Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

Research output: Contribution to journalArticle

Authors

  • 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
  • Rosanna Scarll
  • Timothy Schulz-utermoehl
  • Brett Stevenson

External organisations

  • Winterbourne Botanic Garden
  • X-ray Crystallography Facility
  • ApconiX Ltd
  • Institute for Cancer and Genomic Sciences, University of Birmingham, College of Medical and Dental Sciences, Birmingham, B152TT, UK.
  • Liverpool John Moores University

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.

Details

Original languageEnglish
Pages (from-to)1379-1390
Number of pages12
JournalMedchemcomm
Volume10
Issue number8
Publication statusPublished - 1 Aug 2019