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

Introducing Enantioselective Ultrahigh-Pressure Liquid Chromatography (eUHPLC): Theoretical Inspections and Ultrafast Separations on a New Sub-2-μm Whelk-O1 Stationary Phase

A new chiral stationary phase for ultrahigh-pressure liquid chromatography (UHPLC) applications was prepared by covalent attachment of the Whelk-O1 selector to spherical, high-surface-area 1.7-μm porous silica particles. Columns of varying dimensions (lengths of 50, 75, 100, and 150 mm and internal diameters of 3.0 or 4.6 mm) were packed and characterized in terms of permeability, efficiency, retention, and enantioselectivity, using both organic and water-rich mobile phases. A conventional HPLC Whelk-O1 column based on 5.0-μm porous silica particles and packed in a 250 mm × 4.6 mm column was used as a reference. Van Deemter curves, generated with low-molecular-weight solutes on a 100 mm × 4.6 mm column packed with the 1.7-μm particles, showed <i>H</i>_min (μm) and μ_opt (mm/s) values of 4.10 and 5.22 under normal-phase and 3.74 and 4.34 under reversed-phase elution conditions. The flat C term of the van Deemter curves observed with the 1.7-μm particles allowed the use of higher-than-optimal flow rates without significant efficiency loss. Kinetic plots constructed from van Deemter data confirmed the ability of the column packed with the 1.7-μm particles to afford subminute separations with good efficiency and its superior performances in the high-speed regime, compared to the column packed with 5.0-μm particles. Resolutions in the time scale of seconds were obtained using a 50-mm-long column in the normal phase or polar organic mode. The intrinsic kinetic performances of 1.7-μm silica particles are retained in the Whelk-O1 chiral stationary phase, clearly demonstrating the potentials of enantioselective UHPLC in terms of high speed, throughput, and resolution

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

Reaction of Nitrosonium Cation with Resorc[4]arenes Activated by Supramolecular Control: Covalent Bond Formation

Resorc­[4]­arenes <b>1</b> and <b>2</b>, which previously proved to entrap NO⁺ cation within their cavities under conditions of host-to-guest excess, were treated with a 10-fold excess of NOBF₄ salt in chloroform. Kinetic and spectral UV–visible analyses revealed the formation of isomeric 1:2 complexes as a direct evolution of the previously observed event. Accordingly, three-body <b>1</b>–(NO⁺)₂ and <b>2</b>–(NO⁺)₂ adducts were built by MM and fully optimized by DFT calculations at the B3LYP/6-31G­(d) level of theory. Notably, covalent nitration products <b>4</b>,<b> 5</b> and <b>6</b>,<b> 7</b> were obtained by reaction of NOBF₄ salt with host <b>1</b> and <b>2</b>, respectively, involving macrocycle ring-opening and insertion of a nitro group in one of the four aromatic rings. In particular, compounds <b>4</b> and <b>6</b>, both containing a trans-double bond in the place of the methine bridge, were oxidized to aldehydes <b>5</b> and <b>7</b>, respectively, after addition of water to the reaction mixture. Calculation of the charge and frontier orbitals of the aromatic donor (HOMO) and the NO⁺ acceptor (LUMO) clearly suggests an ipso electrophilic attack by a first NO⁺ unit on the resorcinol ring, mediated by the second NO⁺ unit

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