Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia. Issue 8 (1st August 2019)

• Record Type: Journal Article
• Authors: Li, Xingjian; Payne, Daniel T.; Ampolu, Badarinath; Bland, Nicholas; Brown, Jane T.; Dutton, Mark J.; Fitton, Catherine A.; Gulliver, Abigail; Hale, Lee; Hamza, Daniel; Jones, Geraint; Lane, Rebecca; Leach, Andrew G.; Male, Louise; Merisor, Elena G.; Morton, Michael J.; Quy, Alex S.; Roberts, Ruth; Scarll, Rosanna; Schulz-Utermoehl, Timothy; Stankovic, Tatjana; Stevenson, Brett; Fossey, John S.; Agathanggelou, Angelo
• Is Part Of: MedChemComm. Volume 10:Issue 8(2019)
• Page Start: 1379
• Page End: 1390
• Publication Date: 2019-08-01
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c9md00297a
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : A parthenolide-derivative with favourable pharmacokinetic properties and good activity against drug-resistant chronic lymphocytic leukaemia is reported. 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 amine7 used in the generation of5f .