily epoxidized using nucleophilic oxidants. The Weitz‐Scheffer epoxidation of alpha,beta‐unsaturated ketones to the corresponding epoxy ketones using basic hydrogen peroxide is the classical nucleophilic epoxidation reaction. This chapter considers the more general case of the conversion of an electron deficient alkene into the corresponding epoxide in an enantioselective fashion. Only methods based on chiral reagents or catalysts are covered. This review covers the literature to the end of 2005.

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Total Synthesis of the NF-κB Inhibitor (−)-Cycloepoxydon: Utilization of Tartrate-Mediated Nucleophilic Epoxidation

Cited by 58 publications

References 19 publications

Chemical biology of inflammatory cytokine signaling

Chemical biology of inflammatory cytokine signaling

Jesterone Dimer, a Synthetic Derivative of the Fungal Metabolite Jesterone, Blocks Activation of Transcription Factor Nuclear Factor κB by Inhibiting the Inhibitor of κB Kinase

Asymmetric Epoxidation of Electron‐Deficient Alkenes

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