The molecular structures of three parthenolide analogues, (−)-goyazensolide (1), (−)-15-deoxygoyazensolide (2), and (−)-ereglomerulide (3), isolated from the leaves of Piptocoma rufescens in a previous study were determined by X-ray analysis, and the absolute configuration of (−)-goyazensolide (1) was confirmed crystallographically using Cu Kα radiation at low temperature. Compounds 1–3, (+)-rufesolide A (4), and commercial parthenolide were found to be growth inhibitory toward MOLM-13 and EOL-1 human acute myeloid leukemia cells using PKC412 (midostaurin) as the positive control, with 1–3 being more active than parthenolide. Also, compounds 1–4 exhibited synergistic effects when tested with PKC412, but parthenolide did not show this type of activity. At a concentration lower than 2.0 μM, both 1 and 2 induced approximately 50% of the cells to become apoptotic at a late stage of the cell cycle, but no similar apoptotic effects were observed for 3, 4, or parthenolide. Leukemia cell apoptosis was induced by these compounds through the activation of caspase-3 and the inhibition of NF-κB, as indicated by immunoblotting analysis, and compounds 1 and 2 seem to be promising leads for development as potential antileukemic agents.

中文翻译：

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红花小白菊内酯类似物的晶体结构和人白血病细胞凋亡诱导活性


先前研究中从Piptocoma rufescens叶子中分离出的三种小白菊内酯类似物 (−)-goyazensolide ( 1 )、(−)-15-deoxygoyazensolide ( 2 ) 和 (−)-ereglomerulide ( 3 ) 的分子结构如下：通过X射线分析确定，并使用低温Cu Kα辐射通过晶体学证实(-)-goyazensolide ( 1 )的绝对构型。使用 PKC412（米斯托林）作为阳性对照，发现化合物1 – 3 、(+)-rufesolide A ( 4 ) 和市售小白菊内酯对 MOLM-13 和 EOL-1 人急性髓性白血病细胞具有生长抑制作用，其中1 – 3比小白菊内酯更活跃。此外，当与 PKC412 一起测试时，化合物1 – 4表现出协同效应，但小白菊内酯没有表现出这种类型的活性。当浓度低于 2.0 μM 时， 1和2均诱导约 50% 的细胞在细胞周期后期发生凋亡，但3 、 4或小白菊内酯未观察到类似的凋亡效应。免疫印迹分析表明，这些化合物通过激活 caspase-3 和抑制 NF-κB 来诱导白血病细胞凋亡，并且化合物1和2似乎是开发作为潜在抗白血病药物的有希望的先导化合物。