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Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates
Author(s) -
Wang Yong,
Pigeon Pascal,
Top Siden,
Sanz García Juan,
Troufflard Claire,
Ciofini Ilaria,
McGlinchey Michael J.,
Jaouen Gérard
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201902456
Subject(s) - chemistry , quinone , intramolecular force , supramolecular chemistry , lone pair , stereochemistry , combinatorial chemistry , quinone methide , redox , molecule , organic chemistry
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 p K 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–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.