Quantitative Structure−Activity Relationship of Sesquiterpene Lactones as Inhibitors of the Transcription Factor NF-κB

Siedle, Bettina; Garcı́a-Piñeres, Alfonso; Murillo, R.; Schulte‐Mönting, Jürgen; Castro, Vı́ctor; Rüngeler, Peter; Klaas, Christoph A.; Costa, Fernando B. Da; Kisiel, Wanda; Merfort, Irmgard

doi:10.1021/jm049937r

Cited by 236 publications

(198 citation statements)

References 52 publications

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“…These studies indicated that the SLs more active possessed a rigid skeleton (furanoheliangolides and guaianolides), whereas in the case of flexible skeletons (germacranolides, such as germacrolides and melampolides), inhibition might be mostly determined by the number and type of a, b-unsaturated carbonyl structural elements (Siedle et al, 2004).…”

Section: Anti-inflammatorymentioning

confidence: 99%

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

et al. 2013

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Section: Anti-inflammatorymentioning

confidence: 99%

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

et al. 2013

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“…This notion is consistent with the structure-activity relationship study of the effect of sesquiterpene lactones on NF-kB-binding activity in TNF-a-stimulated cells, which shows that various guaianolides and eudesmanes containing a-methylene-g-lactones manifest inhibitory effects. 79 We have also synthesized (11S)-2a-bromo-3-oxoeudesmano-13,6a-lactone (SRC2, as shown in Figure 4) from the starting material L-asantonin. 80 SRC2 is devoid of the a-methylene-g-lactone moiety, but has a bromoketone structure at the A-ring.…”

Section: Thiol-reactive Ikk Inhibitorsmentioning

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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“…signaling pathway, [7] a central mediator of the human immune response whose deregulation is noted in inflammatory and autoimmune diseases as well as various human cancers. [8] The 5,7-fused bicyclic family of guaianolides is perhaps the flagship subset of sesquiterpene lactone natural products and two major, isomeric sub-types, the 6,12-guaianolides and 8,12-guaianolides, have been isolated ( Figure 1A).…”

mentioning

confidence: 99%

A Double Allylation Strategy for Gram‐Scale Guaianolide Production: Total Synthesis of (+)‐Mikanokryptin

Maimone

2017

Angewandte Chemie

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With over 5000 members isolated to date, sesquiterpene lactones represent a prolific source of medicinal agents with several derivatives in human clinical trials. The guaianolides, a major subset of this group, have been intensely investigated from both medicinal and chemical synthesis perspectives for decades. To date, the myriad stereochemical permutations presented by this enormous family have precluded the synthesis of many unique members. Herein we report the first total synthesis of the trans-fused 8,12-guaianolide (+)-mikanokryptin in 10 steps from (+)-carvone.Notably this represents the first gram-scale total synthesis of any guaianolide natural product. Graphical AbstractKeywords total synthesis; terpene; allylation; natural product; guaianolide Sesquiterpene lactones from the Asteraceae family of plants represent one of the largest and most biologically significant classes of plant secondary metabolites. [1] Their presence in both traditional herbal medicine regimes as well as modern human medicine have been extensively documented. [1][2] In particular, α-methylene-γ-lactone-containing members have strong documented anticancer, [3] anti-inflammatory, [4] anthelmintic, [5] and anti-migraine activity. [6] Multiple members have also been shown to inhibit aspects of the NF-κB Correspondence to: Thomas J. Maimone. Current address of Prof. Dr. Silong Xu: Department of Chemistry, School of Science, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.Supporting information for this article is given via a link at the end of the document. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript signaling pathway, [7] a central mediator of the human immune response whose deregulation is noted in inflammatory and autoimmune diseases as well as various human cancers. [8] The 5,7-fused bicyclic family of guaianolides is perhaps the flagship subset of sesquiterpene lactone natural products and two major, isomeric sub-types, the 6,12-guaianolides and 8,12-guaianolides, have been isolated ( Figure 1A). Despite extensive studies on the chemical synthesis of 6,12-guaianolides, [9] 8,12-guaianolides have received relatively limited attention from the synthetic community. [10] Mikanokryptin (1), isolated in 1975 by Herz and co-workers, belongs to the continually growing family of trans-fused 8,12-guaianolides which are largely unexplored and present stereochemistry patterns not easily addressed by current strategies ( Figure 1A). [11] In developing a synthetic route to this family, we viewed a double allylation disconnection as potentially being capable of constructing the guaianolide ring system (see 2) from two simple, hypothetical fragments (see 3 and 4, Figure 1B). Of significant concern to us was the paucity of examples of 7-membered ring formation via metal-mediated intramolecular Barbier-type allylation relevant to this synthetic problem. [12,13] Herein we disclose the realization of this plan resulting in a simple total synthesis of 1 capable of forming multi-gram ...

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Quantitative Structure−Activity Relationship of Sesquiterpene Lactones as Inhibitors of the Transcription Factor NF-κB

Cited by 236 publications

References 52 publications

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

Chemical biology of inflammatory cytokine signaling

A Double Allylation Strategy for Gram‐Scale Guaianolide Production: Total Synthesis of (+)‐Mikanokryptin

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