Nigratine as dual inhibitor of necroptosis and ferroptosis regulated cell death.

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 EC in the µM range. Taken together, our data showed that nigratine is a dual inhibitor of necroptosis and ferroptosis cell death pathways.

6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury.

Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay.

Synthesis and anti-elastase properties of 6-amino-2-phenyl-4H-3,1-benzoxazin-4-one aminoacyl and dipeptidyl derivatives.

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.

Selective inhibition of rat heart cAMP phosphodiesterases by lipophilic C-methyl-2-phenyl-4H-1-benzopyran-4-ones (C-methylflavones).

A series of eight methoxylated C-methyl-2-phenyl-4H-1-benzopyran-4-ones 3, 6, 10-15 was evaluated as inhibitors of rat heart cytosolic cyclic nucleotide phosphodiesterase (PDE). The 2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-3,8-dimethyl-4H-1-benzopyran-4-one (3) and the 2-(4-methoxyphenyl)-5,7-dimethoxy-3,8-dimethyl-4H-1-benzopyran-4-one (10) have never been previously described. Inhibition was performed on the whole cytosolic preparation and on the four PDE isoforms after HPLC purification.

A new bacterial dehydrogenase oxidizing the lignin model compound guaiacylglycerol beta-O-4-guaiacyl ether.

A lignin model compound, named in short guaiagylglycerol beta-guaiacyl ether (GGE), contains the beta-0-4 ether linkage that is common in the chemical structure of lignin. A Pseudomonas sp. (GU5) had been isolated as an organism able to grow with GGE as the sole source of carbon and energy.