Survey of Leafminers on American Chestnut and other Castanea spp. (Fagales: Fagaceae) on Long Island, NY.

The effect of the 20th-century functional extinction of the American Chestnut (Fagaceae: Castanea dentata (Marshall) Borkh) on associated herbivorous insects is unknown. These insects include leafminers that spend at least part of their larval phase feeding between the epidermises of leaves. We surveyed leafminers on C.

Atropisomerism in Drug Discovery: A Medicinal Chemistry Perspective Inspired by Atropisomeric Class I PI3K Inhibitors.

Atropisomerism is a type of axial chirality resulting from hindered rotation about a σ bond that gives rise to nonsuperimposable stereoisomers (termed "atropisomers"). The inversion of chirality of an atropisomeric axis is a time- and temperature-dependent dynamic process occurring by simple bond rotation. For this reason, the rotational energy barrier (Δ) and the interconversion rate between an atropisomeric pair of biologically active molecules are important parameters to consider in drug discovery.

Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.

A series of PI3Kβ selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of ()-, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines.

Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) β Inhibitor.

Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability.

Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856.

Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

Discovery of Orally Efficacious Phosphoinositide 3-Kinase δ Inhibitors with Improved Metabolic Stability.

Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.

2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors.

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism.

Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rh-Catalyzed [2+2+2] Cycloaddition.

An efficient approach to the tricyclic framework of FR901483 is described. The sequence features a [3, 3]-sigmatropic rearrangement of a cyanate into an isocyanate, followed by its subsequent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a terminal alkyne for the synthesis of the indolizidine core. The -tricyclic core is completed using an intramolecular benzoin reaction to close the last ring of the natural product.

Multi-component cycloaddition approaches in the catalytic asymmetric synthesis of alkaloid targets.

Cycloaddition reactions are attractive strategies for the rapid formation of molecular complexity in organic synthesis, as multiple bonds are formed in a single process. To this end, several research groups have been actively involved in the development of catalytic methods to activate readily accessible pi-components to achieve cycloadditions. However, the use of C-N pi-components for the formation of heterocycles by these processes is less well developed.

Enantioselective rhodium-catalyzed [2 + 2 + 2] cycloadditions of terminal alkynes and alkenyl isocyanates: mechanistic insights lead to a unified model that rationalizes product selectivity.

This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne.

Catalytic asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates.

An asymmetric intermolecular Stetter reaction of glyoxamide and alkylidenemalonates has been developed. Catalyzed by a novel N-heterocyclic carbene, the Stetter adducts are formed in good yield and excellent enantioselectivity. The presence of a sensitive epimerizable stereocenter is tolerated under these mildly basic reaction conditions if a bulky amine base is used.

Mechanism and regioselectivity of the cycloaddition of thiones derived from Meldrum's acid, malonates, or other dicarbonyls.

Several alpha,alpha-dioxothiones were generated in situ and reacted with 1,3-dienes of varying electronic and steric properties. It was found that thiones 10a and 11a reacted well with electron-rich or electron-poor dienes and are complementary in their regioselectivities when steric effects are at play. The calculated preferred mechanistic pathway implies a thiiranium zwitterion intermediate.

A test of self-determination theory with wheelchair basketball players with and without disability.

Guided by Self-Determination Theory (SDT), the present study examined the sport motivation and coping skills of male and female wheelchair basketball players with and without disability (N = 72). In line with SDT, results showed that intrinsic and extrinsic motivation as well as amotivation was found to be present in this sample of wheelchair basketball players. Results also demonstrated that the participants surveyed in the present study scored higher on self-determined types of motivation than non self-determined types of motivation, thus replicating past research with athletes without disability.

Meldrum's acid-derived thione dienophile in a convergent and stereoselective synthesis of a tetracyclic quassinoid intermediate.

An advanced intermediate toward anti-cancer quassinoids has been synthesized using a quadruple diene-transmissive [4+2]-cycloaddition strategy. High convergence is achieved thanks to a regio- and stereoselective hetero-Diels-Alder reaction using a thione. The relative stereochemistry of the final Diels-Alder adduct was controlled by tethered substituents introduced via a highly syn- and gamma-selective vinylogous Mukaiyama aldol.

Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: from benzimidazole to indole scaffolds.

Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole-tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC(50) approximately 50 nM).