Exploring Chemical Diversity of Epoxyquinoid Natural Products:  Synthesis and Biological Activity of (−)-Jesterone and Related Molecules

Hu, Yongbo; Li, Chaomin; Kulkarni, B. A.; Strobel, Gary A.; Lobkovsky, Emil; Torczynski, Richard M.; Porco, John A.

doi:10.1021/ol0159367

Cited by 81 publications

(62 citation statements)

References 24 publications

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“…Chemical biology of inflammatory cytokine signaling T Kataoka epoxyquinol B, 88 epoxyquinone A monomer, 87 jesterone dimer, 89,90 manumycin A 60 and panepoxydone, 91 have been reported to inhibit NF-kB activation. Epoxyquinoids contain the epoxide structure that is known to react with nucleophiles, such as cysteine thiol groups.…”

Section: Epoxyquinoidsmentioning

confidence: 99%

“…94 Jesterone dimer (Figure 5a), which was reported to exert 10-to 100-fold greater antitumor activity than jesterone, has been shown to block TNF-ainduced IKK activation. 89,90 Indeed, jesterone dimer converts constitutively active IKKb into stable higher molecular mass forms, irrespective of its Cys-179 mutation (Figure 5b). 90 It has also been shown that epoxyquinol B is able to bind covalently to cysteine residues of several proteins and to crosslink proteins through the cysteine residues by opening its epoxide ring.…”

Section: Epoxyquinoidsmentioning

confidence: 99%

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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%

Section: Epoxyquinoidsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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“…2 On the other hand, epoxyquinol B (2) is a homodimer of 14a, which would be generated by an exo intermolecular Diels-Alder reaction, also with the sterically favored anti stereochemistry at the C9 and C19 methyl positions. 3 In their recent elegant total synthesis of torreyanic acid 19 and jesterone dimer (unnatural product), 54 Porco, Jr. et al have demonstrated the oxidative dimerization of epoxyquinones, in which only heterodimers form. As shown in the dimerization of (+)-5, not only epoxyquinones, but also epoxycyclohexenones can be oxidatively dimerized to form highly functionalized heptacyclic ring systems, in which both heteroand homo-dimerization occur.…”

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confidence: 99%

Total Synthesis of Epoxyquinonoid Natural Products

Shoji¹

2007

Bulletin of the Chemical Society of Japan

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Asymmetric total synthesis of epoxyquinonoid natural products, such as epoxyquinols A, B, and C, epoxytwinol A, and EI-1941-1, -2, and -3, are described. In the first-generation synthesis of epoxyquinols, the HfCl 4 -mediated diastereoselective Diels-Alder reaction of furan with a chiral acrylate ester was developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone by using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution of a cyclohexenol derivative were developed. This secondgeneration synthesis is suitable for large-scale preparation. A biomimetic cascade reaction involving oxidation, 6-electrocyclization, then Diels-Alder dimerization, is the key reaction in the formation of epoxyquinols A-C. Epoxytwinol A was synthesized by the cascade reaction composed of oxidation, 6-electrocyclization, and formal [4 þ 4] cycloaddition. A 2H-pyran, generated by oxidation/6-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. The asymmetric total synthesis of EI-1941s was accomplished, starting from a chiral epoxy iodoquinone, a key intermediate in the total synthesis of epoxyquinols. They were diastereoselectively synthesized via an intramolecular carboxypalladation in a 6-endo cyclization mode, followed by -hydride elimination, as the key steps.

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“…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%

“…1) kills tumor cells with IC 50 values ranging from approximately 100 to 500 M in three different human tumor cell lines (Hu et al, 2001). However, a dimeric derivative of jesterone, which we have termed "jesterone dimer" (JD) (Fig.…”

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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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Exploring Chemical Diversity of Epoxyquinoid Natural Products: Synthesis and Biological Activity of (−)-Jesterone and Related Molecules

Cited by 81 publications

References 24 publications

Chemical biology of inflammatory cytokine signaling

Chemical biology of inflammatory cytokine signaling

Total Synthesis of Epoxyquinonoid Natural Products

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

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