Stereoinvertive SN1 Through Neighboring Group Participation.

Neighboring group participation, the assistance of non-conjugated electrons to a reaction center, is a fundamental phenomenon in chemistry. In the framework of nucleophilic substitution reactions, neighboring group participation is known to cause rate acceleration, first order kinetics (SN1), and retention of configuration. The latter phenomenon is a result of double inversion: the first one when the neighboring group displaces the leaving group, and the second when a nucleophile substitutes the neighboring group. This powerful control of stereoretention has been widely used in organic synthesis for more than a century. However, neighboring group participation may also lead to inversion of configuration, a phenomenon which is often overlooked. Herein, we review this unique mode of stereoinversion, dividing the relevant reactions into three classes with the aim to introduce a fresh perspective on the different modes of stereoinversion via neighboring group participation as well as the factors that control this stereochemical outcome.

Synthesis of Stereodefined Polysubstituted Bicyclo[1.1.0]butanes.

We report a highly diastereoselective synthesis of polysubstituted bicyclobutanes possessing up to three stereodefined quaternary centers and five substituents. Our strategy involves a diastereoselective carbometalation of cyclopropenes followed by a cyclization to furnish the bicyclobutane ring system. This straightforward approach allows for the incorporation of a diverse range of substituents and functional groups, notably without the need for electron-withdrawing functionalities.

Dynamic Intramolecular Cap for Preserving Metallodrug Integrity─A Case of Catalytic Fluoroquinolones.

A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the cyclen moiety was designed and synthesized to investigate their potential for overcoming the general issue of "metallodrug vulnerability" under physiological conditions. The Cu(II) and Co(III) complexes of the new designer compounds were synthesized, and their potential to operate a dynamic, intramolecular cap with DNase activity was explored. The lead Co(III)-cyclen-ciprofloxacin conjugate showed excellent in vitro hydrolytic DNase activity, which was retained in the presence of strong endogenous chelators and exhibited enhanced antibacterial activity relative to the metal-free ligand (in the absence of any adjuvants), thereby demonstrating a "proof of concept" in vitro and ex vivo, respectively, for the dynamic cap hypothesis. The lead conjugate nicked supercoiled plasmid DNA within the fluoroquinolone-gyrase-DNA ternary complex and thereby disabled the function of gyrase, a new mode of action not previously reported for any fluoroquinolone.

Serum MMP-9: a novel biomarker for prediction of clinical relapse in patients with quiescent Crohn's disease, a post hoc analysis.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is a novel marker of intestinal inflammation. The aim of this study was to assess if serum MMP-9 levels predict clinical flare in patients with quiescent Crohn's disease (CD). METHODS: This study was a post hoc analysis of a prospective observational study in which quiescent CD patients were included and followed until clinical relapse or the end of a 2-year follow-up period. Serial C-reactive protein (CRP) and fecal calprotectin (FC) levels were measured, and the patients underwent repeated capsule endoscopies (CEs) every 6 months. Small bowel inflammation was quantified by Lewis score (LS) for CE. A baseline magnetic resonance enterography was also performed, and MaRIA score was calculated. Serum MMP-9 levels in baseline blood samples were quantified by ELISA. RESULTS: Out of 58 eligible enrolled patients, 16 had a flare. Higher levels of baseline MMP-9 were found in patients who developed subsequent symptomatic flare compared with patients who did not [median 661 ng/ml, 25-75 interquartile range (IQR; 478.2-1441.3) versus 525.5 ng/ ml (339-662.7), respectively, p = 0.01]. Patients with serum MMP-9 levels of 945 ng/ ml or higher were at increased risk for relapse within 24 months [area under the curve (AUC) of 0.72 [95% confidence interval (CI): 0.56-0.88]; hazard ratio 8.1 (95% CI 3.0-21.9, p < 0.001)]. Serum MMP-9 concentrations showed weak and moderate correlation to baseline LS and FC, respectively (r = 0.31, p = 0.02; r = 0.46, p < 0.001). No correlation was found between serum MMP-9 to CRP and MaRIA score. CONCLUSIONS: Serum MMP-9 may be a promising biomarker for prediction of clinical flare in CD patients with quiescent disease.