Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia [post]

Xingjian Li, Daniel Payne, Badarinath Ampolu, Nicholas Bland, Jane T Brown, Mark Dutton, Catherine Fitton, Abigail Guliver, Lee Hale, Daniel Hamza, Geraint Jones, Rebecca Lane (+12 others)
2019 unpublished
A protocol for growing, extracting and derivatising parthenolide obtained from feverfew varieties is reported. Aminated parthenolide derivatives were prepared via 1,4-addition of primary or secondary amines utilising established and modified methods. The parthenolide derivatives' drug-likeness properties were computed and they were screened for anti-leukaemic activity against the TP53-mutant, chemo-refractory, MEC1 chronic lymphocytic leukaemia (CLL) cell line. A screening cascade identified a
more » ... mall number of the most active compounds and their properties, including in vivo pharmacokinetics and in vitro hERG liability, were compared against DMAPT. This cascade culminated in the identification of a new compound with good anti CLL activity, with fewer drawbacks than some headline compounds from the literature and with utility against drug-resistant disease. Literature precedent and molecular docking studies support a multi-target-driven mode of action.<br>
doi:10.26434/chemrxiv.7629680 fatcat:th6ces2fabfylbvkoz4tj4yzoi