Discovery of a novel series of selective macrocyclic PKCTheta inhibitors.

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.

Hydrogen Atom Transfer-Mediated Cyclisations of Nitriles.

Hydrogen atom transfer-mediated intramolecular C-C coupling reactions between alkenes and nitriles, using PhSiH3 and catalytic Fe(acac)3 , are described. This introduces a new strategic bond disconnection for ring-closing reactions, forming ketones via imine intermediates. Of note is the scope of the reaction, including formation of sterically hindered ketones, spirocycles and fused cyclic systems.

Asymmetric palladium-catalyzed directed intermolecular fluoroarylation of styrenes.

A mild catalytic asymmetric direct fluoro-arylation of styrenes has been developed. The palladium-catalyzed three-component coupling of Selectfluor, a styrene and a boronic acid, provides chiral monofluorinated compounds in good yield and in high enantiomeric excess. A mechanism proceeding through a Pd(IV)-fluoride intermediate is proposed for the transformation and synthesis of an sp(3) C-F bond.

Gold Catalysed Redox Synthesis of Imidazo[1,2-a]pyridine using Pyridine N-Oxide and Alkynes.

A mild, catalytic, atom economical synthesis of imidazo[1,2-a]pyridines has been developed: catalytic PicAuCl2 in the presence of an acid produces a range imidazo[1,2-a]pyridines in good yield. This strategy is mild and forseen to be of particular use for the installation of stereogenic centers adjacent to the imidazo[1,2-a]pyridine ring without loss of enantiomeric excess.

Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

Regioselective Synthesis of Fully Substituted Fused Pyrroles through an Oxidant-Free Multicomponent Reaction.

The synthesis of fully substituted fused pyrroles through a multicomponent reaction between a thioamide, an aldehyde, and ammonium acetate is described. This process improves on a route commonly employed in the patent literature by avoiding the use of potentially hazardous oxidants, which cause the formation of side products and require a stringent process of derisking to be utilized on scale. The reaction proceeds under mild conditions, displays excellent functional group tolerance, and facilitates diversification through multiple vectors.

Completion of the impurity profile of lymecycline: Formal identification of impurities E and F.

Lymecycline is the drug substance (DS) used in the Galderma drug product Tetralysal® capsules with 7 impurities currently described in the pharmacopeia labelled as A-G. In the current monograph, the structural identity of all impurities except E and F have been formally identified. In this manuscript, through both formal synthesis and preparative chromatography, we are the first group to confirm the structural identity, response factor of Impurity F and conditions which exacerbate the formation of both impurities.

Exclusive platination of loop adenines in the human telomeric G-quadruplex.

The present article reports on the platination of the human telomeric G-quadruplex by three Pt-terpyridine complexes. It is shown that extension of the aromatic surface of the terpyridine moiety surrounding the platinum atom influences both the binding affinity and the platination activity. Remarkably, the most strongly bound complex Pt-ttpy coordinates exclusively the adenine nucleobases present in the loop of the G-quadruplex. This exclusive single-site platination reflects the interaction of the compound with both the G-tetrad and the loop residues. In addition Pt-ttpy showed promising antiproliferative activity on a panel of cancer cell lines in a parallel study using cisplatin derivatives currently in clinical use.

Copper-Catalyzed Synthesis of Activated Sulfonate Esters from Boronic Acids, DABSO, and Pentafluorophenol.

The synthesis of pentafluorophenyl (PFP) sulfonate esters based on the Pd-catalyzed sulfination of aryl and heteroaryl boronic acids is reported. The sulfinate intermediates are converted in situ to the corresponding sulfonate esters using a copper-catalyzed oxidative process, providing a broad range of PFP esters in good yields.

One-Pot, Three-Step Synthesis of Cyclopropylboronic Acid Pinacol Esters from Synthetically Tractable Propargylic Silyl Ethers.

Simple propargylic silyl ethers can be converted to complex cyclopropylboronic acid pinacol esters in an efficient one-pot procedure. Terminal acetylenes undergo a Schwartz's reagent catalyzed hydroboration; subsequent addition of further Schwartz's reagent and Lewis acid-mediated activation of neighboring silyl ether allows cyclization to access a range of cyclopropylboronic acid pinacol esters. The scope includes aromatic, aliphatic, quaternary, and spiro substituted cyclopropyl rings, which can be transformed via Suzuki coupling into a range of lead-like substituted cyclopropyl aryl products.

Transition-Metal-Free Amine Oxidation: A Chemoselective Strategy for the Late-Stage Formation of Lactams.

A metal-free strategy for the formation of lactams via selective oxidation of cyclic secondary and tertiary amines is described. Molecular iodine facilitates both chemoselective and regioselective oxidation of C-H bonds directly adjacent to a cyclic amine. The mild conditions, functional group tolerance, and substrate scope are demonstrated using a suite of diverse small molecule cyclic amines, including clinically approved drug scaffolds.

The development and mechanistic investigation of a palladium-catalyzed 1,3-arylfluorination of chromenes.

A mild palladium-catalyzed ligand-controlled regioselective 1,3-arylfluorination of 2[H]-chromenes has been developed. The products with a syn-1,3 substitution pattern were obtained with high enantiomeric excess using a PyrOx ligand, wherein the utility of these pyranyl-fluorides was further demonstrated through their participation in a diastereoselective C-C bond forming reaction. Ligand dependent divergent formation of both the 1,3- and 1,2- alkene difunctionalization products was observed. The nature of this bifurcation was investigated through experimental studies in combination with computational and statistical analysis tools. Ultimately, the site selectivity was found to rely on ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.

Effects of predictability and competition on group and individual choice in a free-ranging foraging environment.

The present study examined the social foraging of rats in an open arena. The relative quantity of food varied across two food sources, or "patches." Five food quantity ratios (1:1, 1:2, 1:8, 8:1, 2:1) were presented in a series of 30-min sessions. Ratios varied randomly across 6-min components within sessions (Phase 1), or in a consistent order across sessions (Phase 2). Group and individual preferences were well described by the ideal free distribution and the generalized matching law, respectively, with evidence of undermatching at both group and individual levels. Sensitivity of individual and collective behavior to the relative quantities of food was higher in Phase 2 than in Phase 1. Competitiveness rankings, assessed before and after experimental sessions by delivering food in rapid succession from a single feeder, was positively related to sensitivity values in Phase 1, but less consistently so in Phase 2. This study illustrates a promising experimental method for investigating foraging in a social context.

Synthesis of the anti-trypanosomal agent (±)-hydroxyanthecotulide by Cr(ii)-catalysed allylation and Meyer-Schuster rearrangement.

The first synthesis of the bioactive sesquiterpene lactone hydroxyanthecotulide is achieved in 7 steps, involving a stereocontrolled Cr(ii)-catalysed reaction of 3-(bromomethyl)furan-2(5H)-one with enynal 9 and a mild Au(i)-catalysed Meyer-Schuster rearrangement.

Catalytic asymmetric synthesis of (+)-anthecotulide using enyne and Meyer-Schuster rearrangements.

The bioactive sesquiterpene lactone (+)-anthecotulide (1) is synthesized for the first time, in a six-step sequence devoid of protecting groups. The key transformations are a novel Rh(I)-catalyzed asymmetric enyne rearrangement of a terminal alkynyl ester (4), to form the α-methylene-γ-butyrolactone core, and a final-step mild Au(I)-catalyzed Meyer-Schuster rearrangement.

Stereoselective synthesis of ß-(hydroxymethylaryl/alkyl)-α-methylene-γ-butyrolactones.

Zinc or a chromium(II) source with 3-(bromomethyl)furan-2(5H)-one (3) and an aldehyde gives ß-(hydroxymethylaryl/alkyl)-α-methylene-γ-butyrolactones 5 in good yields and high diastereoselectivities. The methodology is demonstrated in concise syntheses of (±)-hydroxymatairesinol (8) and (±)-methylenolactocin (10) by subsequent arylboronate conjugate addition and translactonization, respectively.