Angiogenesis Inhibitor Epoxyquinol A:  Total Synthesis and Inhibition of Transcription Factor NF-κB

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

doi:10.1021/ol026513n

Cited by 70 publications

(35 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 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%

“…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. 87 Similar to sesquiterpene lactones, epoxyquinone A monomer inhibits IKKb and p65 by targeting Cys-179 and Cys-38, respectively (Figure 5b).…”

Section: Epoxyquinoidsmentioning

confidence: 99%

“…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. 87 Similar to sesquiterpene lactones, epoxyquinone A monomer inhibits IKKb and p65 by targeting Cys-179 and Cys-38, respectively (Figure 5b). 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.…”

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%

Section: Epoxyquinoidsmentioning

confidence: 99%

Section: Epoxyquinoidsmentioning

confidence: 99%

See 2 more Smart Citations

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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“…[8][9][10][11]. With several electrophilic sites and a high degree of unsaturation, 3 was perceived to be a challenging objective for synthesis, and we elected to explore the possibility of producing this potentially transient intermediate in situ from a doubly activated, polyunsaturated acyclic compound of type 1.…”

mentioning

confidence: 99%

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Stark

Pekari

Sorensen

2004

Proc. Natl. Acad. Sci. U.S.A.

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Substantial structural transformations of much use in complex chemical synthesis can be achieved by channeling the reactivity of highly unsaturated molecules. This report describes the direct conversion of an acyclic polyunsaturated diketone to the HIV-1 Rev͞Rev-responsive element inhibitor harziphilone under mild reaction conditions. nucleophilic catalysis ͉ Baylis-Hillman reaction ͉ conjugate additions ͉ electrocyclizations ͉ domino reactions T he reactivity of activated polyenes is the basis for some of the most impressive structural transformations in nature and chemical synthesis. The biosyntheses of the complex structures of the polycyclic triterpenes from squalene and 2,3-oxidosqualene may be viewed as paragons for processes that build polycyclic molecular complexity directly from reactive polyenes (1-3). In connection with our efforts to channel the reactivity of activated polyunsaturated molecules, we sought mild reaction conditions under which compound 1 could be isomerized to the bicyclic structure of harziphilone (2), a naturally occurring inhibitor of the binding interaction between the HIV-1 Rev protein and the Rev-responsive element (RRE) of viral mRNA (4) (Scheme 1). This report describes an enantioselective synthesis of (ϩ)-harziphilone based on the general idea expressed in Scheme 1.The structure of (ϩ)-harziphilone (2) comprises fifteen carbon atoms, two six-membered ring systems, one carbocyclic and the other heterocyclic, a keto group, two contiguous hydroxylbearing stereocenters, and a pentadienyl side chain. All of the polar groupings of harziphilone are confined to the sixmembered carbocycle, whereas the hydrophobic pentadienyl moiety is displayed as a side chain on the ␣-pyran ring. Our approach to the problem of synthesizing this natural product was guided by the retrosynthetic analysis shown in Scheme 2.The independent early investigations of Büchi (5) and Marvell (6, 7) provided a sound basis for the proposal that the oxacyclic ring of harziphilone, with its particular arrangement of alkenes, could arise by a 6 -electrocyclization of a compound of type 3 (for selected examples of this type of valence isomerization in synthesis see refs. 8-11). With several electrophilic sites and a high degree of unsaturation, 3 was perceived to be a challenging objective for synthesis, and we elected to explore the possibility of producing this potentially transient intermediate in situ from a doubly activated, polyunsaturated acyclic compound of type 1. To implement this concept, we would seek a suitable heteroatom nucleophile that could attack the unsubstituted enone moiety in 1. Although almost certainly reversible, such a site-selective, intermolecular conjugate addition reaction could trigger an intramolecular conjugate addition (see arrows in 4), resulting in the production of a key carbon-carbon bond and the carbocyclic ring of (ϩ)-harziphilone (for selected tandem conjugate addition͞Michael cyclization reactions see refs. 12-17). A ␤-elimination of the heteroatom nucleophile might then genera...

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Oxoammonium‐ and Nitroxide‐Catalyzed Oxidations of Alcohols

2009

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The discovery in 1959 of stable nitroxide‐based free radicals such as the prototypical 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) led to their use as electron spin resonance (ESR) spin labels in chemistry, biomedicine, and materials science. These nitroxides are prepared by the oxidation of secondary amines that contain no hydrogen atoms on the alpha‐carbons. The unique redox properties of nitroxides enable their use as oxidants in organic synthesis. The varied preparation and uses of oxoammonium salts as stoichiometric oxidants for alcohols are one subject of this review. Oxoammonium ions as oxidants for alcohols have a number of advantages, for example, the method is heavy‐metal free and some of the reactions can be performed in water or aqueous mixtures. A few side reactions are associated with these oxidations. The most serious is the fast reaction of the oxoammonium ion with free amines The several ways these oxidation reactions can be carried out are discussed in detail. They are: Oxidations using stoichimetric quantities of preformed oxoammonium salts carried out in either acidic, neutral, or basic conditions; reactions in which stoichiometric quantities of oxoammonium salts are generated in situ by disproportionation of a nitroxide in the presence of a strong acid; nitroxide‐catalyzed oxidations using a secondary oxidant; efficient nitroxide‐catalyzed oxidations of primary alcohols to carboxylic acids; and oxidations of primary alcohols or hemiacetals that can lead to lactones.

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Angiogenesis Inhibitor Epoxyquinol A: Total Synthesis and Inhibition of Transcription Factor NF-κB

Cited by 70 publications

References 19 publications

Chemical biology of inflammatory cytokine signaling

Chemical biology of inflammatory cytokine signaling

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Oxoammonium‐ and Nitroxide‐Catalyzed Oxidations of Alcohols

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