Atypical lone pair-π interaction with quinone methides in a series of imido-ferrociphenol anticancer drug candidates.

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)-pi 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-pi interaction markedly enhanced the stability of the QMs and lowered the pK(a) 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-pi interaction in supramolecular chemistry, but also represents a new mode of stabilization of a QM. This unprecedented application of lp-pi interactions in imido-ferrociphenol anticancer drug candidates may also have great potential in drug discovery and organocatalyst design.