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      Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia

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          Abstract

          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.<br>

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          Journal
          American Chemical Society (ACS)
          January 28 2019
          Article
          10.26434/chemrxiv.7629680
          31d7e610-6b68-42bb-9dd7-84f3c3c6fd3d
          © 2019

          https://creativecommons.org/licenses/by-nc-nd/4.0/

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