Synthesis of a Double-Spanned Resorc[4]arene via Ring-Closing Metathesis and Calculation of Aggregation Propensity

Ring-closing metathesis (RCM) catalyzed by a second-generation Grubbs catalyst has been used to synthesize resorc[4]­arenes <b>2b</b>–<b>5b</b> starting from undecenyl resorc[4]­arene <b>1b</b> fixed in the cone conformation. X-ray diffraction analysis of the major metathesis product, <b>3b</b> (50% yield), revealed a cavity-shaped architecture resembling a basket, endowed with a large intramolecular space (∼10 Å) and a strong propensity to self-assemble as a supramolecular trio of heterochiral dimers. This prompted us to investigate the aggregation propensity of basket <b>3b</b> in THF/water solution by UV–visible spectroscopy. The cavitation Gibbs free-energy change (ΔΔ<i>G</i>_cav = 4.78 kcal mol^–1) associated with the self-assembly of macrocycle <b>3b</b> was calculated as a measure of the solvophobic interactions involved in the process

DataSheet1_Inhibition of adenovirus transport from the endosome to the cell nucleus by rotenone.pdf

Regardless of the clinical impact of human adenovirus (HAdV) infections in the healthy population and its high morbidity in immunosuppressed patients, a specific treatment is still not yet available. In this study, we screened the CM1407 COST Action’s chemical library, comprising 1,233 natural products to identify compounds that restrict HAdV infection. Among them, we identified rotenolone, a compound that significantly inhibited HAdV infection. Next, we selected four isoflavonoid-type compounds (e.g., rotenone, deguelin, millettone, and tephrosin), namely rotenoids, structurally related to rotenolone in order to evaluate and characterized in vitro their antiviral activities against HAdV and human cytomegalovirus (HCMV). Their IC50 values for HAdV ranged from 0.0039 µM for rotenone to 0.07 µM for tephrosin, with selective indices ranging from 164.1 for rotenone to 2,429.3 for deguelin. In addition, the inhibition of HCMV replication ranged from 50% to 92.1% at twice the IC50 concentrations obtained in the plaque assay for each compound against HAdV. Our results indicated that the mechanisms of action of rotenolone, deguelin, and tephrosin involve the late stages of the HAdV replication cycle. However, the antiviral mechanism of action of rotenone appears to involve the alteration of the microtubular polymerization, which prevents HAdV particles from reaching the nuclear membrane of the cell. These isoflavonoid-type compounds exert high antiviral activity against HAdV at nanomolar concentrations, and can be considered strong hit candidates for the development of a new class of broad-spectrum antiviral drugs.</p

Synthesis of Bromoundecyl Resorc[4]arenes and Applications of the Cone Stereoisomer as Selector for Liquid Chromatography

As an extension of our studies on the multifaceted properties of C-alkylated resorc[4]­arenes, we planned to immobilize on a solid support resorc[4]­arenes with C₁₁-long side chains in the lower rim. To this purpose, we synthesized two conformationally diverse resorc[4]­arenes containing a bromoundecyl moiety in the four axial pendants. The cone stereoisomer <b>6a</b> (30% yield) was selected for the reaction with an aminopropylated silica gel (APSG) obtained from spherical Kromasil Si 100, 5 μm particles, to give the corresponding immobilized SP-C₁₁-resorc­[4]­arene system. The resulting polar-embedded stationary phase was fully characterized and investigated in the HPLC discrimination of the <i>E</i>/<i>Z</i> stereoisomers of naturally occurring and semisynthetic combretastatins, a family of (<i>Z</i>)-stilbene anticancer drugs. The chair stereoisomer <b>6b</b> (20% yield), when submitted to X-ray diffraction analysis, showed a noteworthy self-assembly in the crystal lattice, with intercalated hydrophobic and polar layers as a result of intermolecular Br···O halogen bond interactions, according to a unique stacking motif. The potential and versatility of the SP-C₁₁-resorc­[4]­arene stationary phase were shown as well in the separation of highly polar natural products (namely, flavonoids), under reversed-phase (RP) conditions, and of fullerenes C60 and C70, by using apolar solvents as mobile phases

Synthesis of Bromoundecyl Resorc[4]arenes and Applications of the Cone Stereoisomer as Selector for Liquid Chromatography

As an extension of our studies on the multifaceted properties of C-alkylated resorc[4]­arenes, we planned to immobilize on a solid support resorc[4]­arenes with C₁₁-long side chains in the lower rim. To this purpose, we synthesized two conformationally diverse resorc[4]­arenes containing a bromoundecyl moiety in the four axial pendants. The cone stereoisomer <b>6a</b> (30% yield) was selected for the reaction with an aminopropylated silica gel (APSG) obtained from spherical Kromasil Si 100, 5 μm particles, to give the corresponding immobilized SP-C₁₁-resorc­[4]­arene system. The resulting polar-embedded stationary phase was fully characterized and investigated in the HPLC discrimination of the <i>E</i>/<i>Z</i> stereoisomers of naturally occurring and semisynthetic combretastatins, a family of (<i>Z</i>)-stilbene anticancer drugs. The chair stereoisomer <b>6b</b> (20% yield), when submitted to X-ray diffraction analysis, showed a noteworthy self-assembly in the crystal lattice, with intercalated hydrophobic and polar layers as a result of intermolecular Br···O halogen bond interactions, according to a unique stacking motif. The potential and versatility of the SP-C₁₁-resorc­[4]­arene stationary phase were shown as well in the separation of highly polar natural products (namely, flavonoids), under reversed-phase (RP) conditions, and of fullerenes C60 and C70, by using apolar solvents as mobile phases

Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61

<p>This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu^−/− mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.</p