Photoaffinity Labeling and Quantitative Chemical Proteomics Identify LXRβ as the Functional Target of Enhancers of Astrocytic apoE.

Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor β (LXRβ) as the target. Binding of the small molecule ligand stabilized LXRβ, as shown by cellular thermal shift assay (CETSA).

Synthesis of F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [F]fluoride.

Herein, we report the radiosynthesis of F-difluoromethylarenes the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated F-fluorodecarboxylation.

Sulfonamide Synthesis via Calcium Triflimide Activation of Sulfonyl Fluorides.

A method using calcium triflimide [Ca(NTf)] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with amines is described. The reaction converts a wide array of sterically and electronically diverse sulfonyl fluorides and amines into the corresponding sulfonamides in good yield.

Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides.

The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C-H functionalization protocol.

Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere.

The synthesis of a new trifluoromethyl oxetane was developed using a Corey-Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the γ-secretase modulator (GSM) program.

Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.

Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets.

Formal Synthesis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehydrative Alkoxylation.

8-Membered cyclic ethers are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. The gold(I)-catalyzed intramolecular dehydrative alkoxylation of ω-hydroxy allylic alcohols was explored to stereoselectively construct α,α'-cis-oxocenes and further applied in a formal synthesis of (+)-laurencin. The gold(I)-catalyzed intramolecular dehydrative alkoxylation may constitute an alternative method for the synthesis of molecular building blocks and natural products that contain highly functionalized 8-membered cyclic ethers.

Mapping the Binding Site of BMS-708163 on γ-Secretase with Cleavable Photoprobes.

γ-Secretase, a four-subunit transmembrane aspartic proteinase, is a highly valued drug target in Alzheimer's disease and cancer. Despite significant progress in structural studies, the respective molecular mechanisms and binding modes of γ-secretase inhibitors (GSIs) and modulators (GSMs) remain uncertain. Here, we developed biotinylated cleavable-linker photoprobes based on the BMS-708163 GSI to study its interaction with γ-secretase.

A new species of Burmeister (Hemiptera: Heteroptera: Coreidae: Coreinae), with a key to the species of India.

A new species from India, Physomerus centralis sp. nov. (Hemiptera: Heteroptera: Coreidae) is described and illustrated with both male and female genitalia.

Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death.

Background: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values.

Associations between single nucleotide polymorphisms in the FAS pathway and acute kidney injury.

Introduction: To determine whether single nucleotide polymorphisms (SNPs) in FAS and related genes are associated with acute kidney injury (AKI) in patients with acute respiratory distress syndrome (ARDS).

Methods: We studied 401 (Caucasian N = 310 and African-American N = 91) patients aged ≥ 13 years with ALI who enrolled in the Fluid and Catheter Treatment Trial (FACTT) between 2000 and 2005 from 20 North American centers. We genotyped 367 SNPs in 45 genes of the Fas/Fas ligand pathway to identify associations between SNPs in Fas pathway genes and the development of AKI by day 2 after enrollment in FACTT, adapting Acute Kidney Injury Network (AKIN) criteria.

A new species of Aulacogenia Stål (Hemiptera: Heteroptera: Reduviidae: Stenopodainae) from India.

A new stenopodaine reduviid, Aulacogenia darjeelingensis sp. nov. belonging to the "corniculata species group" from India is described and illustrated.

A new species of Stenolemus Signoret (Hemiptera: Heteroptera: Reduviidae: Emesinae) from India.

A new species of Stenolemus Signoret, 1858, Stenolemus annulatus sp. nov. (Reduviidae: Emesinae) is described from India.

Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.

Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors.

A new genus, Neoschidium (Hemiptera: Reduviidae: Emesinae), with a redescription of the type genus, Neoschidium phasma (Distant) [Ghilianella phasma Distant and Schidium phasma (Distant)], recorded for the first time from India.

A new genus, Neoschidium was erected with the type genus, Neoschidium phasma (Distant). It was earlier described under Ghilianella Spinola 1850 as G. phasma Distant and later under Schidium Bergroth 1916 as Schidium phasma (Distant) by Bergroth (1916).

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain.

Nitric oxide (NO) is an important signaling molecule in the human body, playing a crucial role in cell and neuronal communication, regulation of blood pressure, and in immune activation. However, overproduction of NO by the neuronal isoform of nitric oxide synthase (nNOS) is one of the fundamental causes underlying neurodegenerative disorders and neuropathic pain. Therefore, developing small molecules for selective inhibition of nNOS over related isoforms (eNOS and iNOS) is therapeutically desirable.

Sterically controlled, palladium-catalyzed intermolecular amination of arenes.

We report the Pd-catalyzed amination of arenes to form N-aryl phthalimides with regioselectivity controlled predominantly by steric effects. Mono-, di-, and trisubstituted arenes lacking a directing group undergo amination reactions with moderate to high yields and high regioselectivities from sequential addition of PhI(OAc)2 as an oxidant in the presence of Pd(OAc)2 as catalyst. This sterically derived selectivity contrasts that for analogous arene acetoxylation.

The regio- and stereospecific intermolecular dehydrative alkoxylation of allylic alcohols catalyzed by a gold(I) N-heterocyclic carbene complex.

A 1:1 mixture of [AuCl(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgClO(4) catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to form allylic ethers. These transformations are regio- and stereospecific with preferential addition of the alcohol nucleophile at the γ-position of the allylic alcohol syn to the departing hydroxyl group and with predominant formation of the E stereoisomer. The minor α regioisomer is formed predominantly through a secondary reaction manifold involving regioselective γ-alkoxylation of the initially formed allylic ether rather than by the direct α-alkoxylation of the allylic alcohol.

Gold(I)-catalyzed enantioselective intramolecular dehydrative amination of allylic alcohols with carbamates.

A 1:2 mixture of [()-](AuCl) [()- = ()-DTBM-MeOBIPHEP] and AgClO catalyzes the intramolecular enantioselective dehydrative amination of allylic alcohols with carbamates to form five- and six-membered aliphatic nitrogen heterocycles in high yield with up to 95% .

Gold(I)-catalyzed intramolecular amination of allylic alcohols with alkylamines.

A 1:1 mixture of (1)AuCl [1 = P(t-Bu)(2)o-biphenyl] and AgSbF(6) catalyzes the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. Gold(I)-catalyzed cyclization of (R,Z)-8-(N-benzylamino)-3-octen-2-ol (96% ee, 95% de) led to isolation of (R,E)-1-benzyl-2-(1-propenyl)piperidine in 99% yield with 96% ee, consistent with the net syn addition of the amine relative to the departing hydroxyl group.

Gold(I)-catalyzed amination of allylic alcohols with cyclic ureas and related nucleophiles.

A 1:1 mixture of [P(t-Bu)(2)-o-biphenyl]AuCl and AgSbF(6) catalyzes the intermolecular amination of allylic alcohols with 1-methylimidazolidin-2-one and related nucleophiles that, in the case of gamma-unsubstituted or gamma-methyl-substituted allylic alcohols, occurs with high gamma-regioselectivity and syn-stereoselectivity.