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Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

Li, X, Payne, DT, Ampolu, B, Bland, N, Brown, JT, Dutton, MJ, Fitton, CA, Gulliver, A, Hale, L, Hamza, D, Jones, G, Lane, R, Leach, AG, Male, L, Merisor, EG, Morton, MJ, Quy, AS, Roberts, R, Scarll, R, Schulz-Utermoehl, T , Stankovic, T, Stevenson, B, Fossey, JS and Agathanggelou, A (2019) Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia. MedChemComm, 10 (8). pp. 1379-1390. ISSN 2040-2503

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Open Access URL: https://doi.org/10.1039/C9MD00297A (Published version)

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.

Item Type: Article
Uncontrolled Keywords: 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Royal Society of Chemistry
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Date Deposited: 17 Mar 2020 13:02
Last Modified: 17 Mar 2020 13:15
DOI or Identification number: 10.1039/c9md00297a
URI: http://researchonline.ljmu.ac.uk/id/eprint/12527

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