A stratified treatment algorithm in psychiatry: a program on stratified pharmacogenomics in severe mental illness (Psych-STRATA): concept, objectives and methodologies of a multidisciplinary project funded by Horizon Europe.

Schizophrenia (SCZ), bipolar (BD) and major depression disorder (MDD) are severe psychiatric disorders that are challenging to treat, often leading to treatment resistance (TR). It is crucial to develop effective methods to identify and treat patients at risk of TR at an early stage in a personalized manner, considering their biological basis, their clinical and psychosocial characteristics. Effective translation of theoretical knowledge into clinical practice is essential for achieving this goal.

Rh(III)-Catalyzed Double C-H Activation toward Peptide-Benzazepine Conjugates.

We herein report the efficient synthesis of peptide-benzazepine conjugates from Lys-based peptides and acroleins via Rh(III)-catalyzed double C-H activation. This reaction features mild reaction conditions, broad scope, high atom and step economies, and excellent chemo- and site selectivity. The synthetic utility of this strategy is further demonstrated by scale-up experiments and product derivatizations, including diverse late-stage ligations based on the aldehyde moiety.

Hydroalkylation of styrenes enabled by boryl radical mediated halogen atom transfer.

In this study, we present an inexpensive, stable, and easily available boryl radical source (BPhNa) employed in a Halogen Atom Transfer (XAT) methodology. This mild and convenient strategy unlocks the use of not only alkyl iodides as radical precursors but also of the more challenging alkyl and aryl bromides to generate C-centered radicals. The generated radicals were further engaged in the -Markovnikov hydroalkylation of electronically diverse styrenes, therefore achieving the formation of C(sp)-C(sp) and C(sp)-C(sp) bonds.

Recent Advances in the Synthesis of Rosettacin.

Camptothecin and its analogues show important antitumor activity and have been used in clinical studies. However, hydrolysis of lactone in the E ring seriously attenuates the antitumor activity. To change this situation, aromathecin alkaloids are investigated in order to replace camptothecins.

A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study.

Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants and or antipsychotics and according to the latest state-of-the-art international dosing recommendations for and metabolizer status in patients with mood, anxiety, and psychotic disorders.

How Real-World Data Can Facilitate the Development of Precision Medicine Treatment in Psychiatry.

Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings.

Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions.

Peptidomimetics have been extensively explored in many area due to their ability to improve pharmacological qualities and interesting biological activities. Cycles could be incorporated in peptides to reduce their flexibility, often enhancing the affinity for a certain receptor. Many efforts have been made to synthesize various peptidomimetics.

Going with the µFlow: Reinterpreting Energy Input in Organic Synthesis.

The popularity of microflow chemistry has skyrocketed in the last 20 years, more and more chemists are switching from macro-batch reactors to miniaturized flow devices. As a result, microfluidics is paving its way into the future by consolidating its position in organic chemistry not only as a trend but as a new, effective, and sustainable way of conducting chemistry, that clearly will continue to grow and evolve. This perspective highlights the most relevant examples of innovative enhancing technologies applied to microflow reactors aimed to improve and intensify chemical processes.

Visible light-mediated halogenation of organic compounds.

The use of visible light and photoredox catalysis emerged as a powerful and sustainable tool for organic synthesis, showing high value for distinctly different ways of bond creation. Halogenated compounds are the cornerstone of contemporary organic synthesis: it is almost impossible to develop a route towards a pharmaceutical reagent, agrochemical, natural product, without the involvement of halogen-containing intermediates. Moreover, the halogenated derivatives as final products became indispensable for drug discovery and materials science.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Light-Driven Four-Component Reaction with Boronic Acid Derivatives as Alkylating Agents: An Amine/Imine-Mediated Activation Approach.

Herein, we describe a one-pot aminoalkylation of styrene derivatives with boronic acids (BAs) and boronic acid pinacol esters as radical precursors for the synthesis of complex secondary amines in moderate to high yields through a mild and easily accessible organophotoredox-catalytic four-component reaction. Additionally, we report for the first time in a photoredox process the activation of alkyl boronic acid derivatives by imines, which play a dual role in the reaction as both substrate and Lewis base activator. The protocol applicability was greatly enhanced by its successful adaptation to photoflow reactors.

Post-Ugi Cyclizations Towards Polycyclic N-Heterocycles.

The Ugi reaction has become one of the highly explored reactions for the formation of multifunctional adducts, due to the mild reaction conditions, wide scope and high variability. By carefully selecting the starting four components, Ugi-adducts could undergo different kinds of post-transformations for the synthesis of bioactive heterocycles, natural products and macrocycles. Considering the significance of polycycles, diverse post-Ugi transformations have been developed over the years for constructing structurally novel polycycles.

Application of Metal-Free Dearomatization Reaction as a Sustainable Strategy to Direct Access Complex Cyclic Compounds.

The highly efficient construction of complicated heterocyclic frameworks in an atom- and step-economic manner is still one of the cores of synthetic chemistry. Dearomatization reactions show the unique advantage for the construction of functionalized heterocycles and have attracted widespread attention over the past two decades. The metal-free approach has proved to be a green and sustainable paradigm for the synthesis of spirocyclic, polycyclic and heterocyclic scaffolds, which are widely present in natural products and bioactive molecules.

Construction of Peptide-Isoquinolone Conjugates via Rh(III)-Catalyzed C-H Activation/Annulation.

Herein, we disclose a Rh(III)-catalyzed C-H activation/annulation reaction for the derivatization of Lys-based peptides, affording diverse peptide-isoquinolone conjugates. This approach features racemization-free conditions, high atom- and step-economy, excellent chemo- and site-selectivity, and broad scope including substrates bearing unprotected Trp and Tyr, free Ser and Gln, and Met residues. The peptide-isoquinolone conjugates also display good fluorescent properties with maximum emission wavelengths up to 460 nm.

Photoinduced copper-catalyzed enantioselective coupling reactions.

Copper-catalyzed enantioselective coupling has been widely investigated, which allows rapid construction of various chiral molecules. Despite important advances polar and radical mechanisms, exploring general and practical strategies for the regio-, enantio- and diastereoselective assembly of stereogenic centers is of significant value but remains highly problematic. The integration of photocatalysis with asymmetric copper catalysis could provide appealing access to the development of new reaction pathways and structurally diverse chiral compounds, and extend the boundaries of radical chemistry.

Effectiveness of Self-guided Tailored Implementation Strategies in Integrating and Embedding Internet-Based Cognitive Behavioral Therapy in Routine Mental Health Care: Results of a Multicenter Stepped-Wedge Cluster Randomized Trial.

Background: Internet-based cognitive behavioral therapy (iCBT) services for common mental health disorders have been found to be effective. There is a need for strategies that improve implementation in routine practice. One-size-fits-all strategies are likely to be ineffective.

Transition Metal-Catalyzed C-H Activation/Annulation Approaches to Isoindolo[2,1-b]isoquinolin-5(7H)-ones.

The isoindolo[2,1-b]isoquinolin-5(7H)-one scaffold is widely present in lots of bioactive natural products. Diverse types of strategies have been developed to construct this scaffold. Recently, transition metal-catalyzed C-H activation/annulation is emerging as a powerful and straightforward method to construct diverse polyheterocycles with high atom- and step-economy.

Visible-Light-Induced Cascade Difunctionalization of Indoles Enabled by the Synergy of Photoredox and Photoexcited Ketones: Direct Access to Alkylated Pyrrolophenanthridones.

Herein, we describe a methodology to construct polycyclic pyrrolophenanthridones with an (amino)alkyl side chain that involves visible-light-induced decarboxylative radical addition for the intermolecular dearomatization of indoles and subsequent photoinduced C(sp)-X bond activation via photoexcited ketones for an intramolecular cyclization cascade. Carboxylic acids serve both as a radical source toward indole dearomatization and as reductants to initiate an electron transfer with photoexcited -acylindole derivatives in the reaction toward pyrrolophenantridone skeletons, which occurs under mild reaction conditions with good functional group tolerance.

Gold(I)-Catalyzed Intramolecular Bicyclization: Divergent Construction of Quinazolinone and Ampakine Analogues.

A gold(I)-catalyzed cascade intramolecular cyclization of Ugi adducts for the divergent construction of quinazolinone and ampakine analogues has been developed in a rapid, highly efficient and step-economical manner. This protocol shows high yields, excellent functional-group tolerance, broad substrate scope and excellent chemo- and regioselectivity. The practicality of this strategy is further demonstrated by a scale-up reaction.

Regio- and Chemoselective Copper-Catalyzed Formal [2+2+2] Cycloaddition of Primary Amines with Arylacetylenes to 2,4,5-Trisubstituted Pyridines.

Disclosed herein is an efficient strategy for the synthesis of 2,4,5-trisubstituted pyridines via CuI/NBS-catalyzed formal intermolecular [2+2+2] cycloaddition of easily available primary amines and nonactivated terminal alkynes. Moreover, this given reaction features a new mode of cycloaddition with high regio- and chemoselectivity, good atom- and step-economy, broad substrate scope, and wide functional group compatibility. Further mechanism studies indicate that this transformation starts with oxidative alkynylation of the amine to form a propargylamine intermediate, followed by radical addition to the alkyne and intramolecular cycloaddition, delivering the pharmacologically interesting multisubstituted pyridines.