A Pd-Catalyzed Annulation Strategy to Linearly Fused Functionalized N-Heterocycles.

Linearly fused polycyclic piperidines represent common substructures in natural products and biologically active small molecules. We have devised a Pd-catalyzed annulation strategy to these compounds that converts readily available 2-tetralones and indanones into these scaffolds with the potential for control of both enantio- and diastereoselectivity. Importantly, these compounds can be chemoselectively functionalized, providing an efficient and robust methodology to these important nitrogen-containing molecules.

Pd-Catalyzed [4 + 1] Annulation Strategy to Functionalized 4-Methyleneproline Derivatives.

A Pd-catalyzed formal [4 + 1] cycloaddition reaction of sulfur ylides and in situ-generated Pd-stabilized zwitterions offers a convenient route to a series of functionalized proline derivatives. The utility of this method is demonstrated by a gram-scale synthesis and chemoselective functionalization of a proline-based derivative.

Asymmetric Synthesis of Functionalizable Type II ß-Turn-Inducing α-Amino Acid Building Blocks.

Peptidomimetics are emerging as a promising class of potent and selective therapeutics. Among the current approaches to these compounds, the utilization of constrained lactams is a key element in enforcing the active peptide conformation, and the development of efficient and stereocontrolled methods for generating such lactam building blocks is an important objective. Current methods typically rely on the elaboration of existing α-amino acids, and in so doing, the side chain is sacrificed during the ring-forming process. We report a new asymmetric approach to lactam-constrained α-amino acid building blocks bearing a range of polar and hydrophobic side chains. The chemistry is amenable to rapidly generating di- and tripeptides, and the potential for these lactams to stabilize type II ß-turns is demonstrated in the synthesis of the melanocyte-inhibiting factor peptidomimetic.

A Dynamic Thermodynamic Resolution Strategy for the Stereocontrolled Synthesis of Streptonigrin.

We report that axially chiral biaryl boronic esters can be generated with control of atroposelectivity by a Binol-mediated dynamic thermodynamic resolution process. These intermediates can be progressed to enantioenriched products through stereoretentive functionalization of the carbon-boron bond. Finally, we have exploited this method in the first highly stereoselective total synthesis of P-streptonigrin.

Development of an Enantioselective Allylic Alkylation of Acyclic α-Fluoro-ß-ketoesters for Asymmetric Synthesis of 3-Fluoropiperidines.

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-ß-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.

A Mild and Regioselective Route to Fluoroalkyl Aromatic Compounds via Directed Cycloaddition Reactions.

The synthesis of perfluoroalkyl-substituted (hetero)arenes by benzannulation strategies is complementary to ring functionalization approaches as it obviates the need for pre-existing functionality and innate regiocontrol. We report a mild and regiospecific boron-directed benzannulation method as a vehicle for accessing a range of perfluoroalkyl-substituted (hetero)aromatic building blocks that can be readily elaborated through established C-B bond functionalization processes.

A Pd-Catalyzed [4 + 2] Annulation Approach to Fluorinated N-Heterocycles.

3-Fluoro- and trifluoromethylthio-piperidines represent important building blocks for discovery chemistry. We report a simple and efficient method to access analogs of these compounds that are armed with rich functionality allowing them to be chemoselectively derivatized with high diastereocontrol.

Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure-Activity Relationships and Optimization.

Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure-activity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists.

Pyrimidin-6-yl Trifluoroborate Salts as Versatile Templates for Heterocycle Synthesis.

We report a novel and general method to access a highly under-studied privileged scaffold-pyrimidines bearing a trifluoroborate at C4, and highlight the broad utility of these intermediates in a rich array of downstream functionalization reactions. This chemistry is underpinned by the unique features of the trifluoroborate group; its robustness provides an opportunity to carry out chemoselective reactions at other positions on the pyrimidine while providing a pathway for elaboration at the C-B bond when suitably activated.

Design and Synthesis of Fused Pyridine Building Blocks for Automated Library Generation.

We demonstrate that a diboration-electrocyclization sequence provides access to a range of pyridine-fused, small-molecule boronic ester building blocks, and that these are amenable to high-throughput synthesis leading to biaryl and ether-linked compound libraries. Moreover, the implementation of an integrated physicochemical and ADME profiling workflow allows accelerated design of novel lead compounds for application in drug-discovery projects.

Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor.

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in the regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumor progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). The CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests that a selective blockade of adrenomedullin-2 receptors would be therapeutically valuable. Here we describe the design, synthesis, and characterization of potent small-molecule adrenomedullin-2 receptor antagonists with 1000-fold selectivity over the adrenomedullin-1 receptor, although retaining activity against the CGRP receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit xenograft tumor growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anticancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.

The ditungsten decacarbonyl dianion.

We report the synthesis and structural authentication of the ditungsten decarbonyl dianion in [(OC)5W-W(CO)5][K(18-crown-6)(THF)2]2 (1), completing the group 6 dianion triad over half a century since the area began. The W-W bond is long [3.2419(8) Å] and, surprisingly, in the solid-state the dianion adopts a D4h eclipsed rather than D4d staggered geometry, the latter of which dominates the structural chemistry of binary homobimetallic carbonyls. Computational studies at levels of theory from DFT to CCSD(T) confirm that the D4d geometry is energetically preferred in the gas-phase, being ∼18 kJ mol-1 more stable than the D4h form, since slight destabilisation of the degenerate W-CO π 5dxz and 5dyz orbitals is outweighed by greater stabilisation of the W-W σ-bond orbital. The gas-phase D4h structure displays a single imaginary vibrational mode, intrinsic reaction coordinate analysis of which links the D4h isomer directly to the D4d forms, which are produced by rotation around the W-W bond by ±45°. It is therefore concluded that the gas-phase transition state becomes a minimum on the potential energy surface when subjected to crystal packing in the solid-state.

The influence of hypoxia and energy depletion on the response of endothelial cells to the vascular disrupting agent combretastatin A-4-phosphate.

Combretastatin A-4 phosphate (CA4P) is a microtubule-disrupting tumour-selective vascular disrupting agent (VDA). CA4P activates the actin-regulating RhoA-GTPase/ ROCK pathway, which is required for full vascular disruption. While hypoxia renders tumours resistant to many conventional therapies, little is known about its influence on VDA activity. Here, we found that active RhoA and ROCK effector phospho-myosin light chain (pMLC) were downregulated in endothelial cells by severe hypoxia. CA4P failed to activate RhoA/ROCK/pMLC but its activity was restored upon reoxygenation. Hypoxia also inhibited CA4P-mediated actinomyosin contractility, VE-cadherin junction disruption and permeability rise. Glucose withdrawal downregulated pMLC, and coupled with hypoxia, reduced pMLC faster and more profoundly than hypoxia alone. Concurrent inhibition of glycolysis (2-deoxy-D-glucose, 2DG) and mitochondrial respiration (rotenone) caused profound actin filament loss, blocked RhoA/ROCK signalling and rendered microtubules  CA4P-resistant. Withdrawal of the metabolism inhibitors restored the cytoskeleton and CA4P activity. The AMP-activated kinase AMPK was investigated as a potential mediator of pMLC downregulation. Pharmacological AMPK activators that generate AMP, unlike allosteric activators, downregulated pMLC but only when combined with 2DG and/or rotenone. Altogether, our results suggest that Rho/ROCK and actinomyosin contractility are regulated by AMP/ATP levels independently of AMPK, and point to hypoxia/energy depletion as potential modifiers of CA4P response.

Design and Synthesis of New Pyrazole-Based Heterotricycles and their Derivatization by Automated Library Synthesis.

Small-molecule heterocycles bearing orthogonal functionality have the potential to deliver diverse structural motifs that aid the drug-discovery effort. This work highlights how a readily assembled N-hydroxyethyl pyrazole trifluoroborate offers rapid access to architecturally distinct 5-6-6- and 5-7-6-fused tricyclic compounds. This chemistry is not only amenable to single compound synthesis, but also to high-throughput experimentation. It gives easy access to diverse compound arrays with various physicochemical and ADME profiles by fully automated library synthesis. The combination of the high-throughput experimentation with rapid testing of the compounds in an integrated physicochemical and ADME profiling workflow allows accelerated design of novel lead compounds in drug-discovery projects.

Exploiting Synergistic Catalysis for an Ambient Temperature Photocycloaddition to Pyrazoles.

Sydnone-based cycloaddition reactions are a versatile platform for pyrazole synthesis, however they operate under harsh conditions (high temperature and long reaction times). Herein we report a strategy that addresses this limitation utilizing the synergistic combination of organocatalysis and visible-light photocatalysis. This new approach proceeds under ambient conditions and with excellent levels of regiocontrol. Mechanistic studies suggest that photoactivation of sydnones, rather than enamines, is key to the successful implementation of this process.

Exploiting Hydrazones To Improve the Efficiency of 6π-Electrocyclization Reactions of 1-Azatrienes.

The greater geometric lability of hydrazones compared to that of oxime ethers is used as a basis to overcome the reluctance of Z-oxime ether azatrienes to undergo electrocyclization toward the synthesis of borylated (heteroaromatic) pyridines and ring-fused analogues. Such hydrazones now allow access to previously inaccessible tri- and tetrasubstituted 3-borylpyridines in high yields.

Repair of complex abdominal wall hernias with a cross-linked porcine acellular matrix: cross-sectional results of a Dutch cohort study.

BACKGROUND: The use of synthetic mesh in potentially contaminated and contaminated incisional hernias may lead to a higher morbidity and mortality. Biological meshes may provide a solution, but since these meshes are rarely used, little is known about long-term results. The aim of this cohort study was to evaluate the long-term clinical efficacy and patient satisfaction following Permacol™ in complex abdominal wall hernia repair (CAWHR) patients in a cross-sectional fashion. MATERIALS AND METHODS: All patients were operated for CAWHR with Permacol™ in the Netherlands between 2009 and 2012. The design was a multicenter cross-sectional cohort study. The STROCSS statement was followed. Patients were interviewed, underwent abdominal examination, and completed quality-of-life questionnaires. ClinicalTrials.gov Identifier NCT02166112. Research Registry Identifier researchregistry4713. RESULTS: Seventy-seven patients were seen in the outpatient clinic. Their hernias were classified as potentially contaminated in 25 patients (32.5%) and infected in 52 patients (67.5%). The mean follow-up was 22.2 ±â€¯12.6 months. The most frequent postoperative complication was wound infection (n = 21; 27.3%), meshes had to be removed in five patients (6.5%). By the time of their visit to the outpatient clinic, 22 patients (28.6%) had a recurrence of whom ten (13%) had undergone reoperation. Thirty-nine patients (50.6%) had bulging of the abdominal wall. Quality-of-life questionnaires revealed that patients graded their health status with a mean 6.8 (± 1.8) out of 10 points. CONCLUSION: Bulging and recurrence are frequently observed in patients treated with Permacol™ for CAWHR. Considering both recurrence and bulging as undesirable outcomes of treatment, a total of 46 patients (59.7%) had an unfavorable outcome. Infection rates were high, but comparable with similar patient cohorts. Quality-of-life questionnaires revealed that patients were satisfied with their general health, but scored significantly lower on most quality-of-life modalities of the Short Form-36 questionnaire.

Actinide-transition metal bonding in heterobimetallic uranium- and thorium-molybdenum paddlewheel complexes.

We report the preparation of four heterobimetallic uranium- and thorium-molybdenum paddlewheel complexes. The characterisation data suggest the presence of Mo → An σ-interactions in all cases. These complexes represent unprecedented actinide-group 6 metal-metal bonds, where before heterobimetallic uranium-metal bonds were restricted to group 7-11 metals.

Evaluation of Sydnone-Based Analogues of Combretastatin A-4 Phosphate (CA4P) as Vascular Disrupting Agents for Use in Cancer Therapy.

The combretastatins have attracted significant interest as small-molecule therapies for cancer due to their ability to function as vascular disrupting agents. We have successfully prepared a range of combretastatin analogues that are based on a novel sydnone heterocycle core, and their potential as tubulin binders has been assessed in vitro and in vivo. The most potent candidate was found to disrupt microtubules and affect cellular morphology at sub-micromolar levels. Moreover, it was found to bind reversibly to tubulin and significantly increase endothelial cell monolayer permeability, in a similar manner to combretastatin A4. Surprisingly, the compound did not exhibit efficacy in vivo, possibly due to rapid metabolism.

Construction and feasibility study of the SOFMER Activity Score (SAS), a new assessment of physical and cognitive activity.

OBJECTIVES: For hospitalizations in rehabilitation centers (RCs) in France, the quantification of healthcare givers' activity is based on the dependency of the patients, defined as a total or partial inability to perform activities required for daily living without help. The tools currently used to quantify dependency are not sufficiently precise. Here we describe the construction of a new tool, the SOFMER Activity Score (SAS scoring), which allows for a good description of the level of activity of patients hospitalized in RCs, and a feasibility study of the tool. METHODS: After a study group proposed the first version of the SAS, the validity of its content was studied by the Delphi consensus method: 26 physicians or healthcare professionals known for their expertise in PMR responded to the first round. The feasibility study was prospective and involved multi-site professionals. Data related to the SAS determined by a multidisciplinary team were collected and compared to the Activité de la Vie Quotidienne (AVQ) scale, which is administered to all patients and included in medical and administrative data. RESULTS: We included 81 patients in the feasibility study. The mean (SD) time to obtain the SAS was 4.5 (3.3) min. For 97.5% of scorings, the participating professionals judged that the SAS was compatible or fairly compatible with clinical practice. The internal structure of the SAS scale seemed better than that of the AVQ scale, for which the present study confirmed a floor effect for all items. CONCLUSIONS: The SAS allows for measuring the level of physical and cognitive activity of a patient hospitalized in an RC. If validation studies for the SAS, exploring its reliability, construct validity or criterion validity, confirm the tool's good metrological qualities, the SAS will allow for a good quantification of the burden of care.