ABSTRACT
Nigratine (also known as 6E11), a flavanone derivative of a plant natural product, was characterized as highly specific non-ATP competitive inhibitor of RIPK1 kinase, one of the key components of necroptotic cell death signaling. We show here that nigratine inhibited both necroptosis (induced by Tumor Necrosis Factor-α) and ferroptosis (induced by the small molecules glutamate, erastin, RSL3 or cumene hydroperoxide) with EC50 in the µM range. Taken together, our data showed that nigratine is a dual inhibitor of necroptosis and ferroptosis cell death pathways. These findings open potential new therapeutic avenues for treating complex necrosis-related diseases.
Subject(s)
Ferroptosis , Apoptosis , Cell Death/physiology , Humans , Necroptosis , Necrosis , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A series of 6-amino-2-phenyl-4H-3,1-benzoxazin-4-one aminoacyl and dipeptidyl derivatives, in which aminoacids and dipeptides are linked to the benzoxazinone moiety via an amide bond, were synthesized and tested in vitro for their inhibitory activity towards human leukocyte elastase (HLE). When compared to their values without inhibitors, the residual enzymatic activities decrease with time, indicating a time-dependent inhibition. The most potent inhibitions were obtained when Z-Arg-(Pmc), Z-Val-Phe, Z-Ala-Val or Z-Val-Ala are linked to the 6-amino group. Twenty-five new compounds were synthesized.