S-Nitrosothiols: Electronic Structure and Substituent Effects

S-nitrosothiols (RSNOs) are biologically important molecules involved in the storage and transport of nitric oxide (NO) and account for much of its signaling activity in living organisms. RSNOs have significant impact on NO signaling through, S-nitrosation, a major post-translational modification of proteins. These unstable thiol derivatives readily undergo homolytic dissociation of the S–N bond to release NO. RSNOs have potential therapeutic applications as NO donors, although the development of novel RSNOs has been slow due to the complex electronic structure of the –SNO group. A specific focus on the impact of the –R group on RSNO properties via substituent effect study, should serve as a reliable means for systematic development of new RSNOs. In this work, electronic structure calculations have been used to investigate substituent effects in RSNOs. A library of substituents was developed for substitution in several RSNO models, with emphasis on aromatic RSNOs (ArSNOs). Para-substituted PhSNOs showed a significant substituent effect despite the lack of conjugation between the –SNO group and substituent due to the non-planar nature of the –SNO group with the aromatic ring. A thorough computational study of PhSNO as the parent ArSNO revealed the primary mode of substituent effect, a novel cascading double conjugation. This conjugation motif involves the long-range delocalization of electron density from the oxygen lone pair to σSN* orbital and then to the phenyl ring π-system, effectively connecting the –SNO group and substituent positions of the aromatic ring. Detailed analysis of vinyl-substituted RSNO (VinSNO) was performed to further understand the fundamental interaction of a π-system with an adjacent –SNO group. The impact of the vinyl π-bond on the adjacent –SNO group of VinSNO again revealed cascading double conjugation as the dominant feature. In general, cascading double conjugation will effectively destabilize the S–N bond in ArSNOs, specifically those RSNOs with a π-system adjacent to the –SNO group. Computational study of PhSNO and VinSNO was also carried out using Lewis acids and external electric fields (EEFs) to explore their effect on the –SNO group as well as the cascading double conjugation. Application of both resulted in substantial modulation of the –SNO group properties. Furthermore, use of Lewis acids or EEF, in tandem with select substituents, is expected to improve the functionality of ArSNOs as NO donors and advance the development of novel RSNOs

Structure, Stability, and Substituent Effects in Aromatic \u3cem\u3eS\u3c/em\u3e-Nitrosothiols: The Crucial Effect of a Cascading Negative Hyperconjugation/Conjugation Interaction

Aromatic S-nitrosothiols (RSNOs) are of significant interest as potential donors of nitric oxide and related biologically active molecules. Here, we address a number of poorly understood properties of these species via a detailed density functional theory and the natural bond orbital (NBO) investigation of the parent PhSNO molecule. We find that the characteristic perpendicular orientation of the −SNO group relative to the phenyl ring is determined by a combination of the steric factors and the donor–acceptor interactions including, in particular, a cascading orbital interaction involving electron delocalization from the oxygen lone pair to the σ-antibonding S–N orbital and then to the π*-aromatic orbitals, an unusual negative hyperconjugation/conjugation long-range delocalization pattern. These interactions, which are also responsible for the relative weakness of the S–N bond in PhSNO and the modulation of −SNO group properties in substituted aromatic RSNOs, can be interpreted as a resonance stabilization of the ionic resonance component RS–/NO+ of the RSNO electronic structure by the aromatic ring, similar to the resonance stabilization of PhS– anion. These insights into the chemistry and structure–property relationships in aromatic RSNOs can provide an important theoretical foundation for rational design of new RSNOs for biomedical applications

Generation of Molecular Complexity from Cyclooctatetraene: Preparation of Aminobicyclo[5.1.0]octitols

A series of eight stereoisomeric N-(tetrahydroxy bicyclo-[5.1.0]oct-2S*-yl)phthalimides were prepared in one to four steps from N-(bicyclo[5.1.0]octa-3,5-dien-2-yl)phthalimide (±)-7, which is readily available from cyclooctatetraene (62 % yield). The structural assignments of the stereoisomers were established by 1H NMR spectral data as well as X-ray crystal structures for certain members. The outcomes of several epoxydiol hydrolyses, particularly ring contraction and enlargement, are of note. The isomeric phthalimides as well as the free amines did not exhibit β-glucosidase inhibitory activity at a concentration of less than 100 μM

Mirc11 Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells

Natural killer (NK) cells generate proinflammatory cytokines that are required to contain infections and tumor growth. However, the posttranscriptional mechanisms that regulate NK cell functions are not fully understood. Here, we define the role of the microRNA cluster known as Mirc11 (which includes miRNA-23a, miRNA-24a, and miRNA-27a) in NK cell–mediated proinflammatory responses. Absence of Mirc11 did not alter the development or the antitumor cytotoxicity of NK cells. However, loss of Mirc11 reduced generation of proinflammatory factors in vitro and interferon-γ–dependent clearance of Listeria monocytogenes or B16F10 melanoma in vivo by NK cells. These functional changes resulted from Mirc11 silencing ubiquitin modifiers A20, Cbl-b, and Itch, allowing TRAF6-dependent activation of NF-κB and AP-1. Lack of Mirc11 caused increased translation of A20, Cbl-b, and Itch proteins, resulting in deubiquitylation of scaffolding K63 and addition of degradative K48 moieties on TRAF6. Collectively, our results describe a function of Mirc11 that regulates generation of proinflammatory cytokines from effector lymphocytes

Structure, Stability, and Substituent Effects in Aromatic <i>S</i>‑Nitrosothiols: The Crucial Effect of a Cascading Negative Hyperconjugation/Conjugation Interaction

Aromatic <i>S</i>-nitrosothiols (RSNOs) are of significant interest as potential donors of nitric oxide and related biologically active molecules. Here, we address a number of poorly understood properties of these species via a detailed density functional theory and the natural bond orbital (NBO) investigation of the parent PhSNO molecule. We find that the characteristic perpendicular orientation of the −SNO group relative to the phenyl ring is determined by a combination of the steric factors and the donor–acceptor interactions including, in particular, a cascading orbital interaction involving electron delocalization from the oxygen lone pair to the σ-antibonding S–N orbital and then to the π*-aromatic orbitals, an unusual negative hyperconjugation/conjugation long-range delocalization pattern. These interactions, which are also responsible for the relative weakness of the S–N bond in PhSNO and the modulation of −SNO group properties in substituted aromatic RSNOs, can be interpreted as a resonance stabilization of the ionic resonance component RS^–/NO⁺ of the RSNO electronic structure by the aromatic ring, similar to the resonance stabilization of PhS^– anion. These insights into the chemistry and structure–property relationships in aromatic RSNOs can provide an important theoretical foundation for rational design of new RSNOs for biomedical applications