SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy.

Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC value of 0.

Synthesis and Pharmacological Evaluation of Tetrahydro-γ-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase.

The activation of cyclic GMP-AMP synthase (cGAS) by double-stranded DNA is implicated in the pathogenesis of many hyperinflammatory and autoimmune diseases, and the cGAS-targeting small molecule has emerged as a novel therapeutic strategy for treating these diseases. However, the currently reported cGAS inhibitors are far beyond maturity, barely demonstrating in vivo efficacy. Inspired by the structural novelty of compound (G140), we conducted a structural optimization on both its side chain and the central tricyclic core, leading to several subseries of compounds, including those unexpectedly cyclized complex ones.

Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold.

The ubiquitin-like protein NEDD8 is a critical signaling molecule implicated in the functional maintenance and homeostasis of cells. Dysregulation of this process is involved in a variety of human diseases, including cancer. Therefore, NEDD8-activating enzyme E1 (NAE), the only activation enzyme of the neddylation pathway, has been an emergent anticancer target.

[Study on patterns and characteristics of in vivo tissue distribution of anti-inflammatory extract of Tetrastigma hemsleyanum aerial part in healthy and inflammatory pathological model rats].

The concentrations of seven anti-inflammatory components in blood and tissues were determined by UPLC-MS/MS after oral administration of Tetrastigma hemsleyanum aerial part(THAA) in healthy and inflammatory pathological model rats. The determination was carried out by using positive and negative ion switching technique, and multiple reaction monitoring(MRM) mode. The tissue distributions of the seven components in different physiological states were compared, and the patterns and characteristics of the effective components of THAA were studied.

Preparation of Sulfamates and Sulfamides Using a Selective Sulfamoylation Agent.

Sulfamates and sulfamides are prevalent in biological molecules, but their universal synthetic methods are limited. We herein report a sulfamoylation agent with high solubility and shelf stability. Various sulfamates and sulfamides can be synthesized directly from alcohols or amines by employing this agent with high selectivity and high yields.

Non-transition Metal-Mediated Diverse Aryl-Heteroatom Bond Formation of Arylammonium Salts.

Aryl-heteroatom (C-X) bonds ubiquitously exist in organic, medicinal, and material chemistry, but a universal method to construct diverse C-X bonds is lacking. Here we report our discovery of a convenient and efficient approach to construct various C-X bonds using arylammonium salts as the substrate via an SAr process. This strategy features mild reaction condition, no request of transition metal catalyst, and easy formation of various C-X bonds (C-S, C-Si, C-Sn, C-Ge, C-Se, C-N).

Highly Stereoselective Assembly of Polycyclic Molecules from 1,6-Enynes Triggered by Rhodium(III)-Catalyzed C-H Activation.

An Rh(III)-catalyzed C-H activation of pyrazolones with 1,6-enynes was investigated. The regioselectivity of the C-H activation/alkyne insertion is readily solved by using symmetric enyne coupling partners, and a C-H activation-triggered cascade reaction is realized, which involves alkyne insertion, tautomerization, and double cyclization to offer a class of structurally complex polycyclic architectures. This cascade reaction tolerates a broad substrate scope in high regioselectivity and stereospecificity and furnishes three new chemical bonds and four chiral centers in a single operation.