Quy Alex S, Li Xingjian, Male Louise, Stankovic Tatjana, Agathanggelou Angelo, Fossey John S
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT, UK.
X-Ray Crystallography Facility, School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT, UK.
Tetrahedron. 2020 Nov 27;76(48):131631. doi: 10.1016/j.tet.2020.131631.
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.
小白菊内酯具有抗白血病活性，虽然之前已采用对其进行合成修饰以赋予其更好的类药物性质的方法，包括伯胺和仲胺的1,4 -共轭加成，但苯胺衍生物与小白菊内酯的1,4 -加成尚未得到充分研究。本文概述了此类与小白菊内酯加成的方案。以郁金香烷作为模型迈克尔受体确定反应条件。随后，在优化条件下制备了含苯胺的小白菊内酯衍生物，并解析了所合成的三种化合物的单晶X射线衍射结构。使用慢性淋巴细胞白血病（CLL）MEC1细胞系对合成的衍生物以及副反应产生的化合物进行了体外抗白血病活性测试。对2RAM蛋白结构的计算研究表明，衍生物的活性与其在计算机模拟中与NF -κB的Cys38残基对接的能力无关。
