Epoxyquinol A, a Highly Functionalized Pentaketide Dimer with Antiangiogenic Activity Isolated from Fungal Metabolites

Kakeya, Hideaki; Onose, Rie; Koshino, Hiroyuki; Yoshida, Arika; Kobayashi, Kimiko; Kageyama, Shun‐Ichiro; Osada, Hiroyuki

doi:10.1021/ja0127279

Cited by 88 publications

(88 citation statements)

References 14 publications

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“…Epoxyquinols A and B (Figure 5a), which are naturally occurring pentaketide dimers, have been isolated from fungal metabolites and found to possess potent antiangiogenic activity. 92,93 It has also been shown that both epoxyquinols A and B block TNF-a-induced NF-kB activation. 87,88 Compared with epoxyquinol A, its structural derivative, epoxyquinone A monomer (Figure 5a), is a potent inhibitor of TNF-a-induced NF-kB activation.…”

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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“…Interestingly, Kakeya et al (2002) recently identified a natural fungal metabolite, epoxyquinol A, that bears striking structural resemblance to JD. However, epoxyquinol A and JD have opposite enantiomeric compositions.…”

Section: Discussionmentioning

confidence: 99%

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

Mol Pharmacol

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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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“…[1] Kakeya, Osada and co-workers have isolated and determined the structures of epoxyquinols A (1), [2] B (2), [3] and C (3) [4] and epoxytwinol A (4) [5] from an unknown soil fungus, and azaspirene [6] and RK-805 [7] from the fungus Neosartorya sp. (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…[2,3] That is, diol monomer 18 is oxidized to aldehyde 17, which undergoes 6π-electrocyclization to afford 2H-pyran derivative 16 (Scheme 1). Diels-Alder dimerization of 2H-pyran 16 proceeds to provide epoxyquinols A (1), B (2), and C (3).…”

Section: Introductionmentioning

confidence: 99%

“…Not only DielsAlder dimers, but also epoxytwinol A (4) has been isolated from the same fungus. [5] Epoxytwinol A (4) possesses the 3,8-dioxatricyclo[4.2.2.2 2,5 ]dodeca-9,11-diene skeleton, a completely different structure from those of epoxyquinols A, B, and C. It is postulated that epoxytwinol A is biosynthetically generated by a formal [4+4] cycloaddition reaction, as used in the construction of the same key 2H-pyran intermediate 16 in the synthesis of epoxyquinols A, B, and C (vide infra). Since these compounds have important biological properties and synthetically challenging structures, several research groups, including ours, [8] have investigated the total synthesis of these compounds.…”

Section: Introductionmentioning

confidence: 99%

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Chemistry of Epoxyquinols A, B, and C and Epoxytwinol A

Shoji

Hayashi

2007

Eur J Org Chem

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The asymmetric total synthesis of epoxyquinols A, B, and C and epoxytwinol A, and computational analysis of the key biomimetic oxidative dimerization procedure are described. In the first-generation synthesis, a HfCl 4 -mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan and a lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale synthesis.

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Epoxyquinol A, a Highly Functionalized Pentaketide Dimer with Antiangiogenic Activity Isolated from Fungal Metabolites

Cited by 88 publications

References 14 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

Chemistry of Epoxyquinols A, B, and C and Epoxytwinol A

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