Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation.

Imidazoquinolines (IMDs), such as resiquimod (R848), are of great interest as potential cancer immunotherapies because of their ability to activate Toll-like receptor 7 (TLR7) and/or TLR8 on innate immune cells. Nevertheless, intravenous administration of IMDs causes severe immune-related toxicities, and attempts to improve their tissue-selective exposure while minimizing acute systemic inflammation have proven difficult. Here, using a library of R848 "bottlebrush prodrugs" (BPDs) that differ only by their R848 release kinetics, we explore how the timing of R848 exposure affects immune stimulation in vitro and in vivo.

Expanded [23]-Helicene with Exceptional Chiroptical Properties via an Iterative Ring-Fusion Strategy.

Expanded helicenes are an emerging class of helical nanocarbons composed of alternating linear and angularly fused rings, which give rise to an internal cavity and a large diameter. The latter is expected to impart exceptional chiroptical properties, but low enantiomerization free energy barriers (Δ) have largely precluded experimental interrogation of this prediction. Here, we report the syntheses of expanded helicenes containing 15, 19, and 23 rings on the inner helical circuit, using two iterations of an Ir-catalyzed, site-selective [2 + 2 + 2] reaction.

Cleavable Comonomers for Chemically Recyclable Polystyrene: A General Approach to Vinyl Polymer Circularity.

Many common polymers, especially vinyl polymers, are inherently difficult to chemically recycle and are environmentally persistent. The introduction of low levels of cleavable comonomer additives into existing vinyl polymerization processes could facilitate the production of chemically deconstructable and recyclable variants with otherwise equivalent properties. Here, we report thionolactones that serve as cleavable comonomer additives for the chemical deconstruction and recycling of vinyl polymers prepared through free radical polymerization, using polystyrene (PS) as a model example.

A sequential cyclization/π-extension strategy for modular construction of nanographenes enabled by stannole cycloadditions.

The synthesis of polycyclic aromatic hydrocarbons (PAHs) and related nanographenes requires the selective and efficient fusion of multiple aromatic rings. For this purpose, the Diels-Alder cycloaddition has proven especially useful; however, this approach currently faces significant limitations, including the lack of versatile strategies to access annulated dienes, the instability of the most commonly used dienes, and difficulties with aromatization of the [4 + 2] adduct. In this report we address these limitations the marriage of two powerful cycloaddition strategies.

Scalable, Divergent Synthesis of a High Aspect Ratio Carbon Nanobelt.

Carbon nanobelts are molecules of high fundamental and technological interest due to their structural similarity to carbon nanotubes, of which they are molecular cutouts. Despite this attention, synthetic accessibility is a major obstacle, such that the few known strategies offer limited structural diversity, functionality, and scalability. To address this bottleneck, we have developed a new strategy that utilizes highly fused monomer units constructed via a site-selective [2 + 2 + 2] cycloaddition and a high-yielding zirconocene-mediated macrocyclization to achieve the synthesis of a new carbon nanobelt on large scale with the introduction of functional handles in the penultimate step.

Shape-Selective Synthesis of Pentacene Macrocycles and the Effect of Geometry on Singlet Fission.

Pentacene's extraordinary photophysical and electronic properties are highly dependent on intermolecular through-space interactions. Macrocyclic arrangements of chromophores have been shown to provide a high level of control over these interactions, but few examples exist for pentacene due to inherent synthetic challenges. In this work, zirconocene-mediated alkyne coupling was used as a dynamic covalent C-C bond forming reaction to synthesize two geometrically distinct, pentacene-containing macrocycles on a gram scale and in four or fewer steps.

Elucidation of Diverse Solid-State Packing in a Family of Electron-Deficient Expanded Helicenes via Microcrystal Electron Diffraction (MicroED)*.

Solid-state packing plays a defining role in the properties of a molecular organic material, but it is difficult to elucidate in the absence of single crystals that are suitable for X-ray diffraction. Herein, we demonstrate the coupling of divergent synthesis with microcrystal electron diffraction (MicroED) for rapid assessment of solid-state packing motifs, using a class of chiral nanocarbons-expanded helicenes-as a proof of concept. Two highly selective oxidative dearomatizations of a readily accessible helicene provided a divergent route to four electron-deficient analogues containing quinone or quinoxaline units.

Expanded Helicenes as Synthons for Chiral Macrocyclic Nanocarbons.

Expanded helicenes are large, structurally flexible π-frameworks that can be viewed as building blocks for more complex chiral nanocarbons. Here we report a gram-scale synthesis of an alkyne-functionalized expanded [11]helicene and its single-step transformation into two structurally and functionally distinct types of macrocyclic derivatives: (1) a figure-eight dimer via alkyne metathesis (also gram scale) and (2) two arylene-bridged expanded helicenes via Zr-mediated, formal [2+2+] cycloadditions. The phenylene-bridged helicene displays a substantially higher enantiomerization barrier (22.

Site-selective [2 + 2 + ] cycloadditions for rapid, scalable access to alkynylated polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) are attractive synthetic building blocks for more complex conjugated nanocarbons, but their use for this purpose requires appreciable quantities of a PAH with reactive functional groups. Despite tremendous recent advances, most synthetic methods cannot satisfy these demands. Here we present a general and scalable [2 + 2 + ] ( = 1 or 2) cycloaddition strategy to access PAHs that are decorated with synthetically versatile alkynyl groups and its application to seven structurally diverse PAH ring systems (thirteen new alkynylated PAHs in total).

Titanocene-Mediated Dinitrile Coupling: A Divergent Route to Nitrogen-Containing Polycyclic Aromatic Hydrocarbons.

A general synthetic strategy for the construction of large, nitrogen-containing polycyclic aromatic hydrocarbons (PAHs) is reported. The strategy involves two key steps: (1) a titanocene-mediated reductive cyclization of an oligo(dinitrile) precursor to form a PAH appended with di(aza)titanacyclopentadiene functionality; (2) a divergent titanocene transfer reaction, which allows final-step installation of one or more o-quinone, diazole, or pyrazine units into the PAH framework. The new methodology enables rational, late-stage control of HOMO and LUMO energy levels and thus photophysical and electrochemical properties, as revealed by UV/vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations.

Expanded Helicenes: A General Synthetic Strategy and Remarkable Supramolecular and Solid-State Behavior.

A divergent synthetic strategy allowed access to several members of a new class of helicenes, the "expanded helicenes", which are composed of alternating linearly and angularly fused rings. The strategy is based on a three-fold, partially intermolecular [2+2+n] (n = 1 or 2) cycloaddition with substrates containing three diyne units. Investigation of aggregation behavior, both in solution and in the solid state, revealed that one of these compounds forms an unusual homochiral, π-stacked dimer via an equilibrium that is slow on the NMR time scale.

Zirconacyclopentadiene-Annulated Polycyclic Aromatic Hydrocarbons.

Syntheses of large polycyclic aromatic hydrocarbons (PAHs) and graphene nanostructures demand methods that are capable of selectively and efficiently fusing large numbers of aromatic rings, yet such methods remain scarce. Herein, we report a new approach that is based on the quantitative intramolecular reductive cyclization of an oligo(diyne) with a low-valent zirconocene reagent, which gives a PAH with one or more annulated zirconacyclopentadienes (ZrPAHs). The efficiency of this process is demonstrated by a high-yielding fivefold intramolecular coupling to form a helical ZrPAH with 16 fused rings (from a precursor with no fused rings).

Facile route to an all-organic, triply threaded, interlocked structure by templated dynamic clipping.

Encaged! Three-terminal interlocked molecular species were obtained by dynamic (2+3) assembly of a cagelike macro-bicycle around a trifurcated trispyridinium π guest. The complex is stabilized by π-π interactions and multiple [C-H⋅⋅⋅O] and [C-H⋅⋅⋅N] interactions. Uncomplexed guest molecules cocrystallize alongside the threaded complexes in the solid state, thus giving extended π-stacked columns.

Introducing candesartan 32 mg plus hydrochlorothiazide 25 mg in previously untreated patients with severe essential hypertension.

Purpose: To investigate the efficacy of candesartan 32 mg and hydrochlorothiazide (HCTZ) 25 mg combination in patients with severe essential hypertension.

Patients And Methods: In this prospective, open-label, single-group study, 106 previously untreated patients with a baseline systolic blood pressure (SBP) of 150-200 mmHg, and a diastolic blood pressure (DBP) of 110 to 120 mmHg, started with candesartan 16 mg during the first week. HCTZ 12.

Ln(III) methyl and methylidene complexes stabilized by a bulky hydrotris(pyrazolyl)borate ligand.

The reaction of Ln(AlMe(4))(3) with bulky hydrotris(pyrazolyl)borate (Tp(t)(Bu,Me))H proceeds via a sequence of methane elimination and C-H bond activation, affording unprecedented rare-earth metal ligand moieties including Ln(Me)[(micro-Me)AlMe(3)] and X-ray structurally characterized "Tebbe-like" Ln[(micro-CH(2))(2)AlMe(2)].

Evaluation of the effect of candesartan cilexetil on the steady-state pharmacokinetics of tacrolimus in renal transplant patients.

Background: Candesartan cilexetil is a possible treatment for hypertension in renal allograft recipients. Tacrolimus is widely used as an immunosuppressant following renal transplantation. The aim of this study was to evaluate the effect of multiple doses of candesartan cilexetil on the steady-state pharmacokinetics of tacrolimus.

Variants of the CYP11B2 gene predict response to therapy with candesartan.

In a prospective trial, patients with an elevated diastolic blood pressure (above 95 mm Hg) received high-dose (16 mg) or low-dose (8 mg) candesartan in addition to standardised medication. A positive response to treatment was defined as a diastolic blood pressure <85 mm Hg at follow-up. Genotyping for two candidate genes was performed in 116 patients.

Effect of 7-day therapy with different doses of the proton pump inhibitor lansoprazole on the intragastric pH in healthy human subjects.

Background: Systematic, randomized, and controlled studies on the effect of low to high doses of the proton pump inhibitor lansoprazole on intragastric acidity and plasma gastrin levels have not previously been performed.

Methods: We investigated the effect of 7-day therapy with different doses of lansoprazole (15 mg once or twice daily, 30 mg once or twice daily, and 15 mg three times daily) on intragastric acidity and meal-stimulated daytime plasma gastrin levels in 12 healthy Helicobacter pylori-negative human subjects in a randomized, double-blind, placebo-controlled, 6-way crossover study. On days 1, 2, and 7 of the study 24-h intragastric pH-metry and 12-h integrated daytime plasma gastrin determinations were done.

Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during and after 12 months of treatment with ranitidine and lansoprazole in patients with duodenal ulcer disease.

Background: Several studies have shown that acid-suppressing treatment leads to aggravation of Helicobacter pylori gastritis in the corpus. It remains unclear whether this augmentation of the inflammation reverts to baseline after termination of treatment.

Methods: In 114 H.

Congenital malformation and maternal occupational exposure to glycol ethers. Occupational Exposure and Congenital Malformations Working Group.

Glycol ethers are found in a wide range of domestic and industrial products, many of which are used in women's work environments. Motivated by concern about their potential reproductive toxicity, we have evaluated the risk of congenital malformations related to glycol ether exposure during pregnancy as part of a multicenter case-control study, conducted in six regions in Europe. The study comprised 984 cases of major congenital malformations and 1,134 controls matched for place and date of birth.

The liver, kidney, and thyroid toxicity of chlorinated benzenes.

The acute toxicity of a number of chlorinated benzenes, ranging from monosubstituted to pentasubstituted benzenes, was studied in rats. Toxic effects on the liver, the kidneys, and the thyroid were monitored after a single ip administration of 1, 2, or 4 mmol/kg monochlorobenzene (MCB), 1,2-dichlorobenzene (1,2-DICB), 1,4-dichlorobenzene (1,4-DICB), 1,2,4-trichlorobenzene (1,2,4-TRCB), and pentachlorobenzene (PECB). Due to its low solubility, 1,2,4,5-tetrachlorobenzene (1,2,4,5-TECB) was tested at a highest dose of 0.

Molecular and crystal structure of flutropium bromide.

(8r)-8-(2-Fluoroethyl)-3 alpha-hydroxy-1 alpha H, 5 alpha H-tropanium bromide benzilic acid ester (flutropium bromide, Ba 598 BR) crystallizes in the monoclinic space group P 2(1)/n and shows disorder. Nevertheless the averaged crystal structure could be solved and refined to R = 0.113.

[Pohl's track screw for the surgical treatment of femoral neck fracture. Reliable surgical principle or obsolete method?].

Pohl's hip screw--the classic form of a dynamic osteosynthesis--is an approved method in the treatment of the fracture of the femoral neck (lateral and pertrochanteric fractures). Between 1963 and 1983 over 200 patients were treated with Pohl's hip screw. At an averaged stay of 29 days in hospital half of them were rehabilitated.