Wang Yong, Pigeon Pascal, Top Siden, Sanz García Juan, Troufflard Claire, Ciofini Ilaria, McGlinchey Michael J, Jaouen Gérard
PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, F-75005, Paris, France.
Sorbonne Université, UPMC Univ Paris 6, UMR 8232 CNRS, IPCM, place Jussieu, F-75005, Paris, France.
Angew Chem Int Ed Engl. 2019 Jun 17;58(25):8421-8425. doi: 10.1002/anie.201902456. Epub 2019 May 14.
Ferrociphenols, especially those possessing a heterocycle at the terminus of an aliphatic chain, display strong anticancer activity through a novel redox mechanism that generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopy reveal that the specific lone pair (lp)-π interaction between a carbonyl group of the imide and the quinone motif of the QM plays an important role in the exceptional cytotoxic behaviour of their imido-ferrociphenol precursors. This intramolecular lp-π interaction markedly enhanced the stability of the QMs and lowered the pK values of the corresponding phenol/phenolate couples. As the first example of such a non-covalent interaction that stabilizes QMs remotely, it not only expands the scope of the lp-π interaction in supramolecular chemistry, but also represents a new mode of stabilization of a QM. This unprecedented application of lp-π interactions in imido-ferrociphenol anticancer drug candidates may also have great potential in drug discovery and organocatalyst design.
二茂铁苯酚，尤其是那些在脂肪链末端带有杂环的二茂铁苯酚，通过一种产生活性代谢物如醌甲基化物（QMs）的新型氧化还原机制展现出强大的抗癌活性。X射线晶体学和紫外/可见光谱表明，酰亚胺羰基与QM的醌基序之间特定的孤对电子（lp）-π相互作用，在其亚氨基二茂铁苯酚前体异常的细胞毒性行为中起重要作用。这种分子内lp-π相互作用显著增强了QMs的稳定性，并降低了相应酚/酚盐对的pK值。作为远程稳定QMs的这种非共价相互作用的首个例子，它不仅扩展了超分子化学中lp-π相互作用的范围，还代表了一种稳定QM的新模式。lp-π相互作用在亚氨基二茂铁苯酚抗癌候选药物中的这种前所未有的应用，在药物发现和有机催化剂设计中也可能具有巨大潜力。
