Synthesis Of Chemical Libraries Research Articles

Diversity-Oriented Synthesis of Macrocycle Libraries for Drug Discovery and Chemical Biology

The identification of new bioactive small molecules is increasingly reliant upon the synthesis and screening of chemical libraries. The extent of structural diversity and the proportion of unique scaffolds in a library are commonly acknowledged to be the most important factors in determining its success in identifying new biologically relevant compounds. Particularly important in this respect are macrocycles, which display unique physicochemical attributes and are used in many clinical applications. Despite these advantages, macrocycles remain under-represented in many contemporary screening collections, predominantly due to their synthetic intractability. Diversity-oriented­ synthesis is a powerful method for the construction of deliberately diverse collections of small molecules, and many research groups are working to apply its principles to the synthesis of structurally and functionally diverse macrocyclic libraries. In this short review we introduce why macrocycles are promising chemotypes in screening libraries, especially for challenging biological targets such as protein–protein interactions, and we review a collection of strategies developed in our laboratory for the diversity-oriented synthesis of macrocycle libraries. We analyse a selection of the macrocycle collections generated using these approaches and conclude with our perspective on future directions of the field. 1 Introduction 1.1 Chemical Libraries in Drug Discovery and Chemical Biology 1.2 Macrocycles in Screening Collections 1.3 Diversity-Oriented Synthesis 2 Build/Couple/Pair 2.1 Strategy Overview 2.2 Typical B/C/P Strategies 2.3 Advanced B/C/P Strategies 2.4 Two-Directional Synthesis 3 Alternative Approaches to Macrocycle Library Synthesis 4 Discussion and Concluding Remarks

Systematic evaluation and optimization of modification reactions of oligonucleotides with amines and carboxylic acids for the synthesis of DNA-encoded chemical libraries.

DNA-encoded chemical libraries are collections of small molecules, attached to DNA fragments serving as identification barcodes, which can be screened against multiple protein targets, thus facilitating the drug discovery process. The preparation of large DNA-encoded chemical libraries crucially depends on the availability of robust synthetic methods, which enable the efficient conjugation to oligonucleotides of structurally diverse building blocks, sharing a common reactive group. Reactions of DNA derivatives with amines and/or carboxylic acids are particularly attractive for the synthesis of encoded libraries, in view of the very large number of building blocks that are commercially available. However, systematic studies on these reactions in the presence of DNA have not been reported so far. We first investigated conditions for the coupling of primary amines to oligonucleotides, using either a nucleophilic attack on chloroacetamide derivatives or a reductive amination on aldehyde-modified DNA. While both methods could be used for the production of secondary amines, the reductive amination approach was generally associated with higher yields and better purity. In a second endeavor, we optimized conditions for the coupling of a diverse set of 501 carboxylic acids to DNA derivatives, carrying primary and secondary amine functions. The coupling efficiency was generally higher for primary amines, compared to secondary amine substituents, but varied considerably depending on the structure of the acids and on the synthetic methods used. Optimal reaction conditions could be found for certain sets of compounds (with conversions >80%), but multiple reaction schemes are needed when assembling large libraries with highly diverse building blocks. The reactions and experimental conditions presented in this article should facilitate the synthesis of future DNA-encoded chemical libraries, while outlining the synthetic challenges that remain to be overcome.

Continuous recycling of homogeneous Pd/Cu catalysts for cross-coupling reactions.

Given the importance of homogeneous catalysts recycling in organic chemistry, we have developed a unique microfluidic loop system for automated continuous recirculation of a soluble polymer supported metal catalyst for novel isocyanide cross-coupling reactions under thermomorphic multicomponent solvent (TMS) conditions. Our system provides an innovative approach for the chemical library synthesis of quinazolinone derivatives as well as an important intermediate of Merck's LTD4 antagonist "Singulair" with efficient continuous homogeneous catalyst recycling.

DNA-Encoded Chemical Libraries: Advancing beyond Conventional Small-Molecule Libraries

DNA-encoded chemical libraries (DECLs) represent a promising tool in drug discovery. DECL technology allows the synthesis and screening of chemical libraries of unprecedented size at moderate costs. In analogy to phage-display technology, where large antibody libraries are displayed on the surface of filamentous phage and are genetically encoded in the phage genome, DECLs feature the display of individual small organic chemical moieties on DNA fragments serving as amplifiable identification barcodes. The DNA-tag facilitates the synthesis and allows the simultaneous screening of very large sets of compounds (up to billions of molecules), because the hit compounds can easily be identified and quantified by PCR-amplification of the DNA-barcode followed by high-throughput DNA sequencing. Several approaches have been used to generate DECLs, differing both in the methods used for library encoding and for the combinatorial assembly of chemical moieties. For example, DECLs can be used for fragment-based drug discovery, displaying a single molecule on DNA or two chemical moieties at the extremities of complementary DNA strands. DECLs can vary substantially in the chemical structures and the library size. While ultralarge libraries containing billions of compounds have been reported containing four or more sets of building blocks, also smaller libraries have been shown to be efficient for ligand discovery. In general, it has been found that the overall library size is a poor predictor for library performance and that the number and diversity of the building blocks are rather important indicators. Smaller libraries consisting of two to three sets of building blocks better fulfill the criteria of drug-likeness and often have higher quality. In this Account, we present advances in the DECL field from proof-of-principle studies to practical applications for drug discovery, both in industry and in academia. DECL technology can yield specific binders to a variety of target proteins and is likely to become a standard tool for pharmaceutical hit discovery, lead expansion, and Chemical Biology research. The introduction of new methodologies for library encoding and for compound synthesis in the presence of DNA is an exciting research field and will crucially contribute to the performance and the propagation of the technology.

Chiral Bicyclic Tetramates as Non‐Planar Templates for Chemical Library Synthesis

Chemoselective Dieckmann cyclization reactions may be used on oxazolidine and thiazolidine templates derived from various aldehydes to access bicyclic tetramates, which have potential as templates for chemical library construction. Bioassay against Staphylococcus aureus and Escherichia coli showed that these systems have little or no intrinsic antibacterial bioactivity.

Mesofluidic Devices for DNA-Programmed Combinatorial Chemistry

Hybrid combinatorial chemistry strategies that use DNA as an information-carrying medium are proving to be powerful tools for molecular discovery. In order to extend these efforts, we present a highly parallel format for DNA-programmed chemical library synthesis. The new format uses a standard microwell plate footprint and is compatible with commercially available automation technology. It can accommodate a wide variety of combinatorial synthetic schemes with up to 384 different building blocks per chemical step. We demonstrate that fluidic routing of DNA populations in the highly parallel format occurs with excellent specificity, and that chemistry on DNA arrayed into 384 well plates proceeds robustly, two requirements for the high-fidelity translation and efficient in vitro evolution of small molecules.

Synthesis of Azaphilone-Based Chemical Libraries

The synthesis of azaphilone scaffolds that have been further diversified by cross coupling acylation and amine addition is reported. Methodology development also led to novel modifications including C5 acetoxylation and condensations producing isoquinolin-6(7H) structures. Overall, the library synthesis afforded three azaphilone sublibraries, including vinylogous pyridones which project diversity elements in four sectors of the azaphilone core.

Direct C–H Arylation of Purine on Solid Phase and Its Use for Chemical Libraries Synthesis

C(8)-H direct arylation of purine derivatives immobilized on Wang resin is described. The purine skeleton was immobilized via C(6)-regioselective substitution of 2,6-dichloropurine with polymer-supported amines. After N(9)-alkylation with two different alkyl iodides and C(2) substitution with two selected amines, reaction conditions for C(8)-H arylation were developed and optimized. Various aryl bromides and aryl iodides were used for the reaction affording the target 2,6,8,9-tetrasubstituted purines in very good purity. The same reaction conditions were also applied for the synthesis of 2,6,8-trisubstituted purines, however, yields were lower. The methodology is applicable for high throughput synthesis of chemical libraries comprised of purine scaffold.

Combinatorial Discovery of Fluorescent Pharmacophores by Multicomponent Reactions in Droplet Arrays

Fluorescence imaging in clinical diagnostics and biomedical research relies to a great extent on the use of small organic fluorescent probes. Because of the difficulty of combining fluorescent and molecular-recognition properties, the development of such probes has been severely restricted to a number of well-known fluorescent scaffolds. Here we demonstrate that autofluorescing druglike molecules are a valuable source of bioimaging probes. Combinatorial synthesis and screening of chemical libraries in droplet microarrays allowed the identification of new types of fluorophores. Their concise and clean assembly by a multicomponent reaction presents a unique potential for the one-step synthesis of thousands of structurally diverse fluorescent molecules. Because they are based upon a druglike scaffold, these fluorophores retain their molecular recognition potential and can be used to design specific imaging probes.

ChemInform Abstract: Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

AbstractReview: 383 refs.

Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2009.

This is the thirteenth installment of the comprehensive survey series in high throughput chemistry.1 Biologically active libraries reported in 2009 are captured in Tables 1–5 under the headings of proteases, nonproteolytic enzymes, GPCRs, nonGPCRs, and oncolytics/antiinfectives. Table 6 lists molecular probes. Compound collections without disclosed biological activity are delineated in Tables 7–10 under the headings of scaffold derivatization/acyclic synthesis, monocyclic-, bicyclic/spirocyclic-, and polycyclic/macrocyclic synthesis. Polymer-supported reagents/scavengers/linkers are presented in Tables 11 (nonfluorous) and Table 12 (fluorous). There are 370 libraries and 24 molecular probes extracted from 355 literature citations.2–491 Approximately 90% of the citations originated from academic laboratories, with the majority of these from European and Asian laboratories. Solution-phase methodology accounted for ca. 85% of chemical library synthesis.

A Modular Approach to Synthetic RNA Binders of the Hepatitis C Virus Internal Ribosome Entry Site

Natural products that target the RNA components of bacterial ribosomes, and thereby act as antibiotics that shut down microbial protein synthesis, have provided a rich source of inspiration for the design and synthesis of small molecule ligands directed at RNA targets.[1, 2] A prominent example of a privileged scaffold for RNA recognition occurring in natural aminoglycoside antibiotics is 2-deoxystreptamine (2-DOS),[3] which contains a rigid framework of hydrogen bond donors among which the rigid cis-1,3 arrangement of amino groups is responsible for selective interaction with structural motifs in RNA targets (Figure 1).[4] In an approach to reduce the complexity of chemical library synthesis involving the highly functionalized 2-DOS scaffold, we have recently developed the 3,5-diaminopiperidine heterocycle (DAP) as a structural mimetic of the RNA-recognizing pharmacophore of the 2-DOS scaffold (Figure 1). Structure-guided design had been applied to discover a series of antibacterial DAP-triazine derivatives that act on the same ribosomal RNA target as the natural aminoglycoside antibiotics which initially served as the inspiration for the conception of the DAP compounds.[5, 6]

4-Arylation of 3-alkoxypyrazoles

Following the study of the alkoxypyrazoles nitrogen's reactivity toward arylation or alkylation reactions, we report here our results on the introduction of various aryl groups on carbon 4 position of 3-alkoxypyrazoles. This was achieved from the corresponding 4-halogeno derivatives via a Suzuki–Miyaura aryl–aryl coupling reaction. The unexpected difficulties (lack of reactivity or unwanted halogen reduction) encountered in the C-4 arylation of NH-free 4-halogenopyrazoles led us to design solutions to this recurrent problem. The cleavage of the 3-alkoxy group was also investigated using hydrogen bromide in acetic acid or boron tribromide in dichloromethane. This led, in one case, to the observation of a remarkable neighboring group-assisted electrophilic aryl boronylation. This second part of our work paves the way to the synthesis of many original chemical libraries featuring 3-alkoxy 1,4-diaryl pyrazoles as well as the corresponding 1,4-diaryl pyrazol-3-ones.

Strategies for Innovation in Multicomponent Reaction Design

By generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-19th century when Strecker first produced alpha-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide. Recently, academic chemists have renewed their interest in MCRs. In part, the pharmaceutical industry has fueled this resurgence because of the growing need to assemble libraries of structurally complex substances for evaluation as lead compounds in drug discovery and development programs. The application of MCRs to that increasingly important objective remains limited by the relatively small number of such reactions that can be broadly applied to prepare biologically relevant or natural-product-like molecular frameworks. We were interested in applying logic-based approaches, such as our single reactant replacement (SRR) approach, as a way both to improve known MCRs and to design new multiple-component routes to bioactive structures. This Account provides several examples that illustrate the use of SRR with known MCRs as starting points for synthetic innovation in this area. As part of our working hypothesis, we initially explored strategies for engineering improvements into known MCRs, either by increasing the dimensionality--that is, changing an n-component to an (n + 1)-component reaction--or broadening the scope of useful input structures, or both. By exhaustively applying retrosynthetic analysis to the cognate MCR to identify and exploit alternative entry points into the overall reaction manifold, we have devised several such re-engineered MCRs. Serendipitous findings have also augmented the yield of useful developments from our logic-inspired approach. In some cases, we have identified surprising links between different compound families that provide useful new entry points for chemical library synthesis. In other cases, the same re-engineering logic made it possible (sometimes in unexpected ways) to transform certain nonelementary two-component reactions into higher order MCRs. While logic may also inspire the search for new MCRs, the design process requires added chemical creativity, which cannot be reduced to a simple formula. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis.

High-throughput synthesis of azide libraries suitable for direct “click” chemistry and in situ screening

A key challenge in current drug discovery is the development of high-throughput (HT) amenable chemical reactions that allow rapid synthesis of diverse chemical libraries of enzyme inhibitors. The Cu(I)-catalyzed, 1,3-dipolar cycloaddition between an azide and an alkyne, better known as "click chemistry", is one such method that has received the most attention in recent years. Despite its popularity, there is still a lack of robust and efficient chemical strategies that give access to diverse libraries of azide-containing building blocks (key components in click chemistry). We report herein a highly robust and efficient strategy for high-throughput synthesis of a 325-member azide library. The method is highlighted by its simplicity and product purity. The utility of the library is demonstrated with the subsequent "click" synthesis of the corresponding bidentate inhibitors against PTP1B.

Immunoassays: Biological Tools for High Throughput Screening and Characterisation of Combinatorial Libraries

In the demanding field of proteomics, there is an urgent need for affinity-catcher molecules to implement effective and high throughput methods for analysing the human proteome or parts of it. Antibodies have an essential role in this endeavour, and selection, isolation and characterisation of specific antibodies represent a key issue to meet success. Alternatively, it is expected that new, well-characterised affinity reagents generated in rapid and cost-effective manners will also be used to facilitate the deciphering of the function, location and interactions of the high number of encoded protein products. Combinatorial approaches combined with high throughput screening (HTS) technologies have become essential for the generation and identification of robust affinity reagents from biological combinatorial libraries and the lead discovery of active/mimic molecules in large chemical libraries. Phage and yeast display provide the means for engineering a multitude of antibody-like molecules against any desired antigen. The construction of peptide libraries is commonly used for the identification and characterisation of ligand-receptor specific interactions, and the search for novel ligands for protein purification. Further improvement of chemical and biological resistance of affinity ligands encouraged the "intelligent" design and synthesis of chemical libraries of low-molecular-weight bio-inspired mimic compounds. No matter what the ligand source, selection and characterisation of leads is a most relevant task. Immunological assays, in microtiter plates, biosensors or microarrays, are a biological tool of inestimable value for the iterative screening of combinatorial ligand libraries for tailored specificities, and improved affinities. Particularly, enzyme-linked immunosorbent assays are frequently the method of choice in a large number of screening strategies, for both biological and chemical libraries.

2,4-Disubstituted-5-acetoxythiazoles: useful intermediates for the synthesis of thiazolones and 2,4,5-trisubstituted thiazoles

A variety of 2,4-disubstituted-5-acetoxythiazoles were prepared from the substituted methyl benzoates in good to moderate yields using a three-step sequence: (1) ester to thionoester conversion, (2) coupling with an amino acid, and (3) acetic anhydride mediated cyclization. In situ hydrolysis and alkylation of 2,4-disubstituted-5-acetoxythiazoles afforded the corresponding thiazolones and 2,4,5-trisubstituted thiazoles. This methodology can be readily applied to the synthesis of thiazole-based chemical libraries.

Current Status of Malaria Control

Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and creating a barrier between the human host and mosquitoes. A number of vaccine candidates are being clinically tried and R&D effort in this direction is coming in a big way. Currently there are only limited safe drugs for the treatment of this disease, however, reports of emerging resistance against existing drugs warrant the introduction of new drugs, which are unlikely to come from pharmaceutical industries because of limited commercial opportunities. One of the most important current approaches to develop new drugs involves the synthesis of chemical libraries and evaluate them against most validated biochemical targets of malarial parasite. Although a number of such targets in antimalarial drug development are known today, yet only validated and selective biochemical targets including mitochondrial transport, glycolic pathway, folate pathway, proteases and heme metabolism, apicoplast metabolism, glycophospatidyl inositol, lipid metabolism (glycerophospholipids), peptidyl deformylase and oxidative stress in parasite-infected erythrocytes have been discussed here. The well known antimalarial drugs and different drug combinations for the treatment of malaria are also briefly reviewed. A survey of the recently discovered new molecules active against malaria has also been narrated. Lastly, the future of malaria chemotherapy and new directions emerging from literature has been elucidated.

Application of Diazocarbonyls in the Synthesis of Chemical Libraries

AbstractFor Abstract see ChemInform Abstract in Full Text.

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.