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Automated batch and flow setups are well‐established for high throughput experimentation in both thermal chemistry and photochemistry. However, the development of automated electrochemical platforms is hindered by cell miniaturization challenges in batch and difficulties in designing effective single‐pass flow systems. In order to address these issues, we have designed and implemented a new, slug‐based automated electrochemical flow platform. This platform was successfully demonstrated for electrochemical C−N cross‐couplings of E3 ligase binders with diverse amines (44 examples), which were subsequently transferred to a continuous‐flow mode for confirmation and isolation, showing its applicability for medicinal chemistry purposes. To further validate the versatility of the platform, Design of Experiments (DoE) optimization was performed for an unsuccessful library target. This optimization process, fully automated by the platform, resulted in a remarkable 6‐fold increase in reaction yield. [ABSTRACT FROM AUTHOR]

The ability to synthesize arrays of related compounds quickly and with good purity has become critical for a rapid exploration of their properties for biological or material applications. While a number of methods have been developed to enable this combinatorial synthesis, the existing options were not readily appliable to the synthesis of aurones using the simple Knoevenagel condensation approach. In order to avoid the time, expense, and lowered yields associated with flash column chromatography, we developed a scavenging approach for their synthesis. This method uses an excess of aldehyde to ensure complete conversion to aurones, followed by selective removal of the remaining aldehyde using a simple, inexpensive scavenger – isoniazid – and subsequent extraction with dilute acid, to produce the desired compounds with good purity under operationally simple conditions. This approach is expected to be applicable to many other reactions involving aldehydes as one of the reactants.

A 'top down' scaffold remodelling approach to library synthesis was applied to spirotricyclic ureas prepared by a complexity‐generating oxidative dearomatisation. Eighteen structurally‐distinct, sp3‐rich scaffolds were accessed from the parent tricycle through ring addition, cleavage and expansion strategies. Biological screening of a small compound library based on these scaffolds using the cell‐painting assay demonstrated distinctive phenotypic responses engendered by different library members, illustrating the functional as well as structural diversity of the compounds. [ABSTRACT FROM AUTHOR]

The ability to synthesize arrays of related compounds quickly and with good purity has become critical for a rapid exploration of their properties for biological or material applications. While a number of methods have been developed to enable this combinatorial synthesis, the existing options were not readily appliable to the synthesis of aurones using the simple Knoevenagel condensation approach. In order to avoid the time, expense, and lowered yields associated with flash column chromatography, we developed a scavenging approach for their synthesis. This method uses an excess of aldehyde to ensure complete conversion to aurones, followed by selective removal of the remaining aldehyde using a simple, inexpensive scavenger – isoniazid – and subsequent extraction with dilute acid, to produce the desired compounds with good purity under operationally simple conditions. This approach is expected to be applicable to many other reactions involving aldehydes as one of the reactants. [ABSTRACT FROM AUTHOR]

Increasing Fsp3 in drug molecules is of high importance in the pharmaceutical industry to escape the flatland. However, there is a lack of diverse methods to introduce C(sp3) into a molecule in library synthesis. In this work, we report the combination of continuous flow chemistry with photochemistry to create an automated platform for library synthesis using halogen atom transfer (XAT) reaction to increase Fsp3 in drug molecules. The chemistry has a broad scope of alkyl halides and electron deficient alkenes. We report a library synthesis of 84 compounds with a productivity of 1.5 reactions per hour, a scope of 51 isolated compounds and the reproducibility and scalability of the chemistry. Providing an efficient automated tool to synthesize drug‐like molecules with increased Fsp3 in drug discovery and development. [ABSTRACT FROM AUTHOR]

Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2‐O‐, 6‐O‐ and N‐sulfation with the glucosamine‐glucuronic acid‐glucosamine‐iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor‐2 binding but a weak affinity for platelet factor‐4. Such a strategy to separate out these two interactions could lead to new HS‐based potential therapeutics without the dangerous adverse effect of heparin‐induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Heparan sulfate (HS) plays important roles in many biological processes. The inherent complexity of naturally existing HS has severely hindered the thorough understanding of their structure‐activity relationship. To facilitate biological studies, a new strategy has been developed to synthesize a HS‐like pseudo‐hexasaccharide library, where HS disaccharides were linked in a "head‐to‐tail" fashion from the reducing end of a disaccharide module to the non‐reducing end of a neighboring module. Combinatorial syntheses of 27 HS‐like pseudo‐hexasaccharides were achieved. This new class of compounds bound with fibroblast growth factor 2 (FGF‐2) with similar structure‐activity trends as HS oligosaccharides bearing native glycosyl linkages. The ease of synthesis and the ability to mirror natural HS activity trends suggest that the new head‐to‐tail linked pseudo‐oligosaccharides could be an exciting tool to facilitate the understanding of HS biology. [ABSTRACT FROM AUTHOR]

Cholesterol transport proteins regulate a vast array of cellular processes including lipid metabolism, vesicular and non‐vesicular trafficking, organelle contact sites, and autophagy. Despite their undoubted importance, the identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol‐binding site. Herein we report a general strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of a diverse sterol‐inspired compound collection. Fusion of a primary sterol fragment to an array of secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster‐C, which displayed a surprising preference for the unnatural‐sterol AB‐ring stereochemistry and new inhibitors of Aster‐A. We propose that this strategy can and should be applied to any therapeutically relevant sterol‐binding protein. [ABSTRACT FROM AUTHOR]

• The updated ELF library is available for screening by academics, SMEs, and charities. • The library contains 300k compounds from pharma and 200k completely novel compounds. • The library can be screened in target-focused, target-agnostic, and HCI assays. Through the European Lead Factory model, industry-standard high-throughput screening and hit validation are made available to academia, small and medium-sized enterprises, charity organizations, patient foundations, and participating pharmaceutical companies. The compound collection used for screening is built from a unique diversity of sources. It brings together compounds from companies with different therapeutic area heritages and completely new compounds from library synthesis. This generates structural diversity and combines molecules with complementary physicochemical properties. In 2019, the screening library was updated to enable another 5 years of running innovative drug discovery projects. Here, we investigate the physicochemical and diversity properties of the updated compound collection. We show that it is highly diverse, drug-like, and complementary to commercial screening libraries. [ABSTRACT FROM AUTHOR]

Heparan sulfate (HS) is a linear, sulfated and highly negatively-charged polysaccharide that plays important roles in many biological events. As a member of the glycosaminoglycan (GAG) family, HS is commonly found on mammalian cell surfaces and within the extracellular matrix. The structural complexities of natural HS polysaccharides have hampered the comprehension of their biological functions and structure–activity relationships (SARs). Although the sulfation patterns and backbone structures of HS can be major determinants of their biological activities, obtaining significant amounts of pure HS from natural sources for comprehensive SAR studies is challenging. Chemical and enzyme-based synthesis can aid in the production of structurally well-defined HS oligosaccharides. In this review, we discuss recent innovations enabling the syntheses of large libraries of HS and how these libraries can provide insights into the structural preferences of various HS binding proteins. [Display omitted] • Heparan sulfate plays important roles in many biological events. • The activities of heparan sulfate can be critically dependent on its fine structure. • Comprehensive libraries of heparan sulfate tetrasaccharides have been assembled. • Structure activity relationship studies can be greatly aided by the large libraries. [ABSTRACT FROM AUTHOR]

[Display omitted] Codification of DNA Encoded Libraries (DELs) is critical for successful ligand identification of molecules that bind a protein of interest (POI). There are different encoding strategies that permit, for instance, the customization of a DEL for testing single or dual pharmacophores (single strand DNA) or for producing and screening large diversity libraries of small molecules (double strand DNA). Both approaches challenges, either from the synthetic and encoding point of view, or from the selection methodology to be utilized for the screening. The Head-Piece contains the DNA sequence that is attached to a chemical compound, allowing the encoding of each molecule with a unique DNA tag. Designing the Head-Piece for a DNA-encoded library involves careful consideration of several key aspects including DNA barcode identity, sequence length and attachment chemistry. Here we describe a double stranded DNA versatile Head-Piece that can be used for the generation of single or dual pharmacophore libraries, but also shows other advanced DEL functionalities, stability and enlarged encoding capacity. [ABSTRACT FROM AUTHOR]

Efficient access to diverse screening compounds with desirable, lead‐like properties can be a bottleneck in early drug discovery and chemical biology. Herein we present an efficient, rapid route to three structurally distinct classes of compounds (A–C) from a single precursor, which in turn is available through a one‐pot Petasis 3‐component reaction/Diels–Alder cascade reaction. We demonstrate the versatility of the approach through the synthesis of 35 exemplary compounds from the three classes, as well as by the production of 2188 final compounds, which have been included in the Joint European Compound Library of the European Lead Factory. An efficient and rapid route to three structurally distinct scaffolds (A–C) from a single precursor which in turn is available through a one‐pot Petasis 3‐component reaction/Diels–Alder cascade reaction. We demonstrate the versatility of the approach through the synthesis of 35 exemplary compounds from the three scaffolds, as well as by the production of 2188 final compounds, which have been included in the Joint European Compound Library of the European Lead Factory. [ABSTRACT FROM AUTHOR]

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate‐derived sulfinimine provides rapid access into a variety of enantiomerically pure α‐amino acids (>85 examples). Characterized by operational simplicity, this radical‐based reaction enables the modular assembly of exotic α‐amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high‐throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns. Acids to acids: A practical method for the preparation of highly valuable enantiomerically pure α‐amino acids has been developed. The described transformation rapidly converts feedstock alkyl carboxylic acids to α‐amino acids, and is enabled by innate radical cross‐coupling with a chiral imine radical acceptor. The scope of this transformation is broad and has been field‐tested in three different industrial medicinal chemistry laboratories. [ABSTRACT FROM AUTHOR]

A new effective strategy for the synthesis of sp3‐rich small molecules for library production is presented. The key steps to generate complexity involve a Petasis three‐component reaction followed by an intramolecular Diels–Alder and cyclization to generate a densely enriched tricyclic or tetracyclic scaffolds with 3–4 stereocenters and three handles for decoration. The strategy was used for the production of 143 molecules for the European Lead Factory. [ABSTRACT FROM AUTHOR]

Large, diverse compound libraries are an essential requisite in target-based drug development. In this work, a robust microwave-assisted synthesis for the diastereoselective generation of 3-saccharinyl- trans -β-lactams is reported. The method is optimised for combinatorial library synthesis in which decoration of the scaffold is varied on both the β-lactam and the saccharine moiety. Within the European Lead Factory (ELF) consortium, a library of 263 compounds was efficiently produced using the developed methodology. [ABSTRACT FROM AUTHOR]

Amphiphilic compounds are used in a variety of applications due to their lyotropic liquid-crystalline phase formation, however only a limited number of compounds, in a potentially limitless field, are currently in use. A library of organic amphiphilic compounds was synthesised consisting of glucose, galactose, lactose, xylose and mannose head groups and double and triple-chain hydrophobic tails. A modular, high-throughput approach was developed, whereby head and tail components were conjugated using the copper-catalysed azide–alkyne cycloaddition (CuAAC) reaction. The tails were synthesised from two core alkyne-tethered intermediates, which were subsequently functionalised with hydrocarbon chains varying in length and degree of unsaturation and branching, while the five sugar head groups were selected with ranging substitution patterns and anomeric linkages. A library of 80 amphiphiles was subsequently produced, using a 24-vial array, with the majority formed in very good to excellent yields. A preliminary assessment of the liquid-crystalline phase behaviour is also presented.

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated. [ABSTRACT FROM AUTHOR]

A new tandem strategy based on a Mannich/Pictet-Spengler sequence has been developed and applied to the synthesis of a new small library (14 examples) of privileged compounds based on the spiro[piperidine-pyridoindole] core. The sequence proceeds by a diastereoselective Pictet-Spengler cyclization after condensation of several tryptamine derivatives with three novel piperidin-4-ones containing the fluorinated substituents F, CF3 and SF5. The piperidin-4-ones were synthesized from readily available starting materials by an enantioselective multi-component organocatalytic Mannich reaction. [ABSTRACT FROM AUTHOR]

Analogues of the nicotinic acetylcholine antagonist epibatidine, suitable for diversification, were synthesized by application of a pyrrole Diels-Alder strategy, allowing rapid generation of azabicyclo[2.2.1]heptane bicyclic cores. Further molecular complexity could be accessed by using intramolecular Diels-Alder reactions, or ring expansion by ozonolysis-reductive amination chemistry. Scaffolds were designed such that they could be orthogonally deprotected, yielding three points of diversity for library synthesis, exemplified by 24 compounds synthesized from four cores. [ABSTRACT FROM AUTHOR]

A series of substituted diaryltriazoles was prepared by a solid-phase-synthesis protocol using a modified Wang resin. The copper(I)- or ruthenium(II)-catalyzed 1,3-cycloaddition on the polymer bead allowed a rapid synthesis of the target compounds in a parallel fashion with in many cases good to excellent yields. Substituted diaryltriazoles resemble a molecular structure similar to established terphenyl-alpha-helix peptide mimics and have therefore the potential to act as selective inhibitors for protein–protein interactions.

We prepared a series of peptide-like 14-membered macrocycles containing an imidazole-4,5-dicarboxylic acid scaffold by using known coupling reagents and protecting group strategies. Yields of the purified macrocycles were poor on average, yet seemingly independent of amino acid substitution or stereochemistry. The macrocycles retain some level of conformational variability as observed by both molecular modeling and X-ray crystallography. These macrocycles represent a new class of structures for further development and for future application in high-throughput screening against a variety of biological targets.

Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method that adapts flow chemistry to the synthesis of libraries of compounds using a fluorous immiscible solvent as a spacer between reactions. The methodology was validated in the synthesis of two small heterocycle containing libraries. The reactions were performed on a 0.2 mmol scale, enabling tens of milligrams of material to be generated in a single 200 mL reaction plug. The methodology allowed library synthesis in half the time of conventional microwave synthesis while maintaining similar yields. The ability to perform multiple, potentially unrelated reactions in a single run is ideal for making small quantities of many different compounds quickly and efficiently.

Hyaluronan (HA) plays important roles in a wide range of biological events. The principal receptor of HA in the human body is the Cluster of Differentiation 44 (CD44). To enhance the binding between HA and CD44, a new approach was designed to take advantage of the four-component Ugi reaction. By modifying the carboxyl group on HA with various amine, aldehyde, and isocyanide moieties through the Ugi reaction, 36 HA like polysaccharides were generated. Two lead compounds were identified with enhanced CD44 binding compared to unmodified HA, which was confirmed by surface plasmon resonance (SPR), cellular studies and an in vivo mouse tumor model. Ski-learn as a machine learning tool was applied to analyze library data and yield predictions with an accuracy over 80 %. In conclusion, modification of HA via the Ugi reaction can be a promising strategy to develop novel binders toward HA receptors such as CD44. [Display omitted] • A library of hyaluronan derivatives was synthesized through the Ugi reaction. • New hyaluronan derivatives with enhanced CD44 binding were discovered. • Machine learning algorithms were applied to analyze CD44 binding data. [ABSTRACT FROM AUTHOR]

Frontispiece: Synthesis of a Systematic 64-Membered Heparan Sulfate Tetrasaccharide Library Keywords: biological activity; carbohydrates; heparan sulfate; library synthesis; oligosaccharides EN biological activity carbohydrates heparan sulfate library synthesis oligosaccharides 1 1 1 01/02/23 20230102 NES 230102 B Carbohydrates b . In their Research Article (e202211985), Xuefei Huang et al. report the synthesis of a systemic 64-membered heparan sulfate tetrasaccharide library. [Extracted from the article]

A 'top down' scaffold remodelling approach to library synthesis was applied to spirotricyclic ureas prepared by a complexity-generating oxidative dearomatisation. Eighteen structurally-distinct, sp 3 -rich scaffolds were accessed from the parent tricycle through ring addition, cleavage and expansion strategies. Biological screening of a small compound library based on these scaffolds using the cell-painting assay demonstrated distinctive phenotypic responses engendered by different library members, illustrating the functional as well as structural diversity of the compounds., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

With the developments in high performance chromatography and mass spectrometry, the analysis of complex mixtures of closely related triacylglycerols has come within reach. Currently, however, the availability of chemically pure triacylglycerols is limited, mainly due to the lack of efficient synthetic methods that allow their synthesis. Here, we report an efficient and operationally simple three-step synthesis of enantiopure triacylglycerols with yields ranging from 79 to 92%, that tolerates a broad range of saturated and unsaturated fatty acids. Furthermore, we developed an automated protocol, which might greatly facilitate the synthesis of triacylglycerol libraries. Practical applications: The analysis of the composition of milk fat and as analytical standards in lipidomics. An efficient three-step synthesis of enantiopure triacylglycerols with yields ranging from 79 to 92% is reported. This is accompanied by an automated protocol for triacylglycerol synthesis. [ABSTRACT FROM AUTHOR]

A novel methodology for the synthesis and purification of drug-like compound libraries has been developed through the use of a microwave reactor with an integrated high-performance liquid chromatography–mass spectrometry (HPLC-MS) system. The strategy uses a fully automated synthesizer with a microwave as energy source and robotic components for weighing and dispensing of solid reagents, handling liquid reagents, capper/crimper of microwave reaction tube assemblies, and transportation. Crude reaction products were filtered through solid-phase extraction cartridges and injected directly onto a reverse-phase chromatography column via an injection valve. For multistep synthesis, crude products were passed through scavenger resins and reintroduced for subsequent reactions. All synthetic and purification steps were conducted under full automation with no handling or isolation of intermediates, to afford the desired purified products. This approach opens the way to highly efficient generation of drug-like compounds as part of a lead discovery strategy or within a lead optimization program. [ABSTRACT FROM AUTHOR]

Within this work we telescoped a batch laboratory scale synthesis towards a two-step-one-flow process to synthesize cardiomyogenesis inducing compounds (4,6-diaminopyrimidines) in continuous manner. Special attention was put on a quick and robust screening protocol and subsequent UHPLC analysis. Finally, the robustness of the method was proven by the multi-gram synthesis of VUT-MK142 using a laboratory scale continuous flow reactor, enabling to deliver enough material for extensive biological testing. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The Ritter-type reaction of arylnitriles and N-acyliminium ions generated in situ from dihydroxy-γ-lactams gave tetrahydropyrrolo[2,3- d]oxazol-5-ones in excellent yields. A subsequent acidic hydrolysis in EtOH/H2O/TFA (trifluoroacetic acid) yielded new (arylamido)pyrrolidinones with excellent cis diastereoselectivity. A combined one-step Ritter-hydrolysis procedure proved to be of equal efficiency. This versatile method, which was successfully used for the construction of a screening library containing 706 molecules within the European Lead Factory consortium, provides a simple way to access new compounds incorporating an arylamido and a pyrrolidinone moiety, both of which are widely found in marketed drugs and in biologically active molecules. [ABSTRACT FROM AUTHOR]

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuousflow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles. [ABSTRACT FROM AUTHOR]

A platform that incorporates computational library design, parallel solution-phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120-member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times. [ABSTRACT FROM AUTHOR]

1,3,5-Triazine derivatives have widespread applications in the pharmaceutical, material, and agrochemical industries. In the biological arena, small-molecule libraries of 2,4,6-trisubstituted 1,3,5-triazines have yielded selective and potent chemical probes for diverse protein families. The structural symmetry and ease of functionalization of the 1,3,5-triazine core renders it a powerful scaffold for the rapid generation of diverse molecular libraries. Numerous synthetic routes, both solid-phase and solution-phase, have been developed to arrive at alkyl/aryl amino- and oxy-substituted triazine libraries. Here, we feature a subset of the recent synthetic advances towards generating 2,4,6-trisubstituted 1,3,5-triazines and highlight biologically active compounds that have resulted from these endeavors. [ABSTRACT FROM AUTHOR]

Abstract: In this study we present the design, synthesis and biological evaluation of a small, first-generation library of small molecule aromatic amides based on the arylopeptoid skeleton. The compounds were efficiently synthesized using a highly convenient submonomer solid-phase methodology which potentially allows for access to great product diversity. The synthesized compounds were tested for their ability to activate peroxisome proliferator-activated receptors (PPARs) and they all acted as PPARγ agonists in the μM range spanning from 2.5- to 14.7-fold activation of the receptor. This is the first discovery of bioactive molecules based on the arylopeptoid architecture. [Copyright &y& Elsevier]

Novel $$N$$-alkyl-2-(alkylthio)-1 $$H$$-imidazole derivatives were synthesized in a single step by an efficient and simple method in high yields. Readily available starting materials, mild reaction conditions, operational simplicity and novelty are the key advantages of this method. Besides their novel structures, these compounds may have important biological activities and industrial applications. [ABSTRACT FROM AUTHOR]

Abstract: The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A3 adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K i on A3 AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A3AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure–activity and structure–selectivity relationships in this series. [Copyright &y& Elsevier]

A novel methodology for the synthesis of druglike heterocycle libraries has been developed through the use of flow reactor technology. The strategy employs orthogonal modification of a heterocyclic core, which is generated in situ, and was used to construct both a 25-membered library of druglike 3-aminoindolizines, and selected examples of a 100-member virtual library. This general protocol allows a broad range of acylation, alkylation and sulfonamidation reactions to be performed in conjunction with a tandem Sonogashira coupling/cycloisomerization sequence. All three synthetic steps were conducted under full automation in the flow reactor, with no handling or isolation of intermediates, to afford the desired products in good yields. This fully automated, multistep flow approach opens the way to highly efficient generation of druglike heterocyclic systems as part of a lead discovery strategy or within a lead optimization program. [ABSTRACT FROM AUTHOR]

A sub-library of 88 information-rich lead-like purine derivatives were prepared and deposited in an open access academic screening facility. The rationale for the synthesis of these rigid low complexity structures was the privileged character of the purine heterocycle associated with its inherent probability of interactions with multiple adenine-related targets. Although generally expected to be weak binders in many assays, such fragment-like compounds are estimated to match diverse binding sites. It is suggested that heterocycles with many anchor points for hydrogen bonds can be anticipated to undergo very specific interactions to produce more negative enthalpies and thus provide superior starting points for lead optimization than compounds that owe their activity to entropic effects. The in vitro cytotoxicity of the small compounds on a panel of human cancer cell lines has been investigated and some of them showed marked unselective or selective toxicity. This data may be useful if these fragments are to be incorporated into drug-like structures via metabolically cleavable connections. The sub-library will be implemented as part of the ChemBioNet () library, and it is open to screening campaigns of academic research groups striving for a fragment-based approach in their biological assays. [ABSTRACT FROM AUTHOR]

We prepared a series of peptide-like 14-membered macrocycles containing an imidazole-4,5-dicarboxylic acid scaffold by using known coupling reagents and protecting group strategies. Yields of the purified macrocycles were poor on average, yet seemingly independent of amino acid substitution or stereochemistry. The macrocycles retain some level of conformational variability as observed by both molecular modeling and X-ray crystallography. These macrocycles represent a new class of structures for further development and for future application in high-throughput screening against a variety of biological targets. [ABSTRACT FROM AUTHOR]

Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method that adapts flow chemistry to the synthesis of libraries of compounds using a fluorous immiscible solvent as a spacer between reactions. The methodology was validated in the synthesis of two small heterocycle containing libraries. The reactions were performed on a 0.2 mmol scale, enabling tens of milligrams of material to be generated in a single 200 μL reaction plug. The methodology allowed library synthesis in half the time of conventional microwave synthesis while maintaining similar yields. The ability to perform multiple, potentially unrelated reactions in a single run is ideal for making small quantities of many different compounds quickly and efficiently. [ABSTRACT FROM AUTHOR]

Abstract: An efficient protocol for the one-pot preparation of alkyl 3-aryl-5-methylisoxazole-4-carboxylates from aryl aldehydes is described. This method is readily amenable to the large scale preparation of isoxazoles as well as the parallel synthesis of isoxazole libraries. [Copyright &y& Elsevier]

Abstract: An efficient and rapid on-bead screening method was established to identify non-natural peptides that target the Androgen Receptor–cofactor interaction. Binding of the Androgen Receptor ligand binding domain to peptide sequences displayed on beads in a One-Bead-One-Compound format could be screened using fluorescence microscopy. The method was applied to generate and screen both a focussed and a random peptide library. Resynthesis of the peptide hits allowed for the verification of the affinity of the selected peptides for the Androgen Receptor in a competitive fluorescence polarization assay. For both libraries strong Androgen Receptor binding peptides were found, both with non-natural and natural amino acids. The peptides identified with natural amino acids showed great similarity in terms of preferred amino acid sequence with peptides previously isolated from biological screens, thus validating the screening approach. The non-natural peptides featured important novel chemical transformations on the relevant hydrophobic amino acid positions interacting with the Androgen Receptor. This screening approach expands the molecular diversity of peptide inhibitors for nuclear receptors. [ABSTRACT FROM AUTHOR]

Abstract: Dysregulated antigen receptor-mediated NF-κB activation can contribute to development of autoimmunity, chronic inflammation, and malignancy. A chemical biology screening strategy has identified a substituted benzimidazole that selectively inhibits antigen receptor-mediated NF-κB activation without blocking other NF-κB activation pathways. A library of analogs was synthesized and the structure–activity relationship and metabolic stability for the series is presented. [Copyright &y& Elsevier]

Abstract: A series of novel 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines is synthesized through the chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]-pyrimidin-4-ones, followed by the nucleophilic displacement of the 4-Cl group of 9, with a variety of anilines. All four steps of this synthesis involve microwave irradiation (MWI) and the entire synthesis requires only 2h. [Copyright &y& Elsevier]

Abstract: A new small molecule inhibitor of bacterial cell division has been discovered using a high-throughput screen in Escherichia coli. Although the lead screening hit (534F6) exhibited modest inhibition of the GTPase activity of FtsZ (20±5% at 100μM of compound), a primary target for bacterial cell division inhibitors, several analogs caused potent bacterial growth inhibition with negligible antagonism of FtsZ GTPase activity. A library of analogs has been prepared and several alkyne-tagged photoaffinity probes have been synthesized for use in experiments to elucidate the primary target of this compound. [Copyright &y& Elsevier]

Abstract: Mechanistic investigations into the multi-component synthesis of pyridine-3,5-dicarbonitriles have established a defined reaction pathway, particularly clarifying the role of aerobic oxidation in conversion of the intermediate 1,4-dihydropyridines into the final products. Based on such improved understanding of the reaction mechanism, optimised conditions for the preparation of compound libraries based on this core structure have been developed and represent a significant improvement in yield over existing protocols. Particularly, microwave assisted synthesis was found to provide a procedure suitable for high-throughput synthesis of pyridine-3,5-dicarbonitrile libraries. [Copyright &y& Elsevier]

A 30-membered library of coumarins has been synthesized in a microwave-assisted Pechmann reaction using neat trifluoroacetic acid both as an acidic reagent and a reaction medium. Alternatively, polymer-supported sulfonic acid Amberlyst-15 could also be employed to facilitate the formation of coumarins. The use of a specially-built microwave synthesizer with liquid handling tools rendered the automated synthesis of a coumarin library feasible. [ABSTRACT FROM AUTHOR]

Abstract: A 30-membered library of amides based on the potent urotensin II (UII) receptor agonist FL104, has been synthesized from ten different carboxylic acids and three amines. A synthetic protocol producing the amides in 47–98% yield has been developed in which the purification involved only extractions and in a few cases filtration through an ion-exchange resin. It was found that 5mg of starting material was enough to obtain reproducible results and excellent purities. Thus, the procedure is estimated to be transferable to fully automated systems. The synthesized compounds were evaluated for their UII receptor agonistic activities using a cell-based assay (R-SAT). The most active compounds were the 4-trifluoromethylcinnamic amides of 1-(4-chlorophenyl)-3-dimethylamino-propylamine and 1-(2-naphthyl)-3-dimethylamino-propylamine, both showed EC50 values of 130nM. [Copyright &y& Elsevier]

Mitogen-activated protein kinase phosphatase 1 is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates mitogen-activated protein kinase substrates, such as p38, c-Jun-N-terminal kinase, and extracellular signal-related kinase. These mitogen-activated protein kinase substrates regulate many cellular processes associated with human diseases. In spite of this potential as a molecular target for chemotherapy, however, pharmacologically tractable inhibitors of mitogen-activated protein kinase phosphatase-1 have yet to be developed. Based on the results from a high-throughput screen for small molecule inhibitors of mitogen-activated protein kinase phosphatase-1, we designed, synthesized, and evaluated a focused library in an effort to further understand the structural requirements for mitogen-activated protein kinase phosphatase-1 inhibitory activity. [ABSTRACT FROM AUTHOR]