Chiral switches of chloroquine and hydroxychloroquine: potential drugs to treat COVID-19

Therapeutic options in response to the COVID-19 pandemic are urgently needed. A keyword in these worldwide effortsis ‘repurposing’ – the development of approved antiviral drugs as candidates for COVID-19. Chloroquine (CQ) and its hydroxyl analog hydroxychloroquine (HCQ) are showing preliminary inhibitory effects against COVID-19 and apparent efficacy in clinical studies. We propose a variant of the repurposing strategy: developing single enantiomers of these old racemic drugs. We call for urgently pursuing the chiral switches of HCQ and/or CQ for the treatment of COVID-19

Hydrophilic Interaction Chromatography (HILIC). Novel Sugar-based Silica Gels

We developed and applied a new sugar-based material in the stereoselective HILIC separation of very polar compounds, such as carbohydrates, amino acids and flavonoids, with particular attention to the occurrence of chromatographic peak shape deformation due to interconversion of sugar anomers

Enantioseparation by ultra-high-performance liquid chromatography

The extraordinary advancement in developing highly efficient packing materials for liquid chromatog- raphy (LC) has only partly touched chiral separations due, in part, to practical problems in synthesis and functionalization of sub-2-μm particles with chiral selectors, and, in part, to the lack of clear under- standing of mass-transfer mechanisms in chiral chromatography. However, there is increasing demand for ultrafast chiral separations, mainly from fine chemical and pharmaceutical companies. This review revisits the most important achievements in enantioselective ultra-high-performance LC (eUHPLC) by focusing, in particular, on brush-type chiral stationary phases, as they are the most prom- ising materials for transition from traditional high-performance LC (HPLC) to ultra-high-speed and ultra- high-pressure regimes. We also attempt to predict possible future trends and solutions that will contribute to making eUHPLC a routine technique in analytical laboratories

Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids

Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, (S)-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes

Resorc[4]arenes as Preorganized Synthons for Surface Recognition and Host-Guest Chemistry

This chapter is aimed at providing an overview of the up-to-now published literature on resorc[4]arene macrocycles exploited as artificial receptors for surface recognition and host-guest chemistry. A concise illustration of the main synthetic strategies developed to afford the resorc[4]arene scaffold is followed by a report on the principles of the investigation of recognition phenomena by nuclear magnetic resonance (NMR), in particular the study of protein-small molecule interactions. Emphasis will be placed on the literature taken largely from our own works on the inhibition of chymotrypsin by suitable N-linked peptidoresorc[4]arenes. Then, the attention was moved towards host-guest studies relying on the entrapment of nitrosonium (NO+) cation inside the cavities of ad hoc functionalized resorc[4]arenes, which yielded both complexes and covalent products. Finally, some recent intriguing resorc[4]arene architectures built up by olefin metathesis reaction occurring between side chains ending with vinylidene groups are presented

Enantioseparation by ultra-high-performance liquid chromatography

The extraordinary advancement in developing highly efficient packing materials for liquid chromatog- raphy (LC) has only partly touched chiral separations due, in part, to practical problems in synthesis and functionalization of sub-2-μm particles with chiral selectors, and, in part, to the lack of clear under- standing of mass-transfer mechanisms in chiral chromatography. However, there is increasing demand for ultrafast chiral separations, mainly from fine chemical and pharmaceutical companies. This review revisits the most important achievements in enantioselective ultra-high-performance LC (eUHPLC) by focusing, in particular, on brush-type chiral stationary phases, as they are the most prom- ising materials for transition from traditional high-performance LC (HPLC) to ultra-high-speed and ultra- high-pressure regimes. We also attempt to predict possible future trends and solutions that will contribute to making eUHPLC a routine technique in analytical laboratories

Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids

Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, (S)-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes

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 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

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