Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Synthesis and biological evaluation of fused thio- and selenopyrans as new indolocarbazole analogues with aryl hydrocarbon receptor affinity
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. (Ulf Rannug)
Department of Bioscience and Nutrition, Karolinska Institute. (Tomasz Janosik)
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. (Ulf Rannug)
Department of Bioscience and Nutrition, Karolinska Institute.
2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 17, no 4, 1648-1653 p.Article in journal (Refereed) Published
Abstract [en]

A series of thio- and selenopyrans having two fused indole units, structurally related to indolocarbazoles, have been prepared and evaluated for aryl hydrocarbon receptor (AhR) affinity, leading to the identification of several new significant AhR ligands. In particular, the parent thiopyrano[2,3-b:6,5-b′]diindole and its derivative having a methyl group in the central ring, as well as the two corresponding selenopyrans, displayed the highest potencies of the compounds tested.

Place, publisher, year, edition, pages
Elsevier , 2009. Vol. 17, no 4, 1648-1653 p.
Identifiers
URN: urn:nbn:se:su:diva-29264DOI: 10.1016/j.bmc.2008.12.072ISI: 000263502300028OAI: oai:DiVA.org:su-29264DiVA: diva2:232051
Available from: 2009-08-19 Created: 2009-08-19 Last updated: 2010-01-11Bibliographically approved
In thesis
1. Direct and indirect mechanisms for aryl hydrocarbon receptor activation mediated by 6-formylindolo[3,2-b]carbazole
Open this publication in new window or tab >>Direct and indirect mechanisms for aryl hydrocarbon receptor activation mediated by 6-formylindolo[3,2-b]carbazole
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aryl hydrocarbon receptor (AhR) is mostly recognized for mediating the adverse effects of dioxins. In addition, endogenous activation of the AhR seems to have important biological functions.

 Several studies have demonstrated an activation of the receptor when no exogenous ligand was added. Furthermore, different physical stimuli such as UV irradiation, fluid shear stress, and hyperoxia have been shown to induce AhR-dependent transcriptional activity. Together these reports indicate either the presence of endogenous ligands or a non-ligand dependent activation. While the mechanisms behind such responses are still elusive, formation of tryptophan photoproducts with high AhR-affinity has been suggested to explain the activation observed after UVB irradiation. The photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) has been proposed to be an endogenous signal substance, and is the focus of the present thesis.

 The objective of the work presented in this thesis was to further characterize the formation and metabolism of FICZ, to identify the biotransforming enzymes required for its metabolism, and subsequently to isolate FICZ-derived metabolites in human urine.

 The studies reveal that FICZ is an excellent substrate for CYP1 enzymes resulting in an efficient metabolism and rapid clearance of FICZ, and a reduced or abolished affinity for the AhR. The hydroxylated metabolites are in turn very good substrates for sulfo-conjugation, and monosulfated derivatives of FICZ were identified in human urine, proving the existence of FICZ in vivo. Furthermore, disturbing the CYP1-dependent metabolic clearance of FICZ efficiently attenuated the rapid depletion of intracellular levels of FICZ, and resulted in a delayed and prolonged AhR-activation. These results suggest that inhibition of degradation of FICZ provides a potent mechanism for indirect regulation of the AhR response.

 The high affinity and AhR activating capacity, together with its rapid clearance by AhR regulated biotransforming enzymes and presence in humans in vivo, all strengthen the hypothesis that FICZ is an endogenous ligand for the AhR and an important biological signaling molecule.

 

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2009. 49 p.
National Category
Pharmacology and Toxicology
Research subject
Genetic Toxicology
Identifiers
urn:nbn:se:su:diva-29266 (URN)978-91-7155-926-5 (ISBN)
Public defence
2009-09-18, G-salen, Svante Arrhenius väg 20 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: In progress.Available from: 2009-08-27 Created: 2009-08-19 Last updated: 2009-08-20Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Wincent, EmmaRannug, Ulf
By organisation
Department of Genetics, Microbiology and Toxicology

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 225 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf