GALIELLALACTONE ANALOGUES – SYNTHESIS AND PROPERTIES
Author
Summary, in English
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.
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.
Department/s
Publishing year
2010
Language
English
Document type
Dissertation
Topic
- Organic Chemistry
Keywords
- Galiellalactone
- one-pot peptide coupling and intramolecular Michael addition
- tandem palladium-catalyzed carbonylation/intramolecular Diels-Alder
- STAT3 inhibition
Status
Published
Supervisor
Defence date
19 November 2010
Defence time
09:30
Defence place
K:C, Kemicentrum, Getingevägen 60, 221 00 Lund
Opponent
- Morten Grötli