Direct and Catalytic C-Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside.

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.

Towards Volatile Organoselenium Compounds with Cost-Effective Synthesis.

The current portfolio of organoselenium compounds applicable as volatile precursors for atomic layer deposition can be denoted as very limited. Hence, we report herein facile and cost-effective preparation of two bis(trialkylstannyl)selenides as well as one selenole and three bis(trialkylsilyl)selenides. Their syntheses have been optimized to: (i) use readily available and inexpensive starting materials, (ii) involve operationally simple methodology (heating in a pressure vessel), (iii) use a minimum amount of additives and catalysts, and (iv) either exclude additional purification or involve only simple distillation. The chemical structure of prepared Se derivatives was confirmed by multinuclear NMR and GC/MS. Their fundamental thermal properties were investigated by differential scanning calorimetry (DSC) and TGA methods that revealed thermal stability within the range of 160-300 °C.

An efficient synthesis tetrazole and oxadiazole analogues of novel 2'-deoxy-C-nucleosides and their antitumor activity.

Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or ß-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First,  the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery.

Stereoselective total synthesis of Patulolide C.

Stereoselective total synthesis of Patulolide C has been accomplished from easily available and inexpensive (S)-chiral epoxide. The key steps involved in the concise synthesis of Patulolide C utilizes ring opening of chiral epoxide, cleavage of 1,2-diol, deprotection of benzyl ether of hydroxyl acid and Yamaguchi macrolactonisation dilution conditions as key steps. The advantage of this method include inexpensive starting material, mild reaction conditions and high purity of products.

Gram-Scale Preparation of C-Terminal-Modified Enkephalin Analogues by Typical Liquid-Phase Peptide Synthesis.

This article describes the gram-scale liquid-phase peptide synthesis of C-terminal-modified enkephalin analogues that possess high analgesic efficacy in animals, high potency for mu and delta opioid receptors, and high metabolic stability and potential blood-brain barrier permeability. Despite the long cycle time and tedious purification steps, liquid-phase synthesis is still a preferred method for large-scale peptide synthesis due to its cost effectiveness (i.e., amount of amino acids and reagents required), easy detection, and isolation of impurities compared with solid-phase synthesis. A robust liquid-phase synthesis protocol is described, involving BOP-assisted coupling and Boc deprotection, which has been well established in the laboratory and is a useful synthetic protocol for cost-effective production of peptide drugs. © 2019 by John Wiley & Sons, Inc.

An Efficient and Scalable Synthesis of Quinolone 006.

Quinolone 006 is under development as an anti-methicillin-resistant Staphylococcus aureus quinolone antibiotic. A linear synthetic route was utilized to prepare the compound on a multi-kilogram scale with an overall yield of 71%. The process was optimized by controlling the temperature and the vacuum pressure. Examples of parameters examined in an effort to control the polymorphism of the 006 active pharmaceutical ingredient are described.

Systematic evaluation of 2'-Fluoro modified chimeric antisense oligonucleotide-mediated exon skipping in vitro.

Antisense oligonucleotide (AO)-mediated splice modulation has been established as a therapeutic approach for tackling genetic diseases. Recently, Exondys51, a drug that aims to correct splicing defects in the dystrophin gene was approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD). However, Exondys51 has relied on phosphorodiamidate morpholino oligomer (PMO) chemistry which poses challenges in the cost of production and compatibility with conventional oligonucleotide synthesis procedures. One approach to overcome this problem is to construct the AO with alternative nucleic acid chemistries using solid-phase oligonucleotide synthesis via standard phosphoramidite chemistry. 2'-Fluoro (2'-F) is a potent RNA analogue that possesses high RNA binding affinity and resistance to nuclease degradation with good safety profile, and an approved drug Macugen containing 2'-F-modified pyrimidines was approved for the treatment of age-related macular degeneration (AMD). In the present study, we investigated the scope of 2'-F nucleotides to construct mixmer and gapmer exon skipping AOs with either 2'-O-methyl (2'-OMe) or locked nucleic acid (LNA) nucleotides on a phosphorothioate (PS) backbone, and evaluated their efficacy in inducing exon-skipping in mdx mouse myotubes in vitro. Our results showed that all AOs containing 2'-F nucleotides induced efficient exon-23 skipping, with LNA/2'-F chimeras achieving better efficiency than the AOs without LNA modification. In addition, LNA/2'-F chimeric AOs demonstrated higher exonuclease stability and lower cytotoxicity than the 2'-OMe/2'-F chimeras. Overall, our findings certainly expand the scope of constructing 2'-F modified AOs in splice modulation by incorporating 2'-OMe and LNA modifications.

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation.

Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure-activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans, and several Candida sp., and also significant antibacterial activities. With fluorescence-based whole cell assays, the aryl amphiphilic kanamycins were observed to permeabilize fungal surface membranes at faster rates than bacterial surface membranes. Also, the antifungal action of the amphiphilic kanamycins was observed to occur in a biphasic mode with an initial fast phase correlated with rapid membrane permeabilization at subminimal inhibitory concentrations and a slower phase membrane permeabilization that elevates the reactive oxygen species production leading to cell death. Inactive hydrophobic amphiphilic kanamycins displayed no membrane permeabilization. The results offer cost-effective methods for producing amphiphilic kanamycins and reveal insights into how nonfungal specific amphiphilic kanamycins can be employed for fungal specific diagnostic and therapeutic applications.

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server.

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.

Rapid and low-cost multiplex synthesis of chemokine analogs.

Peptides represent a promising source of new medicines, but improved technologies are needed to facilitate discovery and optimization campaigns. In particular, longer peptides with multiple disulfide bridges are challenging to produce, and producing large numbers of structurally related variants is dissuasively costly and time-consuming. The principal cost and time drivers are the multiple column chromatography purification steps that are used during the multistep chemical synthesis procedure, which involves both ligation and oxidative refolding steps. In this study, we developed a method for multiplex parallel synthesis of complex peptide analogs in which the structurally variant region of the molecule is produced as a small peptide on a 384-well synthesizer with subsequent ligation to the longer, structurally invariant region and oxidative refolding carried out in-well without any column purification steps. To test the method, we used a panel of 96 analogs of the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 (69 residues, two disulfide bridges), which had been synthesized using standard approaches and characterized pharmacologically in an earlier study. Although, as expected, the multiplex method generated chemokine analogs of lower purity than those produced in the original study, it was nonetheless possible to closely match the pharmacological attributes (anti-HIV potency, capacity to elicit G protein signaling, and capacity to elicit intracellular receptor sequestration) of each chemokine analog to reference data from the earlier study. This rapid, low-cost approach has the potential to support discovery and optimization campaigns based on analogs of other chemokines as well as those of other complex peptide and small protein targets of a similar size.

Integrating thin film microfluidics in developing a concise synthesis of DGJNAc: A potent inhibitor of α-N-acetylgalctosaminidases.

A simple synthesis, which utilizes a thin film microfluidic reactor for a problematic step, of a potent inhibitor of α-N-acetylhexosaminidases, DGJNAc, has been developed.

Facile and cost-effective synthesis of glycogen-based conductive hydrogels with extremely flexible, excellent self-healing and tunable mechanical properties.

In materials science and engineering, the designing of hydrogels with excellent self-healing and tunable mechanical properties is an inviting issue. In this study, we introduce the sacrificial bonds interactions in a hybrid hydrogel of natural and synthetic polymers, to give a hydrogel with autonomous self-healing ability and tunable mechanical properties. Glycogen, a natural polymer tends to strengthen the hydrogel while PVA, a synthetic polymer plays a critical role in the flexibility and stretchability of the hydrogel. Hydrogels were designed by the sacrificial non-covalent interactions with physical cross-linking of the polymer chains to the trivalent metal ions. Functional groups of the polymers interact with sacrificial hydrogen bonds with and with the metal ions, they interact through sacrificial coordination interactions with different strength, results tunable sacrificial bonds. Weaker sacrificial bonds rupture prior to the strong sacrificial bonds upon external loading, which dissipate the energy and endow the hydrogel with adjustable mechanical and self-healing properties. The tunable mechanical properties and excellent self-healing efficiency enlarge the application areas of the developed hydrogel in various fields.

Cost-effective synthesis of three-dimensional nitrogen-doped nanostructured carbons with hierarchical architectures from the biomass of sea-tangle for the amperometric determination of ascorbic acid.

In this work, the three-dimensional nitrogen-doped nanostructured carbons with hierarchical architectures (3D-NNCsHAs) with high density of defective sites, high surface area and pluralities of pore size distributions was prepared through the pyrolysis of sea-tangle (Laminaria japonica), an inexpensive, eco-friendly and abundant precursor. Benefitting from their structural uniqueness, a selective and sensitive ascorbic acid (AA) sensor based on 3D-NNCsHAs was developed. Compared to the glassy carbon electrode (GCE) and the carbon nanotubes modified GCE (CNTs/GCE), the 3D-NNCsHAs modified GCE (3D-NNCsHAs/GCE) presents higher performance towards the electrocatalysis and detection of AA, such as lower detection limit (1 µM), wider linear range (10-4410 µM) and lower electrooxidation peak potential (-0.02 V vs. Ag/AgCl). In addition, 3D-NNCsHAs/GCE also exhibits high anti-interference and anti-fouling abilities for AA detection. Particularly, the fabricated 3D-NNCsHAs/GCE is able to determine AA in real samples and the results acquired are satisfactory. Therefore, the 3D-NNCsHAs can be considered as a kind of novel electrode nanomaterial for the fabrication of selective and sensitive AA sensor for the extensive practical applications ranging from food analysis, to pharmaceutical industry and clinical test.

Rigid Peptide Macrocycles from On-Resin Glaser Stapling.

Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between ß-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 α-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.

Global medicinal chemistry and GPCR conference: interview with Stevan Djuric.

Stevan Djuric speaks to Benjamin Walden, Commissioning Editor. Stevan Djuric is head of the global Medicinal Chemistry Leadership Team at AbbVie and is also Vice President of the Discovery Chemistry and Technology organization within their Discovery organization and chemistry outsourcing activities. He spoke at the Global-Medicinal-Chemistry and GPCR summit on the imperative to develop chemistry related technology that can reduce cycle time, cost of goods and improve probability of success. To this end, he discussed his efforts in the chemistry technology area with a focus on integrated synthesis-purification bioassay, and flow photochemistry and high temperature chemistry platforms.

Iron-Catalyzed Cross-Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability.

The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross-coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.

Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)-Limaspermidine and (+)-Kopsihainanine†A.

Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet-Spengler and Bischler-Napieralski cyclization/reduction cascades furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A.

Thiocarbonyl Ylide Chemistry Enables a Concise Synthesis of (±)-Hippolachnin A.

Hippolachnin A (1) is an antifungal polyketide that bristles with ethyl groups mounted onto a caged heterotricyclic core. It has shown potent activity against Cryptococcus neoformans, a yeast that can affect immunocompromised patients as an opportunistic pathogen. Herein we describe a concise, diversifiable, and scalable synthesis of (±)-hippolachnin A (1). It features a powerful photochemical opening step, a diastereoselective addition of an ethyl cuprate and an unusual strategy to install two additional ethyl groups that makes use of a thiocarbonyl ylide generated in situ.

Easy and rapid preparation of benzoylhydrazides and their diazene derivatives as inhibitors of 15-lipoxygenase.

Two series of diaza derivatives were prepared by solvent-free condensation of benzoic acid and 4-substituted phenylhydrazines in order to obtain phenylhydrazides (HYD series) and, by oxidation of these compounds, the corresponding benzoyldiazenes (DIA series). Both sets were evaluated as inhibitors of soybean 15-lipoxygenase activity and antioxidant capability in the FRAP and CUPRAC assays. The most potent inhibitors of both series exhibited IC50 values in the low micromolar range. Kinetic studies showed that at least the more active compounds were competitive inhibitors. Docking results indicated that the most potent inhibitor interacts strongly with Ile-839 and iron in the active site.

Short-step syntheses of naturally occurring polyoxygenated aromatics based on site-selective transformation.

Wogonin and astringin were synthesized from inexpensive chrysin and piceid in short steps. The key feature of these syntheses is site-selective transformation. The target molecules were obtained in 27 and 62% yields from the starting materials, respectively.