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 prooxidant 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.

Click on the link Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia to read the open access paper.

Xingjian Li,aDaniel T. Payne,aBadarinath Ampolu,bNicholas Bland,bJane T. Brown,bMark J. Dutton,aCatherine A. Fitton,cAbigail Gulliver,dLee Hale,dDaniel Hamza,bGeraint Jones,bRebecca Lane,bAndrew G. Leach,eLouise Male,fElena G. Merisor,bMichael J. Morton,gAlex S. Quy,aRuth Roberts,ghRosanna Scarll,cTimothy Schulz-Utermoehl,bTatjana Stankovic,cBrett Stevenson,bJohn S. Fossey*a  and  Angelo Agathanggelou*

*Corresponding authors

aSchool of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK, bSygnature Discovery, The Discovery Building, BioCity, Pennyfoot Street, Nottingham, UK, cInstitute for Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK, dWinterbourne Botanic Garden, University of Birmingham, 58 Edgbaston Park Road, Edgbaston, Birmingham, UK, eSchool of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, UK, fX-Ray Crystallography Facility, School of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK, gApconiX Ltd, Alderly Park, Nether Alderly, Cheshire, UK, hSchool of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK