O-Phenylenediamine: a privileged pharmacophore of ferrostatins for radical-trapping reactivity in blocking ferroptosis

Organic & Biomolecular Chemistry
Xie-Huang ShengDe-Zhan Chen

Abstract

Ferroptosis is a non-apoptotic, iron dependent form of regulated cell death that is characterized by the accumulation of lipid hydroperoxides. It has drawn considerable attention owing to its putative involvement in diverse neurodegenerative diseases. Ferrostatins are the first identified inhibitors of ferroptosis and they inhibit ferroptosis by efficiently scavenging free radicals in lipid bilayers. However, their further medicinal application has been limited due to the deficient knowledge of the lipid peroxyl radical-trapping mechanism. In this study, experimental and theoretical methods were performed to illustrate the possible lipid hydroperoxide inhibition mechanism of ferrostatins. The results show that an ortho-amine (-NH) moiety from ferrostatins can simultaneously interact with lipid radicals, and then form a planar seven-membered ring in the transition state, and finally present greater reactivity. NBO analysis shows that the formed planar seven-membered ring forces ortho-amines into better alignment with the aromatic π-system. It significantly increases the magnitudes of amine conjugation and improves spin delocalization in the transition state. Additionally, a classical H-bond type interaction was discovered betwee...Continue Reading

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Citations

Feb 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jie LiuDongfeng Chen
Jan 8, 2021·Drug Discovery Today·Yizhen JinXiaowu Dong
Nov 26, 2020·International Journal of Molecular Sciences·Cadiele Oliana ReichertSérgio Paulo Bydlowski
Apr 4, 2021·Biology·Ji-Yoon LeeEun-Woo Lee

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Methods Mentioned

BETA
column chromatography

Software Mentioned

Gaussian

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