Photoinduced Olefin Diamination with Alkylamines.

Vicinal diamines are ubiquitous materials in organic and medicinal chemistry. The direct coupling of olefins and amines would be an ideal approach to construct these motifs. However, alkene diamination remains a long-standing challenge in organic synthesis, especially when using two different amine components. We report a general strategy for the direct and selective assembly of vicinal 1,2-diamines using readily available olefin and amine building blocks. This mild and straightforward approach involves in situ formation and photoinduced activation of N-chloroamines to give aminium radicals that enable efficient alkene aminochlorination. Owing to the ambiphilic nature of the ß-chloroamines produced, conversion into tetra-alkyl aziridinium ions was possible, thus enabling diamination by regioselective ring-opening with primary or secondary amines. This strategy streamlines the preparation of vicinal diamines from multistep sequences to a single chemical transformation.

eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.

Reaction of Nitrogen-Radicals with Organometallics Under Ni-Catalysis: N-Arylations and Amino-Functionalization Cascades.

Herein, we report a strategy for the generation of nitrogen-radicals by ground-state single electron transfer with organyl-NiI species. Depending on the philicity of the N-radical, two types of processes have been developed. In the case of nucleophilic aminyl radicals direct N-arylation with aryl organozinc, organoboron, and organosilicon reagents was achieved. In the case of electrophilic amidyl radicals, cascade processes involving intramolecular cyclization, followed by reaction with both aryl and alkyl organometallics have been developed. The N-cyclization-alkylation cascade introduces a novel retrosynthetic disconnection for the assembly of substituted lactams and pyrrolidines with its potential demonstrated in the short total synthesis of four venom alkaloids.

The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain.

The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.

Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor.

A new flow procedure for the preparation of arylsulfonyl chlorides from aniline starting materials is described. The reaction conditions are mild, requiring no added acid and are amenable to continuous flow processing, in a safe, easily scalable and less labour intensive way than the corresponding batch method.

Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2).

BACKGROUND: Hypertension induced by cyclosporine is associated with renal sodium and water retention. Using immunoblotting of kidney homogenates, we investigated the regulation of sodium and water transport proteins in a rat model of cyclosporine-induced hypertension. METHODS: Rats were treated with cyclosporine (25 mg/kg/day intraperitoneally) during 7 days. Control rats received vehicle. RESULTS: Cyclosporine-treated rats had an increase in blood pressure with a decrease in renal sodium excretion compared with control rats. There were no differences either in sodium intake or in plasma creatinine levels between the two groups of rats. These data suggest that the decrease in sodium excretion in the cyclosporine-treated rats was due to an increase in renal sodium absorption. The densitometric analysis of the renal immunoblot showed an increase in the Na-K-2Cl cotransporter of the loop of Henle (NKCC2) in cyclosporine-treated rats (178% +/- 36) compared with control rats (100% +/- 18; P < 0.05*). This protein rise was associated with an increase in the NKCC2 mRNA pointing to a transcriptional regulation of this sodium transporter. There were no statistically significant changes in the sodium proton exchange (NHE-3) of the proximal tubule although in this renal segment, aquaporin-1 was increased in cyclosporine-treated rats compared with control rats (control 100% +/- 6 vs cyclosporine 119% +/- 6; P < 0.05*). CONCLUSIONS: Our results pointed to the thick ascending limb of the loop of Henle as an important site of sodium retention in cyclosporine-induced hypertension. This data may have potential clinical implications for the treatment of hypertension induced by cyclosporine.