Department of Medicinal Chemistry, University of Minnesota, 2231 6th Street S.E., Minneapolis, MN, 55455, USA.
ChemMedChem. 2018 Feb 20;13(4):303-311. doi: 10.1002/cmdc.201700752. Epub 2018 Jan 19.
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.
标题：Helenalin 模拟物中迈克尔受体对 NF-κB 抑制的贡献
摘要：Helenalin 是一种靶向 NF-κB 转录因子 p65（RelA）DNA 结合域中 Cys38 的伪愈创木烷内酯天然产物。Helenalin 包含两个可以共价修饰半胱氨酸的迈克尔受体：α-亚甲基-γ-丁内酯和环戊烯酮。我们最近报道了两种简化的 helenalin 类似物，它们模拟了 helenalin 的生物学活性，并且都包含两个亲电部分。为了确定迈克尔受体对 NF-κB 抑制的单独贡献，我们合成了一系列基于 helenalin 的类似物，其中包含各种 α-亚甲基-γ-丁内酯和环戊烯酮的组合。测量了一部分类似物中巯基加成的动力学，以确定嵌入亲电体的相对巯基反应性。此外，还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力的贡献。我们的研究表明，α-亚甲基-γ-丁内酯对我们简化的 helenalin 类似物的 NF-κB 抑制作用贡献最大。
