Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates Academic Article uri icon

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  • 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 pKa 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.


  • Wang, Yong
  • Pigeon, Pascal
  • Top, Siden
  • Sanz García, Juan
  • Troufflard, Claire
  • Ciofini, Ilaria
  • Mcglinchey, Michael James
  • Jaouen, Gérard

publication date

  • June 17, 2019