Activity

Neurotensin (NT) receptor type 2 (NTS2) represents an attractive target for the development of new NT-based analgesics. Here, we report the synthesis and functional in vivo characterization of the first constrained NTS2-selective macrocyclic NT analog. While most chemical optimization studies rely on the NT(8-13) fragment, we focused on NT(7-12) as a scaffold to design NTS2-selective macrocyclic peptides. U0126 Replacement of Ile12 by Leu, and Pro7/Pro10 by allylglycine residues followed by cyclization via ring-closing metathesis led to macrocycle 4, which exhibits good affinity for NTS2 (50 nM), high selectivity over NTS1 (>100 μM), and improved stability compared to NT(8-13). In vivo profiling in rats reveals that macrocycle 4 produces potent analgesia in three distinct rodent pain models, without causing the undesired effects associated with NTS1 activation. We further provide evidence of its non-opioid antinociceptive activity, therefore highlighting the strong therapeutic potential of NTS2-selective analogs for the management of acute and chronic pain.In this work bonding and aromaticity of triply bonded atoms of group 13 elements (M≡M, M = B and Al) in recently characterized B2Al3-, Na3Al2-, and Na4Al2 are studied. Here, I show that although molecular orbital-based analyses characterize triple bonds, the electropositive nature of group 13 elements gives these bonds unique characteristics. The bond orders derived from the delocalization index, topology of the electron density, and local characteristics of (3, -1) critical points, as defined within the context of quantum theory of atoms in molecules, do not conform with those of ordinary triple bonds. In Na3Al2- and Na4Al2 clusters non-nuclear attractors form between the electropositive Al atoms acting like pseudo atoms. The bond between boron atoms in B2Al3- is more similar to an ordinary triple covalent bond benefiting from the exchange-correlation component of the interatomic interaction energy as defined via interacting quantum atom theory. However, extreme electrostatic repulsion between negatively charged boron atoms attenuates this bond. Finally, current density analysis suggests that B2Al3- is a magnetic aromatic system, nearly 50% more aromatic compared to benzene.In the present work, 103 novel acyclic nucleosides were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship (SAR) studies revealed that most target compounds inhibited the growth of colon cancer cells in vitro, of which 3-(6-chloro-9H-purin-9-yl)dodecan-1-ol (9b) exhibited the most potent effect against the HCT-116 and SW480 cells with IC50 values of 0.89 and 1.15 μM, respectively. Furthermore, all of the (R)-configured acyclic nucleoside derivatives displayed more potent anticancer activity compared to their (S)-counterparts. Mechanistic studies revealed that compound 9b triggered apoptosis in the cancer cell lines via depolarization of the mitochondrial membrane and effectively inhibited colony formation. Importantly, compound 9b inhibited the growth of the SW480 xenograft in a mouse model with low systemic toxicity. These results indicated that acyclic nucleoside compounds are viable as potent and effective anticancer agents, and compound 9b may serve as a promising lead compound that merits further attention in future anticancer drug discovery.An anisotropic piezoelectric response is demonstrated from InGaN nanowires (NWs) over a pyramid-textured Si(100) substrate with an interfacet composition and topography modulation induced by stationary molecular beam epitaxy growth conditions, taking advantage of the unidirectional source beam flux. The variations of InGaN NWs between the pyramid facets are verified in terms of morphology, element distribution, and crystalline properties. The piezoelectric response is investigated by electrical atomic force microscopy (AFM) with a statistic analyzing method. Representative pyramids from the ensemble, on top of which InGaN NWs grown with a substrate held at an oblique angle, were characterized for understanding and confirming the degree of anisotropy. The positive deviated oscillation of the peak force error is identified as a measure of the effective AFM tip/NW interaction with respect to the electrical contact and mechanical deformation. The Schottky contact between the metal-coated AFM tip and the NWs on the different facets reveals distinctions consistent with the interfacet composition variation. The interfacet variation of the piezoelectric response of the InGaN NWs is first evaluated by electrical AFM under zero bias. The average current monotonically depends on the scan frequency, which determines the average peak force error, that is, mechanical deformation, with a facet characteristic slope. A piezoelectric nanogenerator device is fabricated out of a sample with an ensemble of pyramids, which exhibits anisotropic output under periodic directional pressing. This work provides a universal strategy for the synthesis of composite semiconductor materials with an anisotropic piezoelectric response.The aging of microplastics in the environment changes their physicochemical properties. While this may affect their toxicity, comparative data on the effects of aged compared to pristine microplastics are scarce. One of those aging processes is the sorption of chemicals, which has mainly been studied for individual pollutants present in marine ecosystems. To investigate how the sorption of a complex mixture of freshwater pollutants affects the toxicity of microplastics, we incubated irregular polystyrene particles (≤63 μm) in either wastewater or ultrapure water. We exposed Daphnia magna to these aged microplastics and their pristine counterparts (80, 400, 2000, and 10,000 particles mL-1) over four generations using food limitation as an additional, environmentally realistic stressor. Both particle types affect the survival, reproduction, adult and neonate body lengths, and growth. An exposure to pristine microplastics results in the extinction of the third generation of daphnids. In contrast, wastewater-incubated particles induced a lower mortality.