One-Pot Oxidative Amidation of Aldehydes via the Generation of Nitrile Imine Intermediates.

A one-pot procedure for the oxidative amidation of aldehydes via the in situ generation of reactive nitrile imine (NI) intermediates has been developed. Distinct from our progenitor processes, mechanistic and control experiments revealed that the NI undergoes rapid oxidation to an acyl diazene species, which then facilitates N-acylation of an amine. A range of substrates have been explored, including application in the synthesis of pharmaceutically relevant compounds.

Current and emerging approaches to noncompetitive AR inhibition.

The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand-binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.

UV-Induced 1,3,4-Oxadiazole Formation from 5-Substituted Tetrazoles and Carboxylic Acids in Flow.

A range of 1,3,4-oxadiazoles have been synthesized using a UV-B activated flow approach starting from carboxylic acids and 5-substituted tetrazoles. The application of UV light represents an attractive alternative to the traditional thermolytic approach and has demonstrated comparable efficiency and versatility, with a diverse substrate scope, including the incorporation of highly substituted amino acids.

Transition-Metal-Free Coupling of 1,3-Dipoles and Boronic Acids as a Sustainable Approach to C-C Bond Formation.

The need for alternative, complementary approaches to enable C-C bond formation within organic chemistry is an on-going challenge in the area. Of particular relevance are transformations that proceed in the absence of transition-metal reagents. In the current study, we report a comprehensive investigation of the coupling of nitrile imines and aryl boronic acids as an approach towards sustainable C-C bond formation. In situ generation of the highly reactive 1,3-dipole facilitates a Petasis-Mannich-type coupling via a nucleophilic boronate complex. The introduction of hydrazonyl chlorides as a complementary nitrile imine source to the 2,5-tetrazoles previously reported by our laboratory further broadens the scope of the approach. Additionally, we exemplify for the first time the extension of this protocol into another 1,3-dipole, through the synthesis of aryl ketone oximes from aryl boronic acids and nitrile N-oxides.

One-Pot Suzuki-Hydrogenolysis Protocol for the Modular Synthesis of 2,5-Diaryltetrazoles.

2,5-Diaryltetrazoles are a diverse range of compounds of considerable interest within the field of photochemistry as a valuable precursor of the nitrile imine 1,3-dipole. Current literature approaches toward this heterocycle remain unsuitable for the practical synthesis of a library of these derivatives. Herein, we disclose the development of a modular approach toward 2,5-diaryltetrazoles compatible with an array-type protocol, facilitated by a tandem Suzuki-hydrogenolysis approach.

A fragment-like approach to PYCR1 inhibition.

Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays.

Surface Functionalization with Carboxylic Acids by Photochemical Microcontact Printing and Tetrazole Chemistry.

In this paper, we show that carboxylic acid-functionalized molecules can be patterned by photochemical microcontact printing on tetrazole-terminated self-assembled monolayers. Upon irradiation, tetrazoles eliminate nitrogen to form highly reactive nitrile imines, which can be ligated with several different nucleophiles, carboxylic acids being the most reactive. As a proof of concept, we immobilized trifluoroacetic acid to monitor the reaction with X-ray photoelectron spectroscopy. Moreover, we also immobilized peptides and fabricated carbohydrate-lectin as well as biotin-streptavidin microarrays using this method. Surface-patterning was demonstrated by fluorescence microscopy and time-of-flight secondary ion mass spectrometry.

Atom Efficient Synthesis of Selectively Difluorinated Carbocycles through a Gold(I)-Catalyzed Cyclization.

The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both cyclization processes can be performed under mild conditions allowing access to complex products rich in functionality. The cyclic systems are synthesized concisely (maximum four steps) from trifluoroethanol, an inexpensive fluorinated feedstock.

Cyrene as a bio-based solvent for HATU mediated amide coupling.

Amide bonds are one of the underpinning linkages in all living systems and are fundamental within drug discovery. Current methods towards their synthesis frequently rely on the use of dipolar aprotic solvents; however, due to increasingly stringent regulations and growing societal pressures, safe and more sustainable alternatives are highly sought after. Herein, we evaluate the application of the bio-based solvent Cyrene™ in the HATU mediated synthesis of amides and peptides. We found that Cyrene functioned as a competent replacement for DMF in the synthesis of a series of lead-like compounds and dipeptides (25 examples, 63-100%).

Amidation of unactivated ester derivatives mediated by trifluoroethanol.

A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.

Outcomes following first-episode psychosis - Why we should intervene early in all ages, not only in youth.

OBJECTIVE: To compare baseline demographics and 10-year outcomes of a first-episode psychosis patient incidence cohort in order to establish whether current youth-focussed age-based criteria for early intervention services are justified by patient needs. The patients in this cohort were treated prior to the establishment of early intervention services. The study aimed to test the hypothesis that those who develop psychosis at a younger age have worse outcomes than those who develop psychosis at an older age. METHODS: Data on first-episode psychosis patients from the ÆSOP-10 longitudinal follow-up study were used to compare baseline characteristics, and 10-year clinical, functional and service use outcomes between those patients who would and would not have met age-based criteria for early intervention services, in Australia or in the United Kingdom. RESULTS: In total, 58% men and 71% women with first-episode psychosis were too old to meet current Australian-early intervention age-entry criteria (χ2 = 9.1, p = 0.003), while 21% men and 34% women were too old for UK-early intervention age-entry criteria (χ2 = 11.1, p = 0.001). The 10-year clinical and functional outcomes did not differ significantly between groups by either Australian- or UK-early intervention age-entry criteria. Service use was significantly greater among the patients young enough to meet early intervention age-criteria (Australia: incidence rate ratio = 1.35 [1.19, 1.52], p < 0.001; United Kingdom: incidence rate ratio = 1.65 [1.41, 1.93], p < 0.001). CONCLUSION: Current early intervention services are gender- and age-inequitable. Large numbers of patients with first-episode psychosis will not receive early intervention care under current service provision. Illness outcomes at 10-years were no worse in first-episode psychosis patients who presented within the age range for whom early intervention has been prioritised, though these patients had greater service use. These data provide a rationale to consider extension of early intervention to all, rather than just to youth.

Scope and limitations of a DMF bio-alternative within Sonogashira cross-coupling and Cacchi-type annulation.

Pd-catalysed C-C bond formation is an essential tool within the pharmaceutical and agrochemical industries. Many of these reactions rely heavily on polar aprotic solvents; however, despite their utility, these solvents are incompatible with the drive towards more sustainable chemical synthesis. Herein, we describe the scope and limitations of an alternative to DMF derived from renewable sources (CyreneTM) in Sonogashira cross-coupling and Cacchi-type annulations.

Amidation of esters with amino alcohols using organobase catalysis.

A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate.

A framework for the biophysical screening of antibody mutations targeting solvent-accessible hydrophobic and electrostatic patches for enhanced viscosity profiles.

The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of 24 mutants with modified viscosity profiles accompanied by experimental evaluation. Our experimental observations using a model anti-IL8 mAb and eight engineered mutant variants reveal that viscosity reduction is influenced by the location of hydrophobic interactions, while targeting positively charged patches significantly increases viscosity in comparison to wild-type anti-IL-8 mAb. We conclude that most predicted in silico physicochemical properties exhibit poor correlation with measured experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the need for comprehensive case-by-case evaluation of mAbs. This framework combining molecular design and triage via computational predictions with experimental evaluation aids the agile and rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.

Validity of criteria for dementia in older people with intellectual disability.

OBJECTIVE: Valid definitions of dementia should discriminate dementia from other forms of cognitive impairment such as intellectual disability (ID). We aimed to evaluate the usefulness of criteria for dementia and mild cognitive impairment (MCI) in ID, including predictive validity, and inter-rater reliability. METHOD: We assessed 222 participants in a survey of older adults with ID without Down syndrome at two time points for dementia (T1 and T2). Mean follow-up period was 2.9 years. Dementia diagnoses were made according to International Classification of Diseases, Tenth Revision, Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), Diagnostic criteria for psychiatric disorders for use with adults with learning disabilities (DC-LD) criteria. At follow-up (T2), raters were blind to initial diagnosis. Predictive validity was determined by comparing odds ratios (ORs) of death, or of having a "poor outcome" (i.e., either dying or being diagnosed with dementia at T2). RESULTS: All dementia criteria showed substantial inter-rater reliability (κ > 0.68) and high specificity (~95%). Dementia cases at T1 were more likely to have died at T2 than those with no dementia (33.3% versus 14.9%; OR: 2.85; 95% confidence interval (95% CI): 1.12-7.22) and to have a "poor outcome" (77.8% versus 27.6%; OR: 9.18; 95% CI: 3.43-24.53). At least two dementia cases at T1 were false positives. Those with "MCI" at T1 were similar to "no dementia" cases in terms of poor outcomes at T2. CONCLUSION: Dementia diagnostic criteria show substantial reliability and satisfactory validity in ID. The diagnoses were, however, less stable than in the general population and some caution is advisable in those with more severe ID or additional sensory disability. MCI definitions require further consideration in the ID population.

Enhancing quality and safety standards for older people in Canadian hospitals: a national collaboration.

In this article, the authors present quality and safety standards for older people in hospital, derived from a national dialogue involving inter-professional experts, key stakeholders and opinion leaders. They report the consensus process and present the standard statements with corresponding operational definitions, along with relevant clinical topics. This work can serve as a platform for service planners, evaluators and policy makers who are endeavouring to ensure that older people receive quality care and service when admitted to a Canadian hospital.

Computer vision as a new paradigm for monitoring of solution and solid phase peptide synthesis.

We report a strategy for the camera-enabled non-contact colourimetric reaction monitoring and optimisation of amide bond formation, mediated by coupling reagents. For amide bond formation in solution phase, investigation of reactions mediated by HATU, PyAOP, and DIC/Oxyma evidenced correlations between colour parameters extracted from video data and conversion to amide product measured by off-line HPLC analysis of concentration. These correlations, supported by mutual information analysis, were further investigated using video recordings of solid phase peptide synthesis (SPPS), co-analysed by off-line HPLC to track remaining unreacted substrate in solution. An optimisation method of coupling time in SPPS was derived from ΔE (a measurement of colour contrast), giving comparable isolated peptide yield and purity at 65-95% reduced overall reaction time. The same colour data enabled data-rich monitoring of reaction rate attenuation, consisted with computationally-derived measures of amino acid steric bulk. These findings provide a foundation for exploring the use of camera technology and computer vision towards automated and online mechanistic profiling of SPPS.

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain.

The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure-activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis.

The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement of the ATX-LPA signaling axis in human and murine diseased livers. Then, we evaluated the effects of Cpd17, in comparison with the classic type I inhibitor PF8380, in vitro, where Cpd17 showed higher efficacy. Thereafter, we characterized the mechanism-of-action of both inhibitors and found that Cpd17 was more potent in inhibiting RhoA-mediated cytoskeletal remodeling, and phosphorylation of MAPK/ERK and AKT/PKB. Finally, the therapeutic potential of Cpd17 was investigated in CCl4 -induced acute liver injury and diet-induced nonalcoholic steatohepatitis, demonstrating an excellent potential of Cpd17 in reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases.

Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.

Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.