Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages
DOI
10.1021/acsmedchemlett.1c00561
Document Type
Journal Article
Publication Date
3-10-2022
Publication Title
ACS Medicinal Chemistry Letters
Volume
13
Issue
3
First Page
403
Last Page
408
Keywords
alkene isomerization, Ferroptosis, imine addition, macrophages, vinylogous Mannich reaction
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 (Rα ≠ H) were found to exceed the potency of the corresponding glycine (Rα = H) derivatives.
Open Access
Green Final
Preprint
Repository Citation
Charaschanya, M., Maskrey, T., LaPorte, M., Janjic, J., & Wipf, P. (2022). Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages. ACS Medicinal Chemistry Letters, 13 (3), 403-408. https://doi.org/10.1021/acsmedchemlett.1c00561