The
modulation of phagocyte responses is essential for successful
performance of biomaterials in order to prevent negative outcomes
associated with inflammation. Herein, we developed electrospun poly(ε-caprolactone)
(PCL) scaffolds doped with the novel potent c-Jun N-terminal kinase
(JNK) inhibitors 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and 11H-indeno[1,2-b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime(IQ-1E) as a promising approach for modulating phagocyte activation. Optimized
electrospinning parameters allowed us to produce microfiber composite
materials with suitable mechanical properties. We found that embedded
compounds were bound to the polymer matrix via hydrophobic interactions
and released in two steps, with release mostly controlled by Fickian
diffusion. The fabricated scaffolds doped with active compounds IQ-1 and IQ-1E effectively inhibited phagocyte
inflammatory responses. For example, they suppressed human neutrophil
activation by the biomaterials, as indicated by decreased neutrophil
reactive oxygen species (ROS) production and Ca2+ mobilization.
In addition, they inhibited lipopolysaccharide (LPS)-induced NF-κB/AP-1
reporter activity in THP-1Blue cells and interleukin (IL)-6 production
in MonoMac-6 cells without affecting cell viability. These effects
were attributed to the released compounds rather than cell–surface
interactions. Therefore, our study demonstrates that doping tissue
engineering scaffolds with novel JNK inhibitors represents a powerful
tool for preventing adverse immune responses to biomaterials as well
as serves as a platform for drug delivery.
Direct amination is an extremely valuable reaction, allowing for the one-step preparation of aromatic amines. However, its mechanism was poorly studied. Here, for the first time, using quantum chemical calculations, we have shown that direct amination of arenes by hydrazoic acid follows the classical S E Ar mechanism with aminodiazonium cation H 2 N 3 + as electrophile. The peculiarity of H 2 N 3 + electronic structure has been described using our novel method for tracing the molecular orbitals. The located stationary points and transition states allowed us to define direct amination as S E Ar reaction, which rate is determined by early transition state between πand σcomplexes. Considering the calculated reaction constant 1 and an early transition state, we placed direct amination of arenes by HN 3 somewhere in-between nitration and halogenations. Our results explain the accumulated experimental data and open a prospect for the development of the new aminating agents working in milder conditions.[a] K.
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