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

• Published in: Angewandte Chemie Vol. 131; no. 25; pp. 8509 - 8513
• Main Authors: Wang, Yong, Pigeon, Pascal, Top, Siden, Sanz García, Juan, Troufflard, Claire, Ciofini, Ilaria, McGlinchey, Michael J., Jaouen, Gérard
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 17-06-2019
• Subjects: Aliphatic compounds; Anticancer properties; Antitumor activity; Bioanorganische Chemie; Cancer; Carbonyl groups; Carbonyls; Chemistry; Chinone; Crystallography; Cytotoxicity; Drug development; Ferrocifen; Metabolites; Nichtkovalente Wechselwirkungen; Organic chemistry; Phenols; Quinones; Spectroscopy; Tumortherapeutika
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201902456

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.
Die tumortherapeutische Wirkung Heterocyclen‐substituierter Ferrociphenole ist auf die Bildung aktiver Metaboliten wie z. B. Chinonmethide zurückzuführen. Eine spezifische Wechselwirkung zwischen einer Imid‐Carbonyl‐Gruppe und dem Chinon ist für die Zytotoxizität der Imido‐Ferrociphenol‐Vorstufen entscheidend, da sie die Chinonmethide stabilisiert und den pKa‐Wert der entsprechenden Phenolate senkt.