Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages.
Manwika CharaschanyaTaber S MaskreyMatthew G LaPorteJelena M JanjicPeter WipfPublished 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.
Keyphrases
- structure activity relationship
- cell death
- cell cycle arrest
- induced apoptosis
- molecularly imprinted
- high glucose
- diabetic rats
- high throughput
- quantum dots
- oxidative stress
- drug induced
- signaling pathway
- endoplasmic reticulum stress
- cell proliferation
- energy transfer
- pi k akt
- protein kinase
- single cell
- molecular dynamics simulations
- solid phase extraction