Distinction between 2'- and 3'-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration.

Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2'- and 3'-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2'- and 3'-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2'-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3'-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2'-phosphate over the 3'-phosphate group, in favor of the 2'-phosphate.

Nickel-Catalyzed Anionic Cross-Coupling Reaction of Lithium Sulfonimidoyl Alkylidene Carbenoids With Organolithiums.

The mechanistic platform for a novel nickel0 -catalyzed anionic cross-coupling reaction (ACCR) of lithium sulfonimidoyl alkylidene carbenoids (metalloalkenyl sulfoximines) with organometallic reagents is reported herein, affording substituted alkenylmetals and lithium sulfinamides. The Ni0 -catalyzed ACCR of three different types of metalloalkenyl sulfoximines, including acyclic, axially chiral and exocyclic derivatives, with sp2 organolithiums and sp2 and sp3 Grignard reagents has been studied. The ACCR of metalloalkenyl sulfoximines with PhLi in the presence of the Ni0 -catalyst and precatalyst Ni(PPh3 )2 Cl2 afforded alkenyllithiums, under inversion of configuration at the C atom and complete retention at the S atom. In a combination of experimental and DFT studies, we propose a catalytic cycle of the Ni0 -catalyzed ACCR of lithioalkenyl sulfoximines. Computational studies reveal two distinctive pathways of the ACCR, depending on whether a phosphine or 1,5-cyclooctadiene (COD) is the ligand of the Ni atom. They rectify the underlying importance of forming the key Ni0 -vinylidene intermediate through an indispensable electron-rich Ni0 -center coordinated by phosphine ligands. Fundamentally, we present a mechanistic study in controlling the diastereoselectivity of the alkenyllithium formation via the key lithium sulfinamide coordinated Ni0 -vinylidene complex, which consequently avoids an unselective formation of an alkylidene carbene Ni-complex and ultimately racemic alkenyllithium.

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion.

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described. The CCR generally requires dual Ni catalysis and MgBr2 promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr2 in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl2 as a precatalyst and MgBr2 with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh3 )2 Cl2 as a precatalyst and ZnPh2 does not require salt promotion and is stereoretentive. The reaction with Zn(CH2 SiMe3 )2 , however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh3 )2 Cl2 . Ni-Catalyzed and MgBr2 -promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh2 and Zn(CH2 SiMe3 )2 is stereoretentive with Ni(dppp)Cl2 and Ni(PPh3 )2 Cl2 . CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.

Short protecting-group-free synthesis of 5-acetylsulfanyl-histidines in water: novel precursors of 5-sulfanyl-histidine and its analogues.

The discovery of a non-enzymatic oxidative introduction of sulfur to the 5-position of histidine is reported, by activation with bromine or NBS followed by reaction with thioacetic acid forming novel 5-acetylsulfanyl-histidine. Complementing the previously developed regioselective oxidative S-introduction to the 2-position of histidine by reaction with cysteine, this surprising finding provides straightforward access in multi-gram quantities to naturally occurring 5-sulfanyl-histidine and its N-methylated analogues, including a hitherto unknown regioisomer of l-ergothioneine.

Reproductive safety evaluation of L-Ergothioneine.

L-Ergothioneine is a naturally occurring histidine-derived betaine (CAS No: 497-30-3) synthesized by bacteria and fungi, and found ubiquitously in plants and animals. It is present in many human foodstuffs. We evaluated the potential reproductive toxicity of L-Ergothioneine in Sprague-Dawley rats. L-Ergothioneine was administered at concentrations of 0.1, 0.3 or 0.9% in diet to F0 males (for 10 weeks before pairing and 3 weeks during pairing) and F0 females (for 13 weeks before pairing, during pairing and gestation, and until day 5 of lactation). Systemic exposure increased with dose-level, but not dose proportionally, suggesting saturation of uptake mechanisms. No clinical signs of toxicity were observed and there were no effects of L-Ergothioneine treatment on mating and reproductive performance or parameters of fertility. All animals mated within a similar number of days and pregnancy rates were uniformly high in control and treated groups. There were no effects of treatment with L-Ergothioneine on the duration of gestation, pre- and post-implantation losses, number of pups delivered and viability index, or on litter parameters (litter size, clinical signs, body weight or sex ratio) and the repartition of found dead/cannibalized pups. In conclusion, L-Ergothioneine was well tolerated and without adverse effects on the reproductive parameters evaluated.