Aniline-containing derivatives of parthenolide: Synthesis and anti-chronic lymphocytic leukaemia activity

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Authors

Colleges, School and Institutes

Abstract

Parthenolide exhibits anti-leukaemia activity, whilst its synthetic modification to impart improve drug-like properties, including 1,4-conjugate addition of primary and secondary amines, have previously been used, 1,4-addition of aniline derivatives to parthenolide has not been fully explored. A protocol for such additions to parthenolide is outlined herein. Reaction conditions were determined using tulipane as a model Michael acceptor. Subsequently, aniline-containing parthenolide derivatives were prepared under the optimised conditions and single crystal X-ray diffraction structures were resolved for three of the compounds synthesised. The synthesised derivatives, along with compounds resulting from a side reaction, were tested for their in vitro anti-leukaemia activity using the chronic lymphocytic leukaemia (CLL) MEC1 cell line. Computational studies with the 2RAM protein structure suggested that the activity of the derivatives was independent of their in silico ability to dock with the Cys38 residue of NF-κB.

Bibliographic note

Funding Information: Winterbourne House and Garden, their staff and their volunteers are thanked for tireless efforts in the cultivation of feverfew and varieties thereof. Past and present members of the research group headed by JSF are thanked where appropriate for efforts in harvesting feverfew and extraction of PTL. Dr Daniel T. Payne is thanked for conducting preliminary work that informed the present manuscript. AA and JSF are grateful for the support of internally allocated MRC Confidence in Concepts (14/15) and EPSRC ( ISF 2012 ) pump-priming grants. The authors thank the ERDF AWM II for support. ASQ acknowledges the University of Birmingham for providing a postgraduate studentship, and all authors are grateful to the University of Birmingham for support. JSF thanks the Royal Society for a previous Industrial Fellowship (6955) and the EPSRC for past funding ( EP/J003220/1 ). The laboratory of TS is grateful for the support of Bloodwise ( 14031 ). Jamie R. M. Webster of the University of Birmingham Protein Expression Facility is thanked for providing access to the PHERAstar FS. The Catalysis and Sensing for our Environment (CASE) group is thanked for providing networking opportunities [ 68 , 69 ].

Details

Original languageEnglish
Article number131631
JournalTetrahedron
Volume76
Issue number48
Early online date17 Oct 2020
Publication statusPublished - 27 Nov 2020

Keywords

  • 1,4-Conjugate addition, Aniline, Chronic lymphocytic leukaemia (CLL), Leukemia, Natural product derivatives, Parthenolide (PTL)