Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

Diverse Biological Activity of Benzofuroxan/Sterically Hindered Phenols Hybrids.

Combining two pharmacophores in a molecule can lead to useful synergistic effects. Herein, we show hybrid systems that combine sterically hindered phenols with dinitrobenzofuroxan fragments exhibit a broad range of biological activities. The modular assembly of such phenol/benzofuroxan hybrids allows variations in the phenol/benzofuroxan ratio. Interestingly, the antimicrobial activity only appears when at least two benzofuroxan moieties are introduced per phenol. The most potent of the synthesized compounds exhibit high cytotoxicity against human duodenal adenocarcinoma (HuTu 80), human breast adenocarcinoma (MCF-7), and human cervical carcinoma cell lines. This toxicity is associated with the induction of apoptosis via the internal mitochondrial pathway and an increase in ROS production. Encouragingly, the index of selectivity relative to healthy tissues exceeds that for the reference drugs Doxorubicin and Sorafenib. The biostability of the leading compounds in whole mice blood is sufficiently high for their future quantification in biological matrices.

High-efficiency reduction of p-nitrophenol on green-synthesized gold nanoparticles decorated on ceria nanorods.

A green synthesis using extract from Citrus maxima peel was developed to fabricate Au-Ce catalysts for the reduction of p-nitrophenol (PNP). Au nanoparticles with a diameter of 6.6 ± 2.5 nm were deposited onto the surface of CeO2 nanorods with a length of 33.1 ± 15.0 nm and a diameter of 7.1 ± 2.1 nm. The mesoporous and non-porous capillary structures of these materials were observed. The interaction between Au and CeO2 increased the specific surface area, pore diameter, and pore volume compared with pure CeO2 (90 m2 g-1, 23.8 Å, and 0.110 cm3 g-1 versus 72 m2 g-1, 23.0 Å, and 0.089 cm3 g-1). The splitting peaks of the surface oxygen and their shifting at lower temperatures compared with CeO2 nanorods were found thanks to the Au-CeO2 interaction, suggesting that their reduction occurred more easily. The synthesized Au-Ce catalysts exhibited excellent activity in the reduction of PNP to p-aminophenol. The 0.2Au-Ce catalyst was the most efficient one for PNP reduction, enabling the conversion of PNP in 30 minutes with a catalyst concentration of 20 mg L-1 and a PNP/NaBH4 molar ratio of 1/200. Moreover, the 0.2Au-Ce catalyst could be reused for at least five consecutive cycles without considerable loss of its activity.

Knowledge Sharing Types as Predictors of Job Performance Mediated by Problem-Solving Self-Efficacy in the Information System Integration Service Industry.

Knowledge sharing is an essential approach to creative problem solving in technology firms, but few studies have considered the information system integration service industry. To address this gap, drawing on the micro-ecology theory, we developed a research model to explore the mediating role of four types of knowledge sharing (i.e., automatic response, rational reflection, ridiculed reflection, and stolen reflection) in the relationship between problem solving self-efficacy (PSSE) and IT workers' job performance. Data were collected from 307 System Integration IT workers by using the snowball sampling method via a Google questionnaire. Structural equation modeling was used to test the hypotheses of the relationships between the variables. The results showed that PSSE can positively predict four knowledge sharing types; except for stolen reflection, the others can positively predict job performance. The implication of this study is that automatic response systems and rational reflection systems in knowledge sharing can enhance job performance, supported by PSSE. It is hoped that managers can generate System Integration workers' rational reflection to effectively evoke knowledge sharing.

Impact of controlled shearing on solubility and heat stability of pea protein isolate dispersed in solutions with adjusted ionic strength.

Pea protein isolates (PPI) have sustained an increasing demand in the food industry as a substitute for animal-origin proteins. Shearing is an integral part of food processing that can change properties of proteins and their functionality. PPI dispersions prepared at 4 or 8% concentration (w/w protein), pH 6.8 or 7.5 and under ionic strength (IS) 100, 200 mM or non-adjusted, were subjected to controlled shearing at two levels (100 or 1500 s-1) during heating at 90 °C for 5 min. All main factors had substantial effects on the tested dependent variables. Shearing at 1500 s-1 significantly improved the solubility and heat stability of 4% PPI at pH 6.8 or 7.5 and IS-100 or 200 mM by 27-43% in comparison to 100 s-1. Following 1500 s-1 treatment, all PPI dispersions showed >85% solubility and heat stability except 4% PPI at pH 6.8 and IS 100 mM (60%). Shearing appeared to alter structural and physicochemical properties of pea proteins as well nature of protein aggregation. Heating accompanied with 100 s-1 shearing mostly resulted in insoluble covalent aggregates while shearing at 1500 s-1 mainly contributed to formation of soluble hydrophobic aggregates.