Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia

Abstract

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.<br>

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

“…A pre-peer-Scheme 2 (a) The optimised synthesis of 5f; (b) the designed and executed plan for the synthesis of the required amine 7. reviewed preprint of this article was deposited and may be viewed elsewhere. 44…”