Environment-sensitive emission of anionic hydrogen-bonded urea-derivative–acetate-ion complexes and their aggregation-induced emission enhancement

Anions often quench fluorescence (FL). However, strong ionic hydrogen bonding between fluorescent dyes and anion molecules has the potential to control the electronic state of FL dyes, creating new functions via non-covalent interactions. Here, we propose an approach, utilising ionic hydrogen bonding between urea groups and anions, to control the electronic states of fluorophores and develop an aggregation-induced emission enhancement (AIEE) system. The AIEE ionic hydrogen-bonded complex (IHBC) formed between 1,8-diphenylnaphthalene (p-2Urea), with aryl urea groups at the para-positions on the peri-phenyl rings, and acetate ions exhibits high environmental sensitivities in solution phases, and the FL quantum yield (QY) in ion-pair assemblies of the IHBC and tetrabutylammonium cations is more than five times higher than that of the IHBC in solution. Our versatile and simple approach for the design of AIEE dye facilitates the future development of environment-sensitive probes and solid-state emitting materials.

AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant α-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.

Fluorometric Liposome Screen for Inhibitors of a Physiologically Important Bacterial Ion Channel

The bacterial K+ homeostasis machinery is widely conserved across bacterial species, and different from that in animals. Dysfunction in components of the machinery has an impact on intracellular turgor, membrane potential, adaptation to changes in both extracellular pH and osmolarity, and in virulence. Using a fluorescence-based liposome flux assay, we have performed a high-throughput screen to identify novel inhibitors of the KtrAB ion channel complex from Bacillus subtilis, a component of the K+ homeostasis machinery that is also present in many bacterial pathogens. The screen identified 41 compounds that inhibited K+ flux and that clustered into eight chemical groups. Many of the identified inhibitors were found to target KtrAB with an in vitro potency in the low μM range. We investigated the mechanisms of inhibition and found that most molecules affected either the membrane component of the channel, KtrB alone or the full KtrAB complex without a preference for the functional conformation of the channel, thus broadening their inhibitory action. A urea derivative molecule that inhibited the membrane component of KtrAB affected cell viability in conditions in which KtrAB activity is essential. With this proof-of-concept study, we demonstrate that targeting components of the K+ homeostasis machinery has the potential as a new antibacterial strategy and that the fluorescence-based flux assay is a robust tool for screening chemical libraries.

Solvatochromism in urea/water and urea-derivative/water solutions

Solvent acidity (SA), solvent basicity (SB), and solvent dipolarity and polarizability (SPP) parameters for urea and water mixtures.

Urea-Derivative Catalyzed Enantioselective Hydroxyalkylation of Hydroxyindoles with Isatins

The enantioselective transformations of indoles preferentially take place in the more-reactive azole ring. However, the methods for the enantioselective functionalization of the indole benzene ring are scarce. In this paper, a series of bifunctional (thio)urea derivatives were used to organocatalyze the enantioselective Friedel−Crafts hydroxyalkylation of indoles with isatins. The resulting products were obtained in good yields (65–90%) with up to 94% enantiomer excess (ee). The catalyst type and the substrate scope were broadened in this methodology.