Copper-Catalyzed Diamination of Alkenes of Unsaturated Ketohydrazones with Amines

A convenient copper-catalyzed intra-/intermolecular diamination of <i>β,γ</i>-unsaturated hydrazones has been developed with simple amines as external amine sources. The protocol enables efficient access to various nitrogen-containing pyrazolines under mild reaction conditions

Copper-Mediated Aminoazidation, Aminohalogenation, and Aminothiocyanation of β,γ-Unsaturated Hydrazones: Synthesis of Versatile Functionalized Pyrazolines

A versatile method for the rapid synthesis of diverse functionalized pyrazolines has been developed based on copper-mediated aminofunctionalization of β,γ-unsaturated hydrazones. The scope of this strategy encompasses a range of difunctionalization reactions: aminoazidation, aminohalogenation, and aminothiocyanation. These reactions provide straightforward access to a series of useful pyrazoline building blocks containing various functional groups that are hard to access traditionally

PD-L1 and gastric cancer prognosis: A systematic review and meta-analysis

<div><p>The expression of Programmed cell Death Ligand 1 (PD-L1) is observed in many malignant tumors and is associated with poor prognosis including Gastric Cancer (GC). The relationship between PD-L1 expression and prognosis, however, is controversial in GC. This paper purports to use a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in GC. For this study, the following databases were searched for articles published from June 2003 until February 2017: PubMed, EBSCO, Web of Science and Cochrane Library. The baseline information extracted were: authors, year of publication, country where the study was performed, study design, sample size, follow-up time, baseline characteristics of the study population, pathologic data, overall survival (OS). A total of 15 eligible studies covering 3291 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The analysis showed that the expression level of PD-L1 was associated with the overall survival in GC (Hazard Ratio, HR = 1.46, 95%CI = 1.08–1.98, P = 0.01, random-effect). In addition to the above, subgroup analysis showed that GC patients with deeper tumor infiltration, positive lymph-node metastasis, positive venous invasion, Epstein-Barr virus infection positive (EBV+), Microsatellite Instability (MSI) are more likely to expression PD-L1. The results of this meta-analysis suggest that GC patients, specifically EBV+ and MSI, may be prime candidates for PD-1 directed therapy. These findings support anti-PD-L1/PD-1 antibodies as a kind of immunotherapy which is promising for GC.</p></div

Correlation of PD-L1 expression with clinicopathological characteristics and Begg’s and Egger’s test in subgroup analysis.

<p>Correlation of PD-L1 expression with clinicopathological characteristics and Begg’s and Egger’s test in subgroup analysis.</p

Characteristics of studies included in the meta-analysis.

<p>Characteristics of studies included in the meta-analysis.</p

Begg’s and Egger’s funnel plot with 95% CI for OS publication bias testing.

<p>Begg’s and Egger’s funnel plot with 95% CI for OS publication bias testing.</p

Exploratory subgrouping analysis of heterogeneity.

<p>Exploratory subgrouping analysis of heterogeneity.</p

Forest plot describing the association between PD-L1 positive and HR of patients with GC.

<p>Forest plot describing the association between PD-L1 positive and HR of patients with GC.</p

Flow chart of study selection.

<p>Flow chart of study selection.</p

Discovery of Pyrido[2,3‑<i>d</i>]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3-d]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy