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This article discusses the synthesis of benzylamines, which are important compounds in drug discovery. The authors focus on a nickel-catalyzed cross-electrophile coupling method using N-hydroxyphthalimide esters, which yields good results and is compatible with various functional groups. The method is valuable for medicinal chemistry research and can be carried out under mild conditions using commercially available precursors. The authors acknowledge the support of the Genentech Undergraduate Summer Internship Program and dedicate the article to the late Prof. Keith Fagnou. Supporting information for the article is available online. [Extracted from the article]

This review discusses recent advances in light‐driven radiochemistry for three key isotopes: fluorine‐18, carbon‐11, and zirconium‐89, and their applications in positron emission tomography (PET). In the case of fluorine‐18, the predominant approach involves the use of cyclotron‐produced [18F]fluoride or reagents derived thereof. Light serves to activate either the substrate or the fluorine‐18 labeled reagent. Advancements in carbon‐11 photo‐mediated radiochemistry have been leveraged for the radiolabeling of small molecules, achieving various transformations, including 11C‐methylation, 11C‐carboxylation, 11C‐carbonylation, and 11C‐cyanation. Contrastingly, zirconium‐89 photo‐mediated radiochemistry differs from fluorine‐18 and carbon‐11 approaches. In these cases, light facilitates a postlabeling click reaction, which has proven valuable for the labeling of large biomolecules such as monoclonal antibodies (mAbs). New technological developments, such as the incorporation of photoreactors in commercial radiosynthesizers, illustrate the commitment the field is making in embracing photochemistry. Taken together, these advances in photo‐mediated radiochemistry enable radiochemists to apply new retrosynthetic strategies in accessing novel PET radiotracers. [ABSTRACT FROM AUTHOR]

The crystallographic active site of a thymidylyltransferase from Streptococcus pneumoniae, Cps2L, to engineer the active site of uridylyltransferase and guanidyltransferase. The results obtained from the comparison of active sites of uridylyltransferases and thymidylyltransferases with products bound showed the Q24S variant to provide new pathway to broaden nucleotidylyltransferase activity.

The development of new reaction conditions for intramolecular palladium(II)-catalyzed oxidative carbon-carbon bond formation under air is described. The use of electron-rich diarylamines in the synthesis gave higher yield and broader scope of three naturally occurring carbazole products, Murrayafoline A, Mukonine, and Clausenine.

Abstract: Syntheses of several examples of a new type of trivalent building blocks for the preparation of aliphatic polyester dendrimers are presented. Starting from the well-known mono-O-benzylidenepentaerythritol, AB3 type acid dendrons can be obtained in high yield in only two steps. Other triprotected bis-2,2-(hydroxymethyl)-3-hydroxypropanoic acid derivatives with varying protecting groups were also synthesized readily. This type of dendron was used in combination with 2,2′-bis(hydroxymethyl) propanoic acid (bis-HMPA) divalent dendrons to produce low generation mixed polyester dendrimers with increased number of branching points. [Copyright &y& Elsevier]

Nucleophilic aromatic substitution of 2- or 4-cyanoazines with the anions derived from aliphatic α,α-disubstituted esters and nitriles leads to displacement of the cyanide function. Enabling cyanides to be used as highly active leaving groups in SNAr reactions provides additional flexibility in starting materials for synthesis. We show that, in many cases, the cyanide leaving group is displaced preferentially in the presence of halogens. The resulting heteroaryl iodides, bromides, and chlorides subsequently can be used as handles for further chemical diversification. [ABSTRACT FROM AUTHOR]

A batchwise, multigram preparation of 2-azabicyclo- [2.1.1]hexane hydrochloride (1·HCl) was developed, delivering a total of 195 grams of material. The key synthetic step involves an intramolecular displacement of a primary alkyl chloride with a tert-butylsulfinamide to forge the [2.1.1]-bicyclic ring system. [ABSTRACT FROM AUTHOR]

This review discusses recent advances in light-driven radiochemistry for three key isotopes: fluorine-18, carbon-11, and zirconium-89, and their applications in positron emission tomography (PET). In the case of fluorine-18, the predominant approach involves the use of cyclotron-produced [ 18 F]fluoride or reagents derived thereof. Light serves to activate either the substrate or the fluorine-18 labeled reagent. Advancements in carbon-11 photo-mediated radiochemistry have been leveraged for the radiolabeling of small molecules, achieving various transformations, including 11 C-methylation, 11 C-carboxylation, 11 C-carbonylation, and 11 C-cyanation. Contrastingly, zirconium-89 photo-mediated radiochemistry differs from fluorine-18 and carbon-11 approaches. In these cases, light facilitates a postlabeling click reaction, which has proven valuable for the labeling of large biomolecules such as monoclonal antibodies (mAbs). New technological developments, such as the incorporation of photoreactors in commercial radiosynthesizers, illustrate the commitment the field is making in embracing photochemistry. Taken together, these advances in photo-mediated radiochemistry enable radiochemists to apply new retrosynthetic strategies in accessing novel PET radiotracers., (© 2023 Wiley‐VCH GmbH.)

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 ( 7 ), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7 . In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.

Structure-based design of alkyl sugar-1-phosphates provides an efficient nucleotidylyltransferase-catalyzed synthesis of a series of new lipophilic sugar nucleotides possessing long or branched alkyl chains, thereby demonstrating the utility of nucleotidylyltransferases to catalyze the synthesis of sugar nucleotides with potential applications in lipopolysaccharide and lipoglycopeptide biosynthesis.