Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

Xingjian Li, Daniel T. Payne, Badarinath Ampolu, Nicholas Bland, Jane T. Brown, Mark J. Dutton, Catherine A. Fitton, Abigail Gulliver, Lee Hale, Daniel Hamza, Geraint Jones, Rebecca Lane, Andrew G. Leach, Louise Male, Elena G. Merisor, Michael J. Morton, Alex S. Quy, Ruth Roberts, Rosanna Scarll, Timothy Schulz-Utermoehl, Tatjana Stankovic, Brett Stevenson, John S. Fossey and Angelo Agathanggelou


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 small 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.

Ref: Med. Chem. Commun. 2019, Advance article