Parthenolide derivatives as potential leukaemia drugs

[摘要] Chronic lymphocytic leukaemia (CLL) is a common type of leukaemia and it is frequently diagnosed in Western countries. Current therapy to cure this frequently diagnosed leukaemia is unsatisfactory. Therefore, the search for potential drugs has become an important research topic in recent years. Parthenolide, an active component from the plant Feverfew, is a sesquiterpene lactone which includes an α-methylene-γ-butyrolactone moiety. Parthenolide (PTL) displays a variety of biological activities in drug studies while exhibiting good anti-leukaemic activity against primary AML cells in vitro. The poor aqueous solubility and non-selective reactivity of PTL are two major issues that limit its clinical study as a potential drug. Therefore, a series of PTL derivatives have been synthesised through a Michael addition reaction in this project and try to conquer these problems. The biologically active component, parthenolide, was extracted, isolated and purified from a few different types of medicinal herb Feverfew by novel extraction procedures developed in this project. Before commencing the study of PTL, the α-methylene-γ-butyrolactone, tulipane, will be studied as a model substrate to test both the derivatisation chemistry and the biological screens prior to using the more precious parthenolide. All derivatives have been preliminarily tested by Lipinski rules; they passed the tests and proved almost all the compounds are increasing the water solubility by estimated the LogP values used three different ways. Eight PTL derivatives have been evaluated for their anti-cancer activity. Five compounds, 14a-d and 14f, showed similar anti-cancer activity against CLL cell lines in vitro compared with parent compound, with LD50 values in a range of 5-10 μM. The five active compounds have been taken forward to further in vitro and in vivo studies. Also, in future biological work, 10 unexamined remaining PTL derivatives (15a-g) should also be tested against CLL cell lines. Therefore, a structure-activity relationship will be able to be probed and developed.

[发布机构] University:University of Birmingham;Department:School of Chemistry

[关键词] Q Science;QD Chemistry