Identification and Characterization of a Novel Dual Inhibitor of Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase.

Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO.

Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors.

A structure-activity relationship study unexpectedly showed that carbonothioates and , obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines and , respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates and cyanocarbonimidodithioates as IDO1 inhibitors. Incorporation of an OH group provided the most potent analogue .

Partial Identification of Amyloid-β Degrading Activity in Human Serum.

The major hallmarks of Alzheimer's disease (AD) are the extracellular accumulation of pathological amyloid beta (Aβ) in the brain parenchyma and Aβ deposition in cerebral blood walls (cerebral amyloid angiopathy; CAA). Although CAA occurs in more than 80% of AD patients, the mechanisms of Aβ deposition and clearance around the vessel walls are unknown. We found Aβ-degrading activity in human serum during analysis of the regulatory mechanism of Aβ production in human endothelial cells.