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

Manwika CharaschanyaTaber S MaskreyMatthew G LaPorteJelena M JanjicPeter Wipf
Published in: ACS medicinal chemistry letters (2022)
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.
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