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Issue 8, 2019
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Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

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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.

Graphical abstract: Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

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Supplementary files

Article information


Submitted
28 May 2019
Accepted
03 Jul 2019
First published
01 Aug 2019

This article is Open Access

Med. Chem. Commun., 2019,10, 1379-1390
Article type
Research Article

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

X. Li, D. T. Payne, B. Ampolu, N. Bland, J. T. Brown, M. J. Dutton, C. A. Fitton, A. Gulliver, L. Hale, D. Hamza, G. Jones, R. Lane, A. G. Leach, L. Male, E. G. Merisor, M. J. Morton, A. S. Quy, R. Roberts, R. Scarll, T. Schulz-Utermoehl, T. Stankovic, B. Stevenson, J. S. Fossey and A. Agathanggelou, Med. Chem. Commun., 2019, 10, 1379
DOI: 10.1039/C9MD00297A

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