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

Alexander Quy, Xingjian Li, Louise Male, Tatjana Stankovic, Angelo Agathanggelou, John Fossey

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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