Atropisomers of Arylmaleimides: Stereodynamics and Absolute Configuration

4-Aryl-3-bromo-<i>N</i>-benzylmaleimides and 3,4-biaryl-<i>N</i>-benzylmaleimides have been synthesized by a modified Suzuki cross-coupling reaction from 3,4-dibromo-<i>N</i>-benzylmaleimide. The conformational studies by dynamic NMR and DFT calculations showed that the interconversion barrier between the two available skewed conformations is under steric control. When the aryl group was a 2-methylnaphthyl, thermally stable atropisomers were isolated by enantioselective HPLC and their absolute configurations were assigned by TD-DFT simulations of the ECD spectra

Organocatalytic Atroposelective Formal Diels–Alder Desymmetrization of <i>N</i>‑Arylmaleimides

The atroposelective desymmetrization of <i>N</i>-arylmaleimides was realized by means of a primary amine catalyzed Diels–Alder reaction of enones. The chiral axis as new element of chirality is generated under the remote control of the catalyst that selectively drives the formal Diels–Alder reaction through an exclusive stereochemical outcome

Remote Control of Axial Chirality: Aminocatalytic Desymmetrization of <i>N</i>‑Arylmaleimides via Vinylogous Michael Addition

Remote control of the axial chirality of <i>N</i>-(2-<i>t</i>-butylphenyl)­succinimides was realized via the vinylogous Michael addition of 3-substituted cyclohexenones to <i>N</i>-(2-<i>t</i>-butylphenyl)­maleimides. 9-Amino­(9-deoxy)<i>epi</i>-quinine promoted the enantioselective desymmetrization, leading to atropisomeric succinimides with two adjacent stereocenters

A New Method to Investigate the Intrusion of Water into Porous Hydrophobic Structures under Dynamic Conditions

The intrusion of water into the pores of hydrophobic materials is investigated by means of a dynamic flow system. The porous hydrophobic material is packed into a stainless steel chromatographic column, and water is flushed through by means of a high-pressure pump. Back-pressure control is provided by flow restrictors after the column. The applied pressure forces the water to penetrate the pores of the hydrophobic material. The water volume contained in the column, as a function of the applied pressure, reflects the degree of wetting of the solid by water. This volume is determined by measuring, through a mass spectrometer, the retention time of deuterium oxide injected in the column. The method is applied with alkyl-modified (<i>n</i>-octyl and <i>n</i>-octadecyl) and perfluorinated (alkyl and phenyl) silica surfaces. The information gathered by this study may contribute to explain the retention behavior of reversed-phase chromatographic columns when used under highly aqueous mobile-phase conditions

ABCB1 Structural Models, Molecular Docking, and Synthesis of New Oxadiazolothiazin-3-one Inhibitors

Docking methods are powerful tools for in silico screening and drug lead generation and optimization. Here, we describe the synthesis of new inhibitors of ABCB1 whose design was based on construction and preliminary confirmation of a model for this membrane transporter of the ATP-binding cassette family. We chose the strategy to build our three-dimensional model of the ABCB1 transporter by homology. Atomic coordinates were then assayed for their reliability using the measured activity of some oxadiazolothiazin-3-one compounds. Once established their performance by docking analysis, we synthesized new compounds whose forecasted activity was tested by MTT and cytofluorimetric assays. Our docking model of MDR1, MONBD1, seems to reliably satisfy our need to design and forecast, on the basis of their LTCC blockers ability, the inhibitory activity of new molecules on the ABCB1 transporter

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

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