Synthesis Of Library Research Articles

Development of the Inverse Sonogashira Reaction for DEL Synthesis.

An efficient approach for aryl acetylene DNA-encoded library (DEL) synthesis was developed in this study by transition-metal-mediated inverse Sonogashira reaction of 1-iodoalkyne with boronic acid under ambient conditions, with moderate to excellent conversions and broad substrate adaptability for the first time. Compared to palladium-phosphine, copper iodide performed better in the on-DNA inverse Sonogashira reaction. Interestingly, substrate diversity can be enhanced by first interrogating coupling reagents under copper-promoted conditions, and then revalidating them under palladium-facilitated conditions for those reagents which failed under the former. This complementary validation strategy is particularly well-fitted to any DEL validation studies.

Intervention Programs for First-Episode Psychosis: A Scoping Review Protocol.

Early intervention programs for first-episode psychosis aim to intervene in the early stages of the disease. They are essential to prevent and delay the progression of the illness to a more advanced stage, but information about their characteristics is not systematized. The scoping review considered all studies of first-episode psychosis intervention programs, regardless of their context (hospital or community), and explored their characteristics. The scoping review was developed according to the Joanna Briggs Institute methodology and PRISMA-ScR guidelines. The PCC mnemonic (population, concept, and context) addressed research questions, the inclusion and exclusion criteria, and the search strategy. The scoping review sought to identify the literature that meets the predefined inclusion criteria. The research was conducted in the following databases: Web of Science Core Collection, MEDLINE, CINAHL Complete and PsycINFO, Scopus, Cochrane Library, and JBI Evidence Synthesis. The search for unpublished studies included OpenGrey (a European repository) and MedNar. It used sources in English, Portuguese, Spanish, and French. It included quantitative, qualitative, and multi-method/mixed methods studies. It also considered gray or unpublished literature. After removing duplicates, two independent reviewers extracted the relevant information after selecting the articles. If there were disagreements, a third reviewer was used. The researchers have developed a tool based on the JBI model that will allow them to extract the relevant information for the review. The results are presented schematically in narratives and tables. This scoping review maps first-episode psychosis intervention programs by identifying their characteristics, participants, and specific implementation contexts and allows researchers to create multicomponent programs tailored to different contexts.

Translating the Genome into Drugs.

The Human Genome Project ultimately aimed to translate DNA sequence into drugs. With the draft in hand, the Molecular Libraries Program set out to prosecute all genome-encoded proteins for drug discovery with automated high-throughput screening (HTS). This ambitious vision remains unfulfilled, even while innovations in sequencing technology have fully democratized access to genome-scale sequencing. Why? While the central dogma of biology allows us to chart the entirety of cellular metabolism through sequencing, there is no direct coding for chemistry. The rules of base pairing that relate DNA gene to RNA transcript and amino acid sequence do not exist for relating small-molecule structure with macromolecular binding partners and subsequently cellular function. Obtaining such relationships genome-wide is unapproachable via state-of-the-art HTS, akin to attempting genome-wide association studies using turn-of-the-millennium Sanger DNA sequencing.Our laboratory has been engaged in a multipronged technology development campaign to revolutionize molecular screening through miniaturization in pursuit of genome-scale drug discovery capabilities. The compound library was ripe for miniaturization: it clearly needed to become a consumable. We employed DNA-encoded library (DEL) synthesis principles in the development of solid-phase DELs prepared on microscopic beads, each harboring 100 fmol of a single library member and a DNA tag whose sequence describes the structure of the library member. Loading these DEL beads into 100 pL microfluidic droplets followed by online photocleavage, incubation, fluorescence-activated droplet sorting, and DNA sequencing of the sorted DEL beads reveals the chemical structures of bioactive compounds. This scalable library synthesis and screening platform has proven useful in several proof-of-concept projects involving current clinical targets.Moving forward, we face the problem of druggability and proteome-scale assay development. Developing biochemical or cellular assays for all genome-encoded targets is not scalable and likely impossible as most proteins have ill-defined or unknown activity and may not function outside of their native contexts. These are the dark undruggable expanses, and charting them will require advanced synthesis and analytical technologies that can generalize probe discovery, irrespective of mature protein function, to fulfill the Genome Project's vision of proteome-wide control of cellular pharmacology.

Coordination‐Precipitation Synthesis of Metal Sulfide with Phase Transformation Enhanced Reactivity against Antibiotic‐Resistant Bacteria

AbstractGiven the challenge of bacterial resistance to antibiotics, there is an urgent need to develop alternative antibacterial agents. While some metal sulfides are promising candidates against bacterial resistance, their fundamental mechanism of action (MoA) remains unclear. Herein, a “coordination‐precipitation” method is developed for the synthesis of a metal sulfide library and the evaluation of antibacterial consistency. Employing ethylenediamine as a coordination agent and thioglycolic acid as a precipitation agent, 12 different metal sulfide nanocrystals following the same procedure are synthesized. Antibacterial assessment reveals that six metal sulfides with bactericidal potency perform a common feature of phase transformation. In particular, in the process of manganese sulfide (MnS) transformation to Mn3O4, a highly reactive complex of high‐valance manganese (Mn3+) and polysulfide (S32−) accompanied by superoxide is sustainably generated, which synergistically induces bacterial death with a hallmark of lipid peroxidation (named liperoptosis) specifically toward Gram‐positive Staphylococcus aureus (S. aureus). In addition, this MoA confers MnS with therapeutic effects superior to vancomycin in a methicillin‐resistant S. aureus‐infected skin wound model. This study reveals the correlation between phase transformation and the antibacterial MoA of metal sulfides and provides a general fundamental to design a non‐antibiotic antibacterial candidate against bacterial resistance.

Water‐Assisted Passerini Reactions under Mechanochemical Activation: A Simple and Straightforward Access to Oxindole Derivatives

AbstractA protocol based on the Passerini Multi‐Component reaction (MCR) has been developed for facile, efficient, environmentally benign and atom economical synthesis of a small library of biologically important oxindole derivatives employing isatin, benzoic acid and substituted isocyanides. In contrast to the conventional approach, which requires the use of toxic organic solvents, Passerini reactions were completed in 10–15 minutes under mechanochemical conditions with excellent yields. The protocol described below allows the modular synthesis of diverse compounds under green chemistry principles, specifically in favourable environmental conditions, with great atom economy, shorter reaction time, cleaner reactions with improved yields, and experimental simplicity.

Development of an Automated Platform for C(sp3)−C(sp3) Bond Formation via XAT Chemistry

AbstractIncreasing 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.

Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis.

DNA-encoded library technology (DELT) is a new screening modality that allows efficient, cost-effective, and rapid identification of small molecules with potential biological activity. This emerging technique represents an enormous advancement that, in combination with other technologies such as high-throughput screening (HTS), fragment-based lead generation, and structure-based drug design, has the potential to transform how drug discovery is carried out. DELT is a hybrid technique in which chemically synthesized compounds are linked to unique genetic tags (or "barcodes") that contain readable information. In this way, millions to billions of building blocks (BBs) attached on-DNA via split-and-pool synthesis can be evaluated against a biological target in a single experiment. Polymerase chain reaction (PCR) amplification and next-generation sequencing (NGS) analysis of the unique sequence of oligonucleotides in the DNA tag are used to identify those ligands with high affinity for the target. This innovative fusion of genetic and chemical technologies was conceived in 1992 by Brenner and Lerner (Proc. Natl. Acad. Sci. 1992, 89, 5381-5383) and is under accelerated development with the implementation of new synthetic techniques and protocols that are compatible with DNA. In fact, reaction compatibility is a key parameter to increasing the chances of identification of a drug target ligand, and a central focus has been the development of new transformations and the transition to robust protocols for on-DNA synthesis. Because the sole use of the DNA tag is as an amplifiable identification barcode, its structural integrity during a new chemical process is mandatory. As such, the use of these sensitive, polyfunctional biological molecules as substrates typically requires aqueous solutions within defined pH and temperature ranges, which is considered a notable challenge in DEL synthesis.Using low-energy visible light as the driving force to promote chemical transformations represents an attractive alternative to classical synthetic methods, and it is an important and well-established synthetic tool for forging chemical bonds in a unique way via radical intermediates. Recent advances in the field of photocatalysis are extraordinary, and this powerful research arena is still under continuous development. Several applications taking advantage of the mild reaction conditions of photoinduced transformations have been directed toward DEL synthesis, allowing the expansion of chemical space available for the evaluation of new building blocks on-DNA. There are no doubts that visible-light-driven reactions have become one of the most powerful approaches for DELT, given the easy way they provide to construct new bonds and the challenges to achieve equal success via classical protocols.Key characteristics of photocatalytic synthesis include the short reaction times and efficiency, which translate into retention of DNA integrity. In this Account, we describe recent advances in the photoinduced diversification of building blocks prepared on-DNA, highlighting the amenability of the techniques employed for preserving the genetic structure of the molecules. We demonstrate with recent research from our group the applicability of photocatalysis to the field and include in the summary a table containing all the photoinduced methods reported to date for DELT, demonstrating their key aspects such as scope, applications, and DNA compatibilities. With this information, practitioners are provided with compelling reasons for developing/choosing photocatalytic methods for DELT applications.

Merging Photoinduced Iron-Catalyzed Decarboxylation with Copper Catalysis for C–N and C–C Couplings

We report a photoinduced iron/copper dual-catalytic strategy for the radical decarboxylation functionalization of aliphatic carboxylic acids. The photoinduced ligand-to-iron charge transfer process under light was initially occurred to generate an unstabilized alkyl radical, and the copper catalyst delivered the radical and enabled the subsequent coupling reactions to form C–N or C–C bonds. By merging iron-catalyzed decarboxylation with copper catalysis, this system allows the smooth conversion of a wide range of aliphatic carboxylic acids for the amination, decarboxylative dehydrogenation, and alkylation efficiently. A wide variety of complex drug or natural molecules is applicable, suggesting that this strategy would facilitate rapid compound library synthesis and benefit to the discovery of pharmaceutical agents.

Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase.

One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a-e, 10a-c and 12a-c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (-9.900 and -9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 μM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 μM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer.

C-C Coupling through Nitrogen Deletion: Application to Library Synthesis.

Invited for the cover of this issue are Oleksandr Grygorenko and his Ukrainian colleagues at Enamine Ltd., Taras Shevchenko National University of Kyiv, National Academy of Sciences of Ukraine, and ChemSpace, as well as Mark Levin at the University of Chicago. The image depicts application of a nitrogen-deleting anomeric amide to parallel C(sp3 )-C(sp3 ) coupling. Read the full text of the article at 10.1002/chem.202203470.

Designing polymers for cartilage uptake: effects of architecture and molar mass.

Osteoarthritis (OA) is a progressive disease, involving the progressive breakdown of cartilage, as well as changes to the synovium and bone. There are currently no disease-modifying treatments available clinically. An increasing understanding of the disease pathophysiology is leading to new potential therapeutics, but improved approaches are needed to deliver these drugs, particularly to cartilage tissue, which is avascular and contains a dense matrix of collagens and negatively charged aggrecan proteoglycans. Cationic delivery vehicles have been shown to effectively penetrate cartilage, but these studies have thus far largely focused on proteins or nanoparticles, and the effects of macromolecular architectures have not yet been explored. Described here is the synthesis of a small library of polycations composed of N-(2-hydroxypropyl)methacrylamide (HPMA) and N-(3-aminopropyl)methacrylamide (APMA) with linear, 4-arm, or 8-arm structures and varying degrees of polymerization (DP) by reversible addition fragmentation chain-transfer (RAFT) polymerization. Uptake and retention of the polycations in bovine articular cartilage was assessed. While all polycations penetrated cartilage, uptake and retention generally increased with DP before decreasing for the highest DP. In addition, uptake and retention were higher for the linear polycations compared to the 4-arm and 8-arm polycations. In general, the polycations were well tolerated by bovine chondrocytes, but the highest DP polycations imparted greater cytotoxicity. Overall, this study reveals that linear polymer architectures may be more favorable for binding to the cartilage matrix and that the DP can be tuned to maximize uptake while minimizing cytotoxicity.

A review on high-throughput development of high-entropy alloys by combinatorial methods

High-entropy alloys (HEAs) are an emerging class of alloys with multi-principal elements that greatly expands the compositional space for advanced alloy design. Besides chemistry, processing history can also affect the phase and microstructure formation in HEAs. The number of possible alloy compositions and processing paths gives rise to enormous material design space, which makes it challenging to explore by traditional trial-and-error approaches. This review highlights the progress in combinatorial high-throughput studies towards rapid prediction, manufacturing, and characterization of promising HEA compositions. This review begins with an introduction to HEAs and their unique properties. Then, this review describes high-throughput computational methods such as machine learning that can predict desired alloy compositions from hundreds or even thousands of candidates. The next section of this review presents advances in combinatorial synthesis of material libraries by additive manufacturing for efficient development of high-performance HEAs at bulk scale. The final section of this review discusses the high-throughput characterization techniques that are used to accelerate the material property measurements for systematic understanding of the composition-processing-structure-property relationships in combinatorial HEA libraries.

Exploiting α-benzylated 1,4-butanesultones to expedite the discovery of small-molecule, LCST-type sulfobetaine zwitterionic materials

We report the concise synthesis and discovery of a small library of 16 small-molecule sulfobetaine zwitterionic materials that exhibit LCST phase transitions in water.

Small RNA Profiling by Next-Generation Sequencing Using High-Definition Adapters.

Next-generation sequencing (NGS) of small RNA (sRNA) cDNA libraries permits the identification and characterization of sRNA species de novo. However, the method through which these libraries are constructed can often introduce artifacts such as over- or underrepresentation of specific sequences or adapter oligonucleotides due to sequence biases held by the enzymes used. In this chapter we describe a protocol for sRNA library construction making use of high-definition (HD) adapters for the Illumina sequencing platform, which reduce ligation bias. This protocol leads to drastically reduced direct 5'/3' adapter ligation products and can be used for the synthesis of sRNA libraries from total RNA or sRNA of various plant, animal, and fungal samples. This protocol also includes a method for total RNA extraction from plant leaf and cultured cells or body fluids.

Design of an aryne-platform for the synthesis of non-racemic heterocyclic allocolchicinoids.

A four-step semisynthetic approach towards a highly versatile allocolchicine-related chiral aryne intermediate starting from naturally occurring colchicine was developed, and some of its synthetic transformations were studied. The in situ generated benzyne intermediate afforded a number of non-racemic heterocyclic allocolchicinoids, which were shown to exhibit potent cytotoxicity towards COLO 357, OSA and Raji cells. The proposed methodology is attractive for the synthesis of libraries of new cytotoxic tubulin inhibitors.

Repurposing amine and carboxylic acid building blocks with an automatable esterification reaction.

New methodologies to unite amines and carboxylic acids that complement the popular amide coupling can significantly expand accessible chemical space if they yield products distinct from the classic R-NHC(O)-R' amide arrangement. Here we have developed an amine-acid esterification reaction based on pyridinium salt activation of amine C-N bonds to create products of type R-OC(O)-R' upon reaction with alkyl and aryl carboxylic acids. The protocol is robust and facile as demonstrated by automation on open-source robotics.

Development of a two-phase flow reaction system for DNA-encoded amide coupling

Synthesis platforms are of particular interest to DNA-encoded library (DEL) technologies to facilitate chemistry development, building block validation, and high-throughput library synthesis.

The N-(2,4-diarylthiazol-5-yl)benzamidines library creation and the effect of this compounds on cancer cell growth

A versatile and efficient protocol for the synthesis of library of N-(2,4-diarylthiazol-5-yl)benzamidines is described. We obtained a library of 25 diversity with different of substituents in four positions in key framework. The synthesized amidine derivatives were evaluated for their in vitro anticancer activity. Analysis of anticancer activity on 60 cancer cell lines showed a decrease of proliferation of Colon Cancer and Leukemia cell lines by more than half and allowed to establish the structure-activity relationship

Front Cover: C−C Coupling through Nitrogen Deletion: Application to Library Synthesis (Chem. Eur. J. 4/2023)

Front Cover: C−C Coupling through Nitrogen Deletion: Application to Library Synthesis (Chem. Eur. J. 4/2023)

C-C Coupling through Nitrogen Deletion: Application to Library Synthesis.

A protocol for parallel C(sp3 )-C(sp3 ) coupling of (hetero)aromatic aldehydes and (hetero)arylmethyl amines based on a reductive amination - "nitrogen deletion" reaction sequence has been developed. After preliminary validation experiments, an illustrative compound library of 25 members was prepared with 76 % synthetic efficiency. The estimated chemical space accessible by the proposed approach covers almost 600 000 representatives that are scarcely represented in current compound databases.