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, Alexander Quy, Ruth Roberts, Rosanna Scarll, Timothy Schulz-utermoehlTatjana Stankovic, Brett Stevenson, John S. Fossey, Angelo Agathanggelou

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
231 Downloads (Pure)

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 feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated “drug-likeness” properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro 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 in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.
Original languageEnglish
Pages (from-to)1379-1390
Number of pages12
JournalMedchemcomm
Volume10
Issue number8
DOIs
Publication statusPublished - 1 Aug 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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