Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia

Agathanggelou, Angelo; Fossey, John; Stevenson, Brett; Stankovic, Tatjana; Schulz-Utermoehl, Timothy; Scarll, Rosanna; Roberts, Ruth; Quy, Alex; Morton, Michael; Merisor, Elena; Male, Louise; Leach, Andrew; Lane, Rebecca; Jones, Geraint; Hamza, Daniel; Hale, Lee; Guliver, Abigail; Fitton, Catherine; Dutton, Mark; Brown, Jane T; Bland, Nicholas; Ampolu, Badarinath; Payne, Daniel and Li, Xingjian (2019). Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia. ChemRxiv



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.

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