Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore.
Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore.
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DOI：
10.1021/acscentsci.6b00113
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发表时间：
2016-06-22
影响因子：
18.2
通讯作者：
Shenvi RA
中科院分区：
文献类型：
--
作者：
Tada N;Jansen DJ;Mower MP;Blewett MM;Umotoy JC;Cravatt BF;Wolan DW;Shenvi RA
我们描述了一种合成嵌入二聚 Nuphar 生物碱中的亚胺四氢噻吩的通用方法。与之前的研究相比，硫螺环药效团的硫原子被证明是亲电子的。这种α-硫醚在环境温度下与苯硫酚或谷胱甘肽反应，裂解C-S键并形成二硫键。转化率与相应的铵离子 pKa 成正比，并且在硫醇浓度为 5 mM 时半衰期小于 5 小时。 Nuphar 二聚体的简单噻吩类似物在个位数微摩尔浓度下引起细胞凋亡，并以与不饱和亚胺鎓“弹头”相似的水平标记反应性半胱氨酸。我们的实验与之前的观察相结合表明，Nuphar 二聚体的硫可以在细胞环境中作为亲电子试剂发生反应，并且硫触发的逆二聚化可以在细胞中发生。我们描述了一种合成 Nuphar iminium 噻吩药效团的新方法，并公开了其先前未鉴定的硫亲电性。
We describe a general method to synthesize the iminium tetrahydrothiophene embedded in the dimeric Nuphar alkaloids. In contrast to prior studies, the sulfur atom of the thiaspirane pharmacophore is shown to be electrophilic. This α-thioether reacts with thiophenol or glutathione at ambient temperature to cleave the C–S bond and form a disulfide. Rates of conversion are proportional to the corresponding ammonium ion pKa and exhibit half-lives less than 5 h at a 5 mM concentration of thiol. A simple thiophane analogue of the Nuphar dimers causes apoptosis at single-digit micromolar concentration and labels reactive cysteines at similar levels as the unsaturated iminium “warhead”. Our experiments combined with prior observations suggest the sulfur of the Nuphar dimers can react as an electrophile in cellular environments and that sulfur-triggered retrodimerization can occur in the cell. We describe a new method for the synthesis of the Nuphar iminium thiophane pharmacophore and disclose its previously unidentified sulfur electrophilicity.