Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages

Manwika Charaschanya; Taber S Maskrey; Matthew G LaPorte; Jelena M Janjic; Peter Wipf

doi:10.1021/acsmedchemlett.1c00561

Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages

ACS Med Chem Lett. 2022 Feb 4;13(3):403-408. doi: 10.1021/acsmedchemlett.1c00561. eCollection 2022 Mar 10.

Authors

Manwika Charaschanya¹, Taber S Maskrey¹, Matthew G LaPorte¹, Jelena M Janjic^{2

1}, Peter Wipf¹

Affiliations

¹ Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
² Pharmaceutical Sciences, Duquesne University School of Pharmacy, 415 Mellon Hall, Pittsburgh, Pennsylvania 15282, United States.

Abstract

JP4-039 is an alkene peptide isostere that acts as a low-micromolar inhibitor of erastin- and RSL-3-induced ferroptotic cell death in the HT-1080 cell line. In this work, we have developed new synthetic strategies that allow access to analogues of this lead structure. Enantioselective vinylogous Mannich or cross-metathesis reactions were key to the preparation of a series of analogues that culminated in the preparation of the ca. 30-fold more potent analogue (S)-6c. Structure-activity relationship analyses used both HT-1080 cells and a luminescence-based ferroptosis assay in RAW 264.7 macrophages. In particular, α,α-disubstituted alkene peptide isosteres (R^α ≠ H) were found to exceed the potency of the corresponding glycine (R^α = H) derivatives.