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Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia

preprint
submitted on 28.01.2019 and posted on 28.01.2019 by Xingjian Li, Daniel Payne, Badarinath Ampolu, Nicholas Bland, Jane T Brown, Mark Dutton, Catherine Fitton, Abigail Guliver, Lee Hale, Daniel Hamza, Geraint Jones, Rebecca Lane, Andrew Leach, Louise Male, Elena Merisor, Michael Morton, Alex Quy, Ruth Roberts, Rosanna Scarll, Timothy Schulz-Utermoehl, Tatjana Stankovic, Brett Stevenson, John Fossey, Angelo Agathanggelou
A protocol for growing, extracting and derivatising parthenolide obtained from feverfew varieties is reported. Aminated parthenolide derivatives were prepared via 1,4-addition of primary or secondary amines utilising established and modified methods. The parthenolide derivatives’ drug-likeness properties were computed and they were screened for anti-leukaemic activity against the TP53-mutant, chemo-refractory, MEC1 chronic lymphocytic leukaemia (CLL) cell line. A screening cascade identified a small number of the most active compounds and their properties, including in vivo pharmacokinetics and in vitro hERG liability, were compared against DMAPT. This cascade culminated in the identification of a new compound with good anti CLL activity, with fewer drawbacks than some headline compounds from the literature and with utility against drug-resistant disease. Literature precedent and molecular docking studies support a multi-target-driven mode of action.

Funding

MRC Confidence in Concepts at University of Birmingham

EPSRC internally allocated pump-priming fund at University of Birmingham

ERDF AWM II

Royal Society Industry Fellowship (2012/R1)

EPSRC (EP/J003220/1)

University of Birmingham Postgraduate Studentship

Bloodwise (14031)

History

Email Address of Submitting Author

j.s.fossey@bham.ac.uk

Institution

University of Birmingham

Country

United Kingdom

ORCID For Submitting Author

0000-0002-2626-5117

Declaration of Conflict of Interest

Ruth Roberts and Michael J. Morton are co-founders and co-directors of Apconix Ltd, an integrated toxicology and ion channel company that provides expert advice on nonclinical aspects of drug discovery and drug development to academia, industry and non-for-profit organisations. The remaining authors declare no competing interests.

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