A new radical-based coupling method has been developed for the single-step generation of various γ-amino acids and α,β-diamino acids from α-aminoacyl tellurides. Upon activation by Et3 B and O2 at ambient temperature, α-aminoacyl tellurides were readily converted into α-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (-)-manzacidin A.

A new radical-based coupling method has been developed for the single-step generation of various g-amino acids and a,b-diamino acids from a-aminoacyl tellurides. Upon activation by Et 3 B and O 2 at ambient temperature, a-aminoacyl tellurides were readily converted into a-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (À)-manzacidin A.

Background　Bardoxolone methyl activates nuclear factor erythroid 2 related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein-1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of Bardoxolone methyl show promising effects for patients with chronic kidney disease (CKD). But the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods　We developed a non-covalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on progressive phenotype in Alport syndrome mouse model (Col4a5-G5X). Results　 Similar to Bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation and fibrosis, and prolonged the lifespan of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in renal tissue of Alport mice. Moreover, transcriptome analysis in glomerulus showed that UBE-1099 induced the expression of genes associated with cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphological change. Conclusions　UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and presents a potential therapeutic drug for CKD.

Bardoxolone methyl is an electrophilic agent that induces Nrf2 activation by irreversibly and covalently binding to the cysteine residue of Keap1. Ongoing clinical trials of Bardoxolone methyl show promising effects for patients with chronic kidney disease (CKD). However, irreversible Keap1 inhibitors such as Bardoxolone methyl may covalently bind to other proteins in a non-specific manner and induce side effects due to off-target activities. In this study, we developed a reversible Keap1 inhibitor UBE-1099, which highly selectively and non-covalently inhibits Keap1-Nrf2 protein-protein interaction (PPI) and induces Nrf2 activation. We evaluated its efficacy on glomerulosclerosis in mouse model of CKD (Alport syndrome: Col4a5-G5X). Similar to Bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in CKD model mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation and fibrosis, and prolonged the lifespan of CKD model mice. Moreover, transcriptome analysis in glomerulus showed that UBE-1099 induced the expression of genes associated with cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphological change. Thus, our results firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and CKD.

Decarbonylative Radical Coupling of -Aminoacyl Tellurides: Single-Step Preparation of -Amino and ,-Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A. --Aminoacyl tellurides (III) and (IX) generate -amino carbon radicals via decarbonylation. The radicals react with acrylates or glyoxylic oxime ethers yielding -amino esters or ,-diamino esters respectively. The stereoinformation of tellurides (IX) generated from (S)-amino acids is lost upon radical generation. The utility of this method is demonstrated in a short synthesis of gabapentin hydrochloride (XV). -(NAGATOMO, M.; NISHIYAMA, H.; FUJINO, H.; INOUE*, M.; Angew. Chem., Int. Ed. 54 (2015) 5, 1537-1541, http://dx.doi.org/10.1002/anie.201410186 ; Grad. Sch. Pharm. Sci., Univ. Tokyo, Bunkyo, Tokyo 113, Japan; Eng.) -Mais 24-223