Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

NHC-copper-thiophene-2-carboxylate complex for the hydroboration of terminal alkynes.

An air-stable N-heterocyclic carbene-copper thiophene-2-carboxylate (CuTC) complex has been prepared for the stereoselective hydroboration of terminal alkynes using pinacolborane (HBpin) or 1,8-naphthalenediaminatoborane (HBdan). The newly synthesized complex can be directly activated by hydroboranes without a cocatalyst such as a base, and exhibits high reactivity for the hydroboration of alkynes under mild conditions. A gram-scale hydroboration of terminal phenylacetylene demonstrated the applicability of the copper complex for the preparation of alkenyl boronates.

Protective effect of catechin on apoptosis of the lens epithelium in rats with N-methyl-N-nitrosourea-induced cataracts.

PURPOSE: To investigate the effect of catechin on apoptotic cell death in the lens epithelium of rats with cataract. METHODS: Cataract was induced by intraperitoneal injection of 100 mg/kg N-methyl-N-nitrosourea (MNU) to ten day-old Sprague-Dawley rats. The neonatal rats were randomly divided into five groups (n=15 in each group): a control group, and four cataract-induction groups, treated with either 0, 50, 100, 200 mg/kg catechin. We performed slit-lamp biomicroscopic analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, Western-blot for Bcl-2 and Bax, and immunohistochemistry for caspase-3. RESULTS: Apoptotic cell death in lens epithelial cells that increased following cataract formation in rats was suppressed by cathechin. CONCLUSIONS: Catechin inhibited cataract-induced apoptotic cell death in the lens epithelium and may prove useful for the prevention of cataract progression.

Oligoindole-based foldamers with a helical conformation induced by chloride.

As a new type of foldamers, oligoindoles containing 4, 6, and 8 indole rings were synthesized, and their folding properties were characterized by a combination of 1H NMR techniques and UV/visible titration experiments. When chloride was added, the NH signals of the oligoindoles were downfield shifted as a result of hydrogen-bond formation, and the aromatic signals were upfield shifted by stacking between two indoles. Moreover, the ROESY experiment provided definitive NOE evidence for the helical stacking in the presence of chloride. Finally, the UV/visible titration experiments demonstrated that the oligoindoles formed 1:1 complexes with chloride, and the association constants greatly increased with increasing the number of the indole NHs. These observations are all consistent with the fact that oligoindoles adopt a helical conformation when complexed with chloride by hydrogen-bonding interactions.