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GALIELLALACTONE ANALOGUES – SYNTHESIS AND PROPERTIES

Gidlöf, Ritha LU (2010)
Abstract (Swedish)
Popular Abstract in Swedish

Efter hand som människans livslängd ökar, ökar också frekvensen av och dödligheten i cancer. För att cancer ska kunna överleva och inte selekteras ut och attackeras av kroppens immunförsvar måste den anpassa sig till och styra sin omgivning. Ett sätt att motarbeta cancern är att angripa proteiner som är nödvändiga för cancerns överlevnad. Naturprodukten galiellalakton har visat sig angripa ett sådant protein, kallat STAT3, och därmed hindrat cancer från att fortsätta växa.

I denna avhandling presenteras synteser av nya molekyler med samma grundstruktur som galiellalakton. Dessa substanser har testats mot prostatacancerceller och visat sig hindra deras tillväxt. Denna studie visar på nya... (More)
Popular Abstract in Swedish

Efter hand som människans livslängd ökar, ökar också frekvensen av och dödligheten i cancer. För att cancer ska kunna överleva och inte selekteras ut och attackeras av kroppens immunförsvar måste den anpassa sig till och styra sin omgivning. Ett sätt att motarbeta cancern är att angripa proteiner som är nödvändiga för cancerns överlevnad. Naturprodukten galiellalakton har visat sig angripa ett sådant protein, kallat STAT3, och därmed hindrat cancer från att fortsätta växa.

I denna avhandling presenteras synteser av nya molekyler med samma grundstruktur som galiellalakton. Dessa substanser har testats mot prostatacancerceller och visat sig hindra deras tillväxt. Denna studie visar på nya möjligheter att behandla elakartad prostatacancer. De nya substanserna har även potential att vara verksam mot andra typer av cancer. (Less)
Abstract
Cancer cells use normal cell signalling pathways in a proliferative fashion in order to prolong their own survival. Inhibition of one of the major signal proteins, STAT3 (Signal Transducer and Activator of Transcription 3) has previously been shown to induce apoptosis. Galiellalactone, a fungal metabolite, inhibits STAT3, thus presenting a potential lead for cancer treatment. The inhibition is believed to take place via a Michael addition of a cysteine residue at the surface of STAT3 to the α,β-unsaturated lactone moiety of galiellalactone, which blocks DNA binding to STAT3 and prevents the subsequent transcription.

In order to further investigate the biological mechanism of galiellalactone, a precursor of a biotin-substituted... (More)
Cancer cells use normal cell signalling pathways in a proliferative fashion in order to prolong their own survival. Inhibition of one of the major signal proteins, STAT3 (Signal Transducer and Activator of Transcription 3) has previously been shown to induce apoptosis. Galiellalactone, a fungal metabolite, inhibits STAT3, thus presenting a potential lead for cancer treatment. The inhibition is believed to take place via a Michael addition of a cysteine residue at the surface of STAT3 to the α,β-unsaturated lactone moiety of galiellalactone, which blocks DNA binding to STAT3 and prevents the subsequent transcription.

In order to further investigate the biological mechanism of galiellalactone, a precursor of a biotin-substituted galiellalactone was synthesized. Living cells absorb the precursor, the galiellalactone derivative reacts with STAT3, the cells are lysed, and the mixture is subjected to biotin coupling conditions. If STAT3 has reacted with the galiellalactone derivative and biotin has become attached to the complex, it should be possible to isolate and identify the assembly. Although not yet optimized, the aim is to employ this technique with other galiellalactone precursors with the ability to covalently modify the STAT3 protein and covalently link to biotin.

A novel class of aza-ketogaliellalactams has been prepared, in which the [6,5,5]-tricyclic scaffold of galiellalactone is maintained. The major differences compared to galiellalactone are the conversion of the lactone into a lactam and the introduction of an additional tertiary lactam functionality. The key steps in the synthesis of aza-ketogaliellalactams are a one-pot peptide coupling and intramolecular Michael addition.

Furthermore, a tandem palladium-catalyzed carbonylation/intramolecular Diels-Alder has been developed and employed for the synthesis of several epi-galiellactone analogues. This synthesis is promising as it may enable the preparation of several different classes of analogues and may be an efficient tool for the preparation of labelled compounds. The substances were assayed in prostate cancer cell lines with constitutively active STAT3 signalling, and displayed anti-proliferative activity. We have also studied the addition of nucleophiles, e.g. cysteine methyl ester, to galiellalactone and its analogues, and these results suggest that a Michael addition may not suffice to fully explain the observed biological activity of these compounds. Instead other reactions, in practice a nucleofilic substitution, may be important for the bioactivity. (Less)
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author
supervisor
opponent
  • Grötli, Morten, Medicinal Chemistry, Göteborgs universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Galiellalactone, one-pot peptide coupling and intramolecular Michael addition, tandem palladium-catalyzed carbonylation/intramolecular Diels-Alder, STAT3 inhibition
defense location
K:C, Kemicentrum, Getingevägen 60, 221 00 Lund
defense date
2010-11-19 09:30
language
English
LU publication?
yes
id
aa1ac300-dab0-4a6e-a490-372c82789264 (old id 1710592)
date added to LUP
2010-11-01 09:02:22
date last changed
2016-09-19 08:45:19
@misc{aa1ac300-dab0-4a6e-a490-372c82789264,
  abstract     = {Cancer cells use normal cell signalling pathways in a proliferative fashion in order to prolong their own survival. Inhibition of one of the major signal proteins, STAT3 (Signal Transducer and Activator of Transcription 3) has previously been shown to induce apoptosis. Galiellalactone, a fungal metabolite, inhibits STAT3, thus presenting a potential lead for cancer treatment. The inhibition is believed to take place via a Michael addition of a cysteine residue at the surface of STAT3 to the α,β-unsaturated lactone moiety of galiellalactone, which blocks DNA binding to STAT3 and prevents the subsequent transcription.<br/><br>
In order to further investigate the biological mechanism of galiellalactone, a precursor of a biotin-substituted galiellalactone was synthesized. Living cells absorb the precursor, the galiellalactone derivative reacts with STAT3, the cells are lysed, and the mixture is subjected to biotin coupling conditions. If STAT3 has reacted with the galiellalactone derivative and biotin has become attached to the complex, it should be possible to isolate and identify the assembly. Although not yet optimized, the aim is to employ this technique with other galiellalactone precursors with the ability to covalently modify the STAT3 protein and covalently link to biotin.<br/><br>
A novel class of aza-ketogaliellalactams has been prepared, in which the [6,5,5]-tricyclic scaffold of galiellalactone is maintained. The major differences compared to galiellalactone are the conversion of the lactone into a lactam and the introduction of an additional tertiary lactam functionality. The key steps in the synthesis of aza-ketogaliellalactams are a one-pot peptide coupling and intramolecular Michael addition.<br/><br>
Furthermore, a tandem palladium-catalyzed carbonylation/intramolecular Diels-Alder has been developed and employed for the synthesis of several epi-galiellactone analogues. This synthesis is promising as it may enable the preparation of several different classes of analogues and may be an efficient tool for the preparation of labelled compounds. The substances were assayed in prostate cancer cell lines with constitutively active STAT3 signalling, and displayed anti-proliferative activity. We have also studied the addition of nucleophiles, e.g. cysteine methyl ester, to galiellalactone and its analogues, and these results suggest that a Michael addition may not suffice to fully explain the observed biological activity of these compounds. Instead other reactions, in practice a nucleofilic substitution, may be important for the bioactivity.},
  author       = {Gidlöf, Ritha},
  keyword      = {Galiellalactone,one-pot peptide coupling and intramolecular Michael addition,tandem palladium-catalyzed carbonylation/intramolecular Diels-Alder,STAT3 inhibition},
  language     = {eng},
  title        = {GALIELLALACTONE ANALOGUES – SYNTHESIS AND PROPERTIES},
  year         = {2010},
}