Biological activities of natural and semi-synthetic pseudo-guaianolides: Inhibition of transcription factors.

5.00
Hdl Handle:
http://hdl.handle.net/10146/332973
Title:
Biological activities of natural and semi-synthetic pseudo-guaianolides: Inhibition of transcription factors.
Authors:
Villagomez, Rodrigo
Abstract:
Damsin (1) is a natural sesquiterpene lactone (SL) isolated from Ambrosia arborescens Mill., a plant used in the Andes as antiinflammatory medicine. This natural product is an inhibitor of NF-κB, a protein complex that controls the transcription of many genes in mammalian cells, and has a potential for standing model for the development of new anti-cancer lead structures. In order to improve the anti-cancer activity, the chemistry of 1 was explored and in the process, dozens of derivatives were prepared. Damsin (1) inhibited cell proliferation, DNA biosynthesis and formation of cytoplasmic DNA histone complex in Caco-2 cells and further studies using the luciferase reporter system showed that it also inhibited expressions of NF-κB and STAT3. Therefore, the NF-κB inhibitory capacity of some derivatives was evaluated and two analogues, 31 and 32, were found to be more potent. In order to have a preliminary evaluation method of the derivatives, we developed fast and cheap biochemical assay to study the effect of SLs in the binding capacity of NF-κB (heterodimer RelA/p50) to the DNA recognition target. In this assay the compounds 21, 22, 24, 25 and 26 had a high dissociation capacity of the complex NF-κB/DNA. Finally, four compounds were selected for MS characterization studies with recombinant NF-κB, the most selective compound was 26 (compared with 1) by selective alkylation of Cys-38 and Cys-120 in RelA. The Cystein-38 is crucial for the transcriptional activity of NF-κB.
Citation:
Villagomez R.: Biological activities of natural and semi-synthetic pseudo-guaianolides: Inhibition of transcription factors. PhD theses. Lund University, 2014.
Publisher:
Media-Tryck, Lund University, Sweden, 2014
Issue Date:
Jun-2014
URI:
http://hdl.handle.net/10146/332973
Additional Links:
http://www.lunduniversity.lu.se/lup/publication/4438537
Type:
Thesis
Language:
en
ISBN:
978-91-7422-358-3
Sponsors:
Some studies described in this thesis were financially supported by ECNIS (European Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: "Food Quality and Safety" (Contract No 513943) and its successor ECNIS2.
Appears in Collections:
Theses

Full metadata record

DC FieldValue Language
dc.contributor.authorVillagomez, Rodrigoen
dc.date.accessioned2014-10-21T09:44:54Zen
dc.date.available2014-10-21T09:44:54Zen
dc.date.issued2014-06en
dc.identifier.citationVillagomez R.: Biological activities of natural and semi-synthetic pseudo-guaianolides: Inhibition of transcription factors. PhD theses. Lund University, 2014.en
dc.identifier.isbn978-91-7422-358-3en
dc.identifier.urihttp://hdl.handle.net/10146/332973en
dc.description.abstractDamsin (1) is a natural sesquiterpene lactone (SL) isolated from Ambrosia arborescens Mill., a plant used in the Andes as antiinflammatory medicine. This natural product is an inhibitor of NF-κB, a protein complex that controls the transcription of many genes in mammalian cells, and has a potential for standing model for the development of new anti-cancer lead structures. In order to improve the anti-cancer activity, the chemistry of 1 was explored and in the process, dozens of derivatives were prepared. Damsin (1) inhibited cell proliferation, DNA biosynthesis and formation of cytoplasmic DNA histone complex in Caco-2 cells and further studies using the luciferase reporter system showed that it also inhibited expressions of NF-κB and STAT3. Therefore, the NF-κB inhibitory capacity of some derivatives was evaluated and two analogues, 31 and 32, were found to be more potent. In order to have a preliminary evaluation method of the derivatives, we developed fast and cheap biochemical assay to study the effect of SLs in the binding capacity of NF-κB (heterodimer RelA/p50) to the DNA recognition target. In this assay the compounds 21, 22, 24, 25 and 26 had a high dissociation capacity of the complex NF-κB/DNA. Finally, four compounds were selected for MS characterization studies with recombinant NF-κB, the most selective compound was 26 (compared with 1) by selective alkylation of Cys-38 and Cys-120 in RelA. The Cystein-38 is crucial for the transcriptional activity of NF-κB.en
dc.description.sponsorshipSome studies described in this thesis were financially supported by ECNIS (European Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: "Food Quality and Safety" (Contract No 513943) and its successor ECNIS2.en
dc.language.isoenen
dc.publisherMedia-Tryck, Lund University, Sweden, 2014en
dc.relation.urlhttp://www.lunduniversity.lu.se/lup/publication/4438537en
dc.subjectPseudo-guaianolidesen
dc.subjectSesquiterpene lactonesen
dc.subjectNF-κBen
dc.subjectMedicinal plantsen
dc.subjectAnti-inflammatoryen
dc.subjectAnticancer drugen
dc.subjectDamsinen
dc.subjectAmbrosia arborescensen
dc.subjectCell proliferationen
dc.titleBiological activities of natural and semi-synthetic pseudo-guaianolides: Inhibition of transcription factors.en
dc.typeThesisen
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