Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

Abstract

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from <i>feverfew</i> and protocols for growing, extracting and derivatising it are reported<i>.</i> A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on <i>in vitro</i> anti-leukaemic activity and calculated "drug-likeness" properties, <i>in vitro</i> and <i>in vivo</i> pharmacokinetics studies and hERG liability testing. <i>In vitro</i> studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and <i>in silico</i> molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine <b>7</b> used in the generation of <b>5f</b>.