Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates. (14th May 2019)

• Record Type: Journal Article
• Authors: Wang, Yong; Pigeon, Pascal; Top, Siden; Sanz García, Juan; Troufflard, Claire; Ciofini, Ilaria; McGlinchey, Michael J.; Jaouen, Gérard
• Is Part Of: Angewandte Chemie. Volume 131:Number 25(2019)
• Page Start: 8509
• Page End: 8513
• Publication Date: 2019-05-14
• Subjects: Bioanorganische Chemie -- Chinone -- Ferrocifen -- Nichtkovalente Wechselwirkungen -- Tumortherapeutika; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201902456
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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. Abstract : 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 p K a ‐Wert der entsprechenden Phenolate senkt.