A Comparative Review of Metal-Based Charge Carriers in Nonaqueous Flow Batteries.

Invited for this month's cover is the joint redox flow battery team from Sandia and Los Alamos National Laboratories. The cover image shows the stylized components of a redox flow battery (RFB) in the foreground, with renewable sources of energy generation in the background. The Review itself is available at 10.1002/cssc.202002354.

A Comparative Review of Metal-Based Charge Carriers in Nonaqueous Flow Batteries.

Energy storage is becoming the chief barrier to the utilization of more renewable energy sources on the grid. With independent service operators aiming to acquire gigawatts in the next 10-20 years, there is a large need to develop a suite of new storage technologies. Redox flow batteries (RFB) may be part of the solution if certain key barriers are overcome. This Review focuses on a particular kind of RFB based on nonaqueous media that promises to meet the challenge through higher voltages than the organic and aqueous variants. This class of RFB is divided into three groups: molecular, macromolecular, and redox-targeted systems. The growing field of theoretical modeling is also reviewed and discussed.

Synthesis of spiro-2,6-dioxopiperazine and spiro-2,6-dioxopyrazine scaffolds using amino acids in a three-component reaction to generate potential Sigma-1 (σ1) receptor selective ligands.

A library-friendly approach to generate new scaffolds is decisive for the development of molecular probes, drug like molecules and preclinical entities. Here, we present the design and synthesis of novel heterocycles with spiro-2,6-dioxopiperazine and spiro-2,6-pyrazine scaffolds through a three-component reaction using various amino acids, ketones, and isocyanides. Screening of select compounds over fifty CNS receptors including G-protein coupled receptors (GPCRs), ion channels, transporters, and enzymes through the NIMH psychoactive drug screening program indicated that a novel spiro-2,6-dioxopyrazine scaffold, UVM147, displays high binding affinity at sigma-1 (σ1) receptor in the nanomolar range. In addition, molecular docking of UVM147 at the human σ1 receptor have shown that it resides in the same binding site that was occupied by the ligand 4-IBP used to obtain a crystal structure of the human sigma-1 (σ1) receptor.

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit ß-Arrestin-2.

Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit ß-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.

Isocyanide-Based Multicomponent Reactions for the Synthesis of Heterocycles.

Multicomponent reactions (MCRs) are extremely popular owing to their facile execution, high atom-efficiency and the high diversity of products. MCRs can be used to access various heterocycles and highly functionalized scaffolds, and thus have been invaluable tools in total synthesis, drug discovery and bioconjugation. Traditional isocyanide-based MCRs utilize an external nucleophile attacking the reactive nitrilium ion, the key intermediate formed in the reaction of the imine and the isocyanide. However, when reactants with multiple nucleophilic groups (bisfunctional reactants) are used in the MCR, the nitrilium intermediate can be trapped by an intramolecular nucleophilic attack to form various heterocycles. The implications of nitrilium trapping along with widely applied conventional isocyanide-based MCRs in drug design are discussed in this review.

Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction.

We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [(35)S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.

Mild, Pd-catalyzed stannylation of radioiodination targets.

Trialkylstannanes are versatile precursors for chemical transformations, including radiolabeling with a variety of halogens, particularly iodine. In the present work a convenient, Pd-mediated stannylation method is presented that can be performed in an open flask. The method is selective for aryl iodides allowing selective stannylations in the presence of other halogen atoms. The reaction conditions are mild, making the method compatible with chemically sensitive bioactive compounds.

Three-component coupling approach for the synthesis of diverse heterocycles utilizing reactive nitrilium trapping.

The formation of an unexpected heterocyclic scaffold, a benzoxazole, in a three-component reaction between a ketone, isocyanide, and 2-aminophenol was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of the aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles. The reaction scope includes simple linear as well as complex cyclic ketones and substituted 2-aminophenols. A representative benzoxazole product could be further diversified to yield drug-like compounds.