Helenalin Analogues Targeting NF‐κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles,ChemMedChem

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Helenalin Analogues Targeting NF‐κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles
ChemMedChem ( IF 3.6 ) Pub Date : 2018-01-19 , DOI: 10.1002/cmdc.201700752
John C. Widen ₁ , Aaron M. Kempema ₁ , Jordan W. Baur ₁ , Hannah M. Skopec ₁ , Jacob T. Edwards ₁ , Tenley J. Brown ₁ , Dennis A. Brown ₁ , Frederick A. Meece ₁ , Daniel A. Harki ₁

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Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF‐κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α‐methylene‐γ‐butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties. To determine the individual contributions of the Michael acceptors toward NF‐κB inhibition, we synthesized a small library of helenalin‐based analogues containing various combinations of α‐methylene‐γ‐butyrolactones and cyclopentenones. The kinetics of thiol addition to a subset of the analogues was measured to determine the relative thiol reactivities of the embedded electrophiles. Additionally, the cellular NF‐κB inhibitory activities of the analogues were determined to elucidate the contributions of each Michael acceptor to biological potency. Our studies suggest the α‐methylene‐γ‐butyrolactone contributes most significantly to the NF‐κB inhibition of our simplified helenalin analogues.

中文翻译：

针对NF-κBp65的Helenalin类似物：各种亲电试剂的硫醇反应性和细胞效能研究

Helenalin是一种伪愈创木酚内酯的天然产物，靶向NF-κB转录因子p65（RelA）的DNA结合域内的Cys38。Helenalin包含两个共价修饰半胱氨酸的Michael受体：α-亚甲基-γ-丁内酯和环戊烯酮。我们最近报道了两个简化的海伦纳林类似物，它们模仿海伦纳林的生物活性并包含两个亲电部分。为了确定Michael受体对NF-κB抑制作用的个体贡献，我们合成了一个小型的基于海伦素的类似物文库，其中包含α-亚甲基-γ-丁内酯和环戊烯酮的各种组合。测量了硫醇添加到一部分类似物的动力学，以确定嵌入的亲电试剂的相对硫醇反应性。此外，确定了类似物的细胞NF-κB抑制活性，以阐明每个迈克尔受体对生物效能的贡献。我们的研究表明，α-亚甲基-γ-丁内酯对我们简化的海蓝素类似物的NF-κB抑制作用最大。

更新日期：2018-01-19

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