Deciphering the Diversified Metabolic Behavior of Hydroxyalkyl Ferrocidiphenols as Anticancer Complexes

Abstract

Ferrocidiphenols possessing appropriate substituents in the aliphatic chain have very promising anticancer properties, but a systematic approach to deciphering their diversified metabolic behavior has so far been lacking. Herein, we show that a series of novel ferrocidiphenols bearing different hydroxyalkyl substituents exhibit strong anticancer activity as revealed in a range of in vitro and in vivo experiments. Moreover, they display diversified oxidative transformation profiles very distinct from those of previous complexes, shown by the use of chemical and enzymatic methods and in cellulo and in vivo metabolism studies. In view of this phenomenon, unprecedented chemo-evolutionary sequences that connect all the ferrocidiphenol-related intermediates and analogues have been established. In addition, a comprehensive density functional theory (DFT) study has been performed to decipher the metabolic diversification profiles of these complexes and demonstrate the delicate modulation of carbenium ions by the ferrocenyl moiety, via either αor β-positional participation.

How does ferrocene correlate with ferroptosis? Multiple approaches to explore ferrocene-appended GPX4 inhibitors as anticancer agents

“…The bioorganometallic community has explored the use of ferrocenyl compounds as inhibitors or as auxiliary groups to augment the efficacy of existing organic moieties, and some of them, such as ferroquine, 42 have entered clinical trials. In an initial approach to explore the potential of ferrocenyl compounds as ferroptosis inducers, an in-house ferrocene-based compound library was constructed, consisting of simple mono- or di-substituted ferrocenes, known ferrocene-based drug candidates such as the ferrocifen derivatives developed in our own laboratories, 43–46 aminoferrocene analogues from the Mokhir group 40,47 and ferroquine, as well as several chiral ferrocene derivatives reported by the You group 48–50 (Fig. 2A).…”