Paullone
Paullones are a cytostatic class of substances with an indolobenzazepinone basic structure. Many paullones are selective kinase inhibitors ; they inhibit cyclin-dependent kinases and glycogen synthase kinase 3 . They are used in basic biochemical research and serve as lead structures in drug development .
history
Paullones were first synthesized in 1992 as structural isomers of compounds that counteract convulsions . In a screening with various human cancer cell lines by the National Cancer Institute (NCI) it was discovered that kenpaullone (with R = 9-Br) has an antiproliferative effect (inhibits tissue proliferation) and inhibits cyclin-dependent kinases . In 1998, in memory of Dr. Ken Paull, who was a medical chemist at NCI, called the class of substances with these anti-profile properties called Paullone. A study with 28 kinases showed that kenpaullone selectively inhibits cyclin-dependent kinases, glycogen synthase kinase 3 and Lck (member of the tyrosine kinase Src family). Kenpaullone was used as a lead structure for the development of optimized protein kinase inhibitors. More than 300 Paullone and Paullon derivatives were synthesized.
Mechanism of action
Kenpaullon acts as a kinase inhibitor by displacing the phosphate group donor ATP from its binding pocket in the enzyme. The selectivity is achieved through interactions with binding sites in the immediate vicinity of the ATP binding pocket of the kinase.
Use in basic biochemical research
Paullones are used in many areas of basic biochemical research. In studies of the cell cycle z. It has been shown, for example, that kenpaullone, as an inhibitor of glycogen synthase kinase 3 , can influence the regulation of the internal clock . In diabetes research it has been shown that cazpaullone (a 1-azapaullone) can increase the rate of division and decrease the rate of apoptosis in beta cells . In apoptosis research it was found that, in contrast to beta cells, Paullone induces apoptosis in certain cancer cell lines. Paullones are used to study neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease . In combination with certain transcription factors , kenpaullone can be used to reprogram somatic cells into induced pluripotent stem cells . Paullones act as inhibitors of parasitic kinases, e.g. B. from Leishmania , Trypanosoma and Plasmodium species. It could be shown that in addition to kinases, mitochondrial malate dehydrogenase is a target of Paullonen.
literature
- C. Kunick, T. Lemcke: Paullone as selective kinase inhibitors. In: Pharmaceutical newspaper . Volume 23, 2002, full text
- F. Maiwald, et al .: 9- and 11-Substituted 4-azapaullones are potent and selective inhibitors of African trypanosoma. In: European Journal of Medicinal Chemistry . Volume 83, 2014, pp. 274-283, PMID 24973661 .
Web links
Individual evidence
- ↑ N. Tolle, C. Kunick: Paullones as Inhibitors of Protein Kinases. In: Current Topics in Medicinal Chemistry . Volume 11, 2011, pp. 1320-1332, PMID 21513499 .