Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization.

Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-catalyzed Suzuki Csp2-Csp3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility. Preliminary mechanistic studies provided insights into the underlying mechanism, wherein the ring opening of ABB with a catalytic quantity of bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source (NiBr2). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter (VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon quaternary centers.

Desulfurative Ni-Catalyzed Reductive Cross-Coupling of Benzyl Mercaptans/Mercaptoacetates with Aryl Halides.

The C-S activation and sulfur removal from native thiols is challenging, which limits their application as feedstock materials in organic synthesis despite their natural abundance. Herein, we introduce a per-/polyfluoroaryl moiety, which serves as a redox-active scaffold, into sp3-hybridized thiols to activate the C-S bond. Using a Ni catalyst with MgBr2 as an additive, the S group can be removed to yield an aliphatic radical that can react with an aryl halide in a reductive cross-coupling.

The Development of Diabetes after Subtotal Gastrectomy with Billroth II Anastomosis for Peptic Ulcer Disease.

PURPOSE: A duodenal bypass after a Roux-en-Y gastric bypass operation for obesity can ameliorate the development of diabetes mellitus (DM). We attempted to determine the subsequent risk of developing DM after subtotal gastrectomy with Billroth II anastomosis (SGBIIA) for peptic ulcer disease (PUD). METHODS: We identified 662 patients undergoing SGBIIA for PUD between 2000 and 2011 from the Longitudinal Health Insurance Database as the study cohort, and we randomly selected 2647 controls from the peptic ulcer population not undergoing SGBIIA and were frequency-matched by age, sex, and index year for the control cohort. All patient cases in both cohorts were followed until the end of 2011 to measure the incidence of DM. We analyzed DM risk by using a Cox proportional hazards regression model. RESULTS: The patients who underwent SGBIIA demonstrated a lower cumulative incidence of DM compared with the control cohort (log-rank test, P < .001 and 6.73 vs 12.6 per 1000 person-y). The difference in the DM risk between patients with and without SGBIIA increased gradually with the follow-up duration. Age and sex did not affect the subsequent risk of developing DM, according to the multivariable Cox regression model. Nevertheless, the SGBIIA cohort exhibited a lower DM risk after we adjusted for the comorbidities of hypertension, hyperlipidemia, and coronary artery disease (adjusted hazard ratio (aHR): 0.56, 95% confidence interval (CI): 0.40-0.78). The incidence rate ratio (IRR) of DM in the SGBIIA cohort was lower than that in the control cohort for all age groups (age ≤ 49 y, IRR: 0.40, 95% CI: 0.16-0.99; age 50-64 y, IRR: 0.54, 95% CI: 0.31-0.96; age ≧ 65 y, IRR: 0.57, 95% CI: 0.36-0.91). Moreover, the IRR of DM was significantly lower in the SGBIIA cohort with comorbidities (IRR: 0.50, 95% CI: 0.31-0.78) compared with those without a comorbidity (IRR: 0.65, 95% CI: 0.40-1.04). CONCLUSION: The findings of this population-based cohort study revealed that SGBIIA was associated with a reduced risk of DM development, and the inverse association was greater in the presence of a comorbidity.

Electrical stimulation promotes nerve growth factor-induced neurite outgrowth and signaling.

BACKGROUND: Neurotrophins are important regulators for neural development and regeneration. Nerve growth factor (NGF) therapy has been tested in various models of neural injury and degeneration. However, whether NGF can reach target tissues and maintain effective concentration for a certain period of time remains uncertain. To facilitate neural regeneration, we investigate the possibility of combining NGF and electrical stimulation (ES) in promoting neurite outgrowth, an essential process during neural regeneration. METHODS: PC12 cells were seeded on collagen and indium tin oxide (ITO)-coated area on the transparent conductive devices. Cells were then subjected to the combination of ES and NGF treatment. Neurite outgrowth was compared. RESULTS: Our findings suggest that ES of 100mV/mm together with NGF provides optimal effect on neurite outgrowth of PC12 cells. ES increases NGF-induced neurite length but reduces neurite branching, indicative of its primary effect on neurite elongation instead of initiation. One mechanism that ES enhances neurite outgrowth is through increasing NGF-induced phosphorylation of ERK1/2 (pERK1/2) and expression of Egr1 gene. ES has previously been demonstrated to increase the activity of protein kinase C (PKC). Our result indicates that activating PKC further increases NGF-induced pERK1/2 and thus neurite outgrowth. CONCLUSION: It is likely that ES promotes NGF-induced neurite outgrowth through modulating the activity of ERK1/2. GENERAL SIGNIFICANCE: Findings from this study suggest that combining ES and NGF provides a promising strategy for promoting neurite outgrowth.