Synthesis and Optimization of Nitroxide-Based Inhibitors of Ferroptotic Cell Death in Cancer Cells and Macrophages.
| Autor: | Charaschanya M; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States., Maskrey TS; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States., LaPorte MG; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States., Janjic JM; Pharmaceutical Sciences, Duquesne University School of Pharmacy, 415 Mellon Hall, Pittsburgh, Pennsylvania 15282, United States.; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States., Wipf P; Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Feb 04; Vol. 13 (3), pp. 403-408. Date of Electronic Publication: 2022 Feb 04 (Print Publication: 2022). |
| DOI: | 10.1021/acsmedchemlett.1c00561 |
| Abstrakt: | 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. Competing Interests: The authors declare no competing financial interest. (© 2022 American Chemical Society.) |
| Databáze: | MEDLINE |
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