Triazenyl Radicals Stabilized by N-Heterocyclic Carbenes.

Notwithstanding the notable progress in the synthesis of N-heterocyclic carbene-stabilized radicals, aminyl radicals, supported by NHCs or otherwise, have been scarcely studied due to synthetic challenges. Triazenyl radical is a particular form of aminyl radical that contains three adjacent nitrogen atoms, and offers intriguing possibilities for unique reactivity and physical properties stemming from expected delocalization of the spin density over the NNN moiety and its conjugated substituents. Here, we report the synthesis and full characterization of the first NHC-stabilized triazenyl radicals, obtained by one-electron reduction of the corresponding triazenyl cations with potassium metal. These radicals reversibly oxidize back to the cations upon treatment with transition metal sources or electrophiles, and abstract H atom from xanthene to form a new N-H bond at the center nitrogen atom. Potential application of the redox couple between triazenyl cation and triazenyl radical was demonstrated as cathode active materials in lithium ion batteries.

In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease.

Although the pathogenesis of inflammatory bowel disease (IBD) is complex, attachment and infiltration of leukocytes to gut epithelium induced by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) represents the initial step of inflammation in IBD. Previously, we have reported that some 6-amino-2,4,5-trimethylpyridin-3-ols have significant levels of antiangiogenic activity via PI3K inhibition. Based on the reports that angiogenesis is involved in the aggravation of IBD and that PI3K is a potential target for IBD therapy, we investigated whether the scaffold has inhibitory activity against in vitro and in vivo models of colitis. Many analogues showed >80% inhibition against TNF-α-induced monocyte adhesion to colon epithelial cells at 1µM. Compound 8m showed IC50=0.19µM, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA, IC50=18.1mM), a positive control. In a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, orally administered 8m dramatically ameliorated TNBS-induced colon inflammation. It was demonstrated by a high level of suppression in myeloperoxidase (MPO), a surrogate marker of colitis, as well as almost perfect recovery of colon and body weights in a dose-dependent manner. Compared to sulfasalazine, a prodrug of 5-ASA, compound 8m showed >300-fold better efficacy in those parameters. Taken together, 6-amino-2,4,5-trimethylpyridin-3-ols can provide a novel platform for anti-IBD drug discovery.

All-Solid-State Lithium-Organic Batteries Comprising Single-Ion Polymer Nanoparticle Electrolytes.

Advances in lithium battery technologies necessitate improved energy densities, long cycle lives, fast charging, safe operation, and environmentally friendly components. This study concerns lithium-organic batteries comprising bioinspired poly(4-vinyl catechol) (P4VC) cathode materials and single-ion conducting polymer nanoparticle electrolytes. The controlled synthesis of P4VC results in a two-step redox reaction with voltage plateaus at around 3.1 and 3.5 V, as well as a high initial specific capacity of 352 mAh g-1 . The use of single-ion nanoparticle electrolytes enables high electrochemical stabilities up to 5.5 V, a high lithium transference number of 0.99, high ionic conductivities, ranging from 0.2×10-3 to 10-3  S cm-1 , and stable storage moduli of >10 MPa at 25-90 °C. Lithium cells can deliver 165 mAh g-1 at 39.7 mA g-1 for 100 cycles and stable specific capacities of >100 mAh g-1 at a high current density of 794 mA g-1 for 500 cycles. As the first successful demonstration of solid-state single-ion polymer electrolytes in environmentally benign and cost-effective lithium-organic batteries, this work establishes a future research avenue for advancing lithium battery technologies.

Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-α-induced cell adhesion and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract with complex pathogenesis. Here, we synthesized 6-heteroarylamino analogues to inhibit TNF-α-induced adhesion of monocytes to colon epithelial cells which are implicated in the initial inflammation process of IBD. The best analogue, 16a, showed IC50 = 0.29 µM, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA), a positive control. Oral administration of 6f and 16a dramatically ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colon inflammation in rat. The ameliorating effects were accompanied by a high level of recovery in colon and body weights and in the myeloperoxidase (MPO) level. Consistently, the compounds suppressed the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1). Moreover, they significantly suppressed the expression of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 while increasing the level of IL-10, an anti-inflammatory cytokine.

Antitumor activity of BJ-1207, a 6-amino-2,4,5-trimethylpyridin-3-ol derivative, in human lung cancer.

Enhanced expression of NADPH oxidase (NOX) and the subsequent production of reactive oxygen species (ROS) are associated with lung cancer. In the present study, fifty 6-amino-2,4,5-trimethylpyridin-3-ol derivatives were screened for anticancer activity by targeting NOX2-derived ROS. The compounds suppressed ROS production and decreased cancer cell viability (R2 = 0.79). Among the derivatives, the compound coded BJ-1207, which contained a 4-(hydroxydiphenylmethyl)piperidine moiety, exhibited the most effective anticancer activity against A549 lung cancer cell line and eight other cancer cell lines, including H1299, MCF-7, MDA-MB-231, HT-29, SW620, Mia PaCa-2, PANC-1, and U937. BJ-1207 also showed significantly lower inhibitory effects on kinase insert domain receptor (KDR) and c-KIT tyrosine kinase but higher inhibitory activity on NOX than those of sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor. In addition, BJ-1207-induced inhibition of RTK-downstream signaling pathways, such as ROS production, and expression of target genes, such as stem cell factor and transforming growth factor-α, were similar to those induced by sunitinib. In the xenograft chick tumor model, BJ-1207 inhibited lung tumor growth to a similar or much greater extent than that of sunitinib or cisplatin, respectively. Overall, the present study showed that BJ-1207, a vitamin B6-derived 2,4,5-trimethylpyridin-3-ol compound with azacyclonol moiety at C (6)-position of the pyridine ring, inhibited NOX activity and that it is a promising lead compound for developing anticancer drugs against lung cancer.