Developments in the chemistry and biology of 1,2,3-triazolyl-C-nucleosides.

In the last 50 years, nucleoside analogs have been introduced to drug therapy as antivirals for different types of cancer due to their interference in cellular proliferation. Among the first line of nucleoside treatment drugs, ribavirin (RBV) is a synthetic N-nucleoside with a 1,2,4-triazole moiety that acts as a broad-spectrum antiviral. It is on the World Health Organization (WHO) list of essential medicines. However, this important drug therapy causes several side effects due to its nonspecific mechanism of action. There is thus a need for a continuous study of its scaffold. A particular approach consists of connecting  d-ribose to the nitrogen-containing base with a C-C bond. It provides more stability against enzymatic action and a better pharmacologic profile. The coronavirus disease (COVID) pandemic has increased the need for more solutions for the treatment of viral infections. Among these solutions, remdesivir, the first C-nucleoside, has been approved by the Food and Drug Administration (FDA) for clinical use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It drew attention to the study of the C-nucleoside scaffold. Different C-nucleoside patterns have been synthesized over the years. They show many important activities against viruses and cancer cell lines. 1,2,3-Triazolyl-C-nucleoside derivatives are a prolific and efficient subclass of RBV analogs close to the already-known RBV with a C-C bond modification. These compounds are often prepared by alkynylation of the  d-ribose ring followed by azide-alkyne cycloaddition. They are reported to be active against the Crimean-Congo hemorrhagic fever virus and several tumoral cell lines, showing promising biological potential. In this review, we explore such approaches to 1,2,3-triazolyl-C-nucleosides and their evolution over the years.

Studies on the synthesis of 1'-CN-triazolyl-C-ribosides.

The search for broad-spectrum antiviral compounds is a continuous mandatory effort. The recent approval of the first C-nucleoside carrying a nitrile as a substituent at the C1' position of the ribose ring has raised interest in this underexplored substitution pattern. We have previously reported the development of different 1,2,3-triazolyl-C-ribonucleosides with anticancer and antiviral activities. Herein we report our results on the incorporation of a C1'-CN group in 1,2,3-triazolyl-C-ribonucleosides.

Anti-HCV and Zika activities of ribavirin C-nucleosides analogues.

Ribavirin is an unnatural nucleoside exhibiting broad spectrum of antiviral and antitumor activities, still very widely studied particularly in a repositioning approach. C-triazolyl nucleoside analogues of ribavirin have been synthesized, as well as prodrugs and glycosylated or peptide conjugates to allow a better activity by vectorization into the liver or by facilitating uptake into the cells. The antiviral properties of all synthesized compounds have been evaluated in vitro against two important human viral pathogens belonging to the Flaviviridae family: hepatitis C virus (HCV) and Zika virus (ZIKV). There are no therapeutic options for Zika virus, whereas those available for HCV can be still improved. Our results indicated that compound 2 carrying an N-hydroxy carboxamide function exhibits the most inhibitory activities against both viruses. This compound moderately inhibited the propagation of HCV with an IC50 value of 49.1 µM and Zika virus with an IC50 of 33.2 µM comparable to ribavirin in the Vero cell line. The results suggest that compound 2 and its new derivatives may be candidates for further development of new anti-HCV and anti-ZIKV antiviral drugs.

Synthesis, antiviral and antitumor activities investigations of a series of Ribavirin C-nucleoside analogue prodrugs.

Phosphoramidates obtained according to the ProTide strategy are known for their ability to increase the biological activity of various nucleosides. A series of such prodrugs of SRO-91, a non-natural ribofuranosyl-1,2,3-triazole C-nucleoside obtained by a synthetic sequence involving an indium mediated alkynylation and a Huisgen cycloaddition, was prepared and the antitumor activity on 3 strains of tumor cells was investigated. Two compounds 9a and 9c exhibited interesting cell proliferative inhibitions (IC50 = 2.5-12.1 µM) on two cell lines (pancreas and lung). Moreover, concerning the antiviral activity, another phosphoramidate 14 bearing a different aryl masking group exhibited an IC50 of 5 µM on Crimean-Congo Hemorrhagic Fever orthonairovirus. In both cases, free SRO-91 presented no activity on these cell lines.

Organocatalysis applied to carbohydrates: from roots to current developments.

Organocatalysis emerged in the last decade as a powerful tool for the synthesis of complex molecules. In the field of carbohydrates, it found widespread use in the synthesis of rare and non-natural carbohydrate derivatives. Additionally, it has also found important application in the stereoselective functionalization of the anomeric carbon in glycosylation reactions. These efforts culminated in the development of different types of catalysts operating through distinct activation modes that allow the selective synthesis of α- or ß-glycosides even on daunting substrates. All these advances starting from its first examples in carbohydrate synthesis to the current developments in glycosylation reactions are reviewed.

Direct Synthesis of Mesoporous Organosilica and Proof-of-Concept Applications in Lysozyme Adsorption and Supported Catalysis.

Mesoporous materials represent a useful alternative for exploiting the effects of confinement on molecular trapping and catalysis. Their efficiency often depends on the interactions between the surface and the targeted molecules. One way to enhance these interactions is to adjust the hydrophobic/hydrophilic balance of the surface. In the case of mesoporous silica, the incorporation of organic groups is an efficient solution to adapt the material for specific applications. In this work, we have used the co-condensation method to control the hydrophobicity of mesoporous organosilica. The obtained materials are methyl- or phenyl-containing silica with a pore size between 3 and 5 nm. The surface chemistry control has shown the enhanced performance of the materials in two proof-of-concept (PoC) applications: lysozyme adsorption and supported catalysis. The lysozyme adsorption is observed to be over 3 times more efficient with the phenyl-functionalized material than MCM-41, due to π-π interactions. For the catalysis, copper(II) was immobilized on the organosilica surface. In this case, the presence of methyl groups significantly enhanced the product yield for the catalyzed synthesis of a triazole derivative; this was attributed to the enhanced hydrophobic surface-reactant interactions. It was also found that the materials have a higher water adsorption capacity and an improved resistance to hydrolysis. The modulation of water properties in confinement with hydrophobic surfaces, consistently with the water as tuneable solvent (WaTuSo) concept, is a crucial aspect in the efficiency of mesoporous materials for dedicated applications.

Synthesis and antitumor activities investigation of a C-nucleoside analogue of ribavirin.

SRO-91 is a non-natural ribofuranosyl-1,2,3-triazole C-nucleoside obtained by a synthetic sequence involving a C-alkynyl glycosylation mediated by metallic indium and a Huisgen cycloaddition for the construction of the triazole. Its structure is close to the one of ribavirin, a drug presenting a broad-spectrum against viral infections. SRO-91 antitumor activities were investigated on 9 strains of tumor cells and IC50 of the order of 1 µM were obtained on A431 epidermoid carcinoma cells and B16F10 skin melanoma cells. In addition, studies of ovarian tumor cell inhibitions show an interesting activity in regard to the need for new drugs for this pathology. Finally, cytotoxicity and mouse toxicity studies reveal a favorable therapeutic index for SRO-91.

Studies of membranotropic and fusogenic activity of two putative HCV fusion peptides.

Over the past decades, membranotropic peptides such as positively charged cell-penetrating peptides (CPPs) or amphipathic antimicrobial peptides (AMPs) have received increasing interest in order to improve therapeutic agent cellular uptake. As far as we are concerned, we were interested in studying HCV fusion peptides as putative anchors. Two peptides, HCV6 and HCV7, were identified and conjugated to a fluorescent tag NBD and tested for their interaction with liposomes as model membranes. DSC and spectrofluorescence analyses demonstrate HCV7 propensity to insert or internalize in vesicles containing anionic lipids DMPG whereas no activity was observed with zwitterionic DMPC. This behavior could be explained by the peptide sequence containing a cationic arginine residue. On the contrary, HCV6 did not exhibit any membranotropic activity but was the only sequence able to induce liposomes' fusion or aggregation monitored by spectrofluorescence and DLS. This two peptides mild activity was related to their inefficient structuration in contact with membrane mimetics, which was demonstrated by CD and NMR experiments. Altogether, our data allowed us to identify two promising membrane-active peptides from E1 and E2 HCV viral proteins, one fusogenic (HCV6) and the other membranotropic (HCV7). The latter was also confirmed by fluorescence microscopy with CHO cells, indicating that HCV7 could cross the plasma membrane via an endocytosis process. Therefore, this study provides new evidences supporting the identification of HCV6 as the HCV fusion peptide as well as insights on a novel membranotropic peptide from the HCV-E2 viral protein.

Enantioselective Access to Robinson Annulation Products and Michael Adducts as Precursors.

The Robinson annulation is a reaction that has been useful for numerous syntheses since its discovery in 1935, especially in the field of steroid synthesis. The products are usually obtained after three consecutive steps: the formation of an enolate (or derivative), a conjugate addition, and an aldol reaction. Over the years, several methodological improvements have been made for each individual step or alternative routes have been devised to access the Robinson annulation products. The first part of this Review outlines the most relevant developments towards the formation of monocarbonyl-derived Robinson annulation products (MRA products, MRAPs) and activated monocarbonyl-derived Robinson annulation products (AMRA products, AMRAPs). The following sections are then devoted to the diastereoselective and enantioselective synthesis of these products, while the last section describes the enantiomeric resolution of racemic mixtures.

Hetero-Diels-Alder reactions of cyclic ketone derived enamide. A new and efficient concept for the asymmetric Robinson annulation.

Chiral enamides, easily prepared in one step from a cyclic ketone and an oxazolidinone, are successfully employed in high-yielding, endo, and facially selective Hetero-Diels-Alder reactions involving activated oxadienes and Siever's reagent as catalyst. From the resulting bicyclic heteroadducts, a novel and efficient asymmetric modification for the Robinson annulation of cyclic monoketones is described.

Glycosidations of 2-deoxy glycosyl dithiophosphates using a tagged iodine(III)-promoter for simple purification.

The preparation of the 4-i-butylsulfonate derivative of the Zefirov reagent (5) and its use in a novel purification strategy for iodine(III)-promoted glycosidations of 2-deoxy diethyldithiophosphate glycosides is described.

Tagged hypervalent iodine reagents: a new purification concept based on ion exchange through SN2 substitution.

The preparation of phenylsulfonate-tagged iodine(III) reagents as well as their use in a novel purification strategy for iodine(III)-promoted reactions is described. The concept is based on ion exchange and is initiated by an azide-promoted SN2-reaction at the alkyl sulfonate followed by trapping of the resulting aryl sulfonate anion with an ion-exchange resin. The concept is successfully proven for Ru-catalyzed oxidations of alcohols, the activation and glycosidation of thioglycosides, and the SuArez reaction of pyranoses.