Multicomponent Reaction Chemistry Research Articles

Fragment Screening in the Development of a Novel Anti-Malarial

Fragment-based approaches offer rapid screening of chemical space and have become a mainstay in drug discovery. This manuscript provides a recent example that highlights the initial and intermediate stages involved in the fragment-based discovery of an allosteric inhibitor of the malarial aspartate transcarbamoylase (ATCase), subsequently shown to be a potential novel anti-malarial. The initial availability of high-resolution diffracting crystals allowed the collection of a number of protein fragment complexes, which were then assessed for inhibitory activity in an in vitro assay, and binding was assessed using biophysical techniques. Elaboration of these compounds in cycles of structure-based drug design improved activity and selectivity between the malarial and human ATCases. A key element in this process was the use of multicomponent reaction chemistry as a multicomponent compatible fragment library, which allowed the rapid generation of elaborated compounds, the rapid construction of a large (70 member) chemical library, and thereby efficient exploration of chemical space around the fragment hits. This review article details the steps along the pathway of the development of this library, highlighting potential limitations of the approach and serving as an example of the power of combining multicomponent reaction chemistry with fragment-based approaches.

De Novo Assembly of Highly Substituted Morpholines and Piperazines.

The morpholine and piperazine with their remarkable physical and biochemical properties are popular heterocycles in organic and medicinal chemistry used in rational property design. However, in the majority of cases these rings are added to an existing molecule in a building block approach thus limiting their substitution pattern and diversity. Here we introduce a versatile de novo synthesis of the morpholine and piperazine rings using multicomponent reaction chemistry. The large scale amenable building blocks can be further substituted at up to four positions, making this a very versatile scaffold synthesis strategy. Our methods thus fulfill the increasing demand for novel building block design and nontraditional scaffolds which previously were not accessible

Multicomponent Reactions for de Novo Synthesis of BODIPY Probes: In Vivo Imaging of Phagocytic Macrophages

Multicomponent reactions are excellent tools to generate complex structures with broad chemical diversity and fluorescent properties. Herein we describe the adaptation of the fluorescent BODIPY scaffold to multicomponent reaction chemistry with the synthesis of BODIPY adducts with high fluorescence quantum yields and good cell permeability. From this library we identified one BODIPY derivative (PhagoGreen) as a low-pH sensing fluorescent probe that enabled imaging of phagosomal acidification in activated macrophages. The fluorescence emission of PhagoGreen was proportional to the degree of activation of macrophages and could be specifically blocked by bafilomycin A, an inhibitor of phagosomal acidification. PhagoGreen does not impair the normal functions of macrophages and can be used to image phagocytic macrophages in vivo.

Prebiotic chemistry: a new modus operandi

A variety of macromolecules and small molecules-(oligo)nucleotides, proteins, lipids and metabolites-are collectively considered essential to early life. However, previous schemes for the origin of life-e.g. the 'RNA world' hypothesis-have tended to assume the initial emergence of life based on one such molecular class followed by the sequential addition of the others, rather than the emergence of life based on a mixture of all the classes of molecules. This view is in part due to the perceived implausibility of multi-component reaction chemistry producing such a mixture. The concept of systems chemistry challenges such preconceptions by suggesting the possibility of molecular synergism in complex mixtures. If a systems chemistry method to make mixtures of all the classes of molecules considered essential for early life were to be discovered, the significant conceptual difficulties associated with pure RNA, protein, lipid or metabolism 'worlds' would be alleviated. Knowledge of the geochemical conditions conducive to the chemical origins of life is crucial, but cannot be inferred from a planetary sciences approach alone. Instead, insights from the organic reactivity of analytically accessible chemical subsystems can inform the search for the relevant geochemical conditions. If the common set of conditions under which these subsystems work productively, and compatibly, matches plausible geochemistry, an origins of life scenario can be inferred. Using chemical clues from multiple subsystems in this way is akin to triangulation, and constitutes a novel approach to discover the circumstances surrounding the transition from chemistry to biology. Here, we exemplify this strategy by finding common conditions under which chemical subsystems generate nucleotides and lipids in a compatible and potentially synergistic way. The conditions hint at a post-meteoritic impact origin of life scenario.

Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists.

The discovery of a lead compound is an essential process in early drug discovery, hopefully eventually resulting into a clinical candidate and a drug for the treatment of a disease. Besides affinity and selectivity for the target, however, other target unrelated compound properties are equally important for the fate of drug candidate, e.g. water solubility, lipophilicity and molecular weight since they determine important aspects such as oral bioavailability, dosing schedule and side effects. The parallel discovery and early development of several leads is therefore now pursued whenever possible, an approach that takes into account the high attrition rate of early drug discovery projects. Currently, hits as starting points for medicinal chemistry optimisations are mostly found by high-throughput screening (HTS) campaigns and to a much less extent by structure-based approaches including fragment-based and computational drug discovery. For certain target classes, however, HTS often yields very low numbers of hits.[1] For example, protein-protein interactions (PPIs) are notoriously difficult to hit with drug-like small molecules.[2] This has been assigned to the unusual structure, topology and flexibility of protein-protein interfaces.[3] The recent advancement of several drugs into clinical development clearly shows that certain PPIs, e.g., Bcl-x and XIAP, can be efficiently targeted by small molecules.[4] Here, we describe a complementary process that led to the parallel discovery of several compounds belonging to seven different scaffold classes, amenable to synthesis by efficient multicomponent reaction (MCR) chemistry in just one step, that antagonize the PPI between the transcription factor p53 and its negative regulator Hdm2.

Efficient Synthesis Of Arrays Of Amino Acid Derived Ugi Products With Subsequent Amidation

Several amino acid derived iminodicarboxylicacid monomethylesters have been converted into a small array of amide derivatives. Sequentially, we were using an Ugi reaction of alpha-amino acids, followed by a mild and efficient amidation. Thus we added to this well-known Ugi scaffold another dimension of diversity, thereby enhancing it is potentially use in the combinatorial and medicinal chemistry of multi component reactions (MCRs) and drug discovery. Synthesis of an exemplary array and pharmacophore features are discussed.

Desosamine in multicomponent reactions

Desosamine occurring ubiquitously in natural products is introduced into isocyanide based multicomponent reaction chemistry. Corresponding products are of potential interest for the design of novel antibiotics.

Parallel Synthesis of Arrays of Amino-Acid-Derived Isocyanoamides Useful As Starting Materials in IMCR

Arrays of amino-acid-derived isocyanoamides are conveniently produced on a multigram scale in one step by the solventless aminolysis of the corresponding methyl esters with primary or secondary aliphatic amines. Most of the corresponding isocyanides precipitate during the reaction and can be filtered to yield highly pure, colorless, and odorless solids. They are potentially useful in the combinatorial chemistry of multicomponent reactions.

New Heterocycle Synthesis by Using Bifunctional Reactants in Multicomponent Reaction Chemistry: The Use of Arylglyoxals and Cinnamaldehyde in the Ugi‐4CR and Passerini‐3CR

AbstractFor Abstract see ChemInform Abstract in Full Text.

Recent progress in the chemistry of multicomponent reactions

Abstract The chemistry of multicomponent reactions (MCRs) and isocyanides belongs to three periods: In the century 1859­1958, isocyanide chemistry was moderately active and was separate from the classical name reactions of the MCRs. In the next period, isocyanides became well available, and MCRs of isocyanides became the most variable way of forming chemical compounds. The year 1993 began a new era of the formation and investigation of the products and the libraries of the Ugi reaction (U-4CR) and higher MCRs of the isocyanides. This chemistry is primarily accomplished in the industrial search and preparation of new pharmaceutical and plant-protecting products.

ChemInform Abstract: Since 1995 the New Chemistry of Multicomponent Reactions and Their Libraries Including Their Heterocyclic Chemistry

A growing number of products, including many heterocycles, can be prepared by the one-pot MultiComponent Reactions (MCRs) just by mixing three or more educts, and in many cases practically quantitative yields of pure products can be obtained. The 3CR by α-aminoalkylations of nucleophiles began in the middle of the last century, and the syntheses of heterocycles by MCRs of three and four components were introduced by Hantzsch in the 1880s. The MCRs of the isocyanides with four and more educts began in 1959, and their compound libraries were mentioned since 1961. However, only since 1995 the often automated one-pot chemistry of the MCR of the isocyanides is used extensively. If a chemical compound can be prepared by a sequence of two component reactions or a suitable MCR, the latter is always a superior procedure. The U-4CR can be combined with other chemical reactions and MCRs as one-pot reactions of n > 4 components, and such unions even have a much greater variety of structurally and stereochemically different products. The educts and products of Ugi-type MCRs are more variable than those of all previous chemical reactions and other MCRs. Due to the progress in screening and automation processes in the last few years, many new compounds have been formed and investigated more rapidly than ever before. The search for new desirable products can be accomplished more than 10,000 times faster than by the older conventional methods. The now popular chemistry of the MCRs of the isocyanides fills the since long empty part of organic chemistry.

Since 1995 the new chemistry of multicomponent reactions and their libraries, including their heterocyclic chemistry

AbstractA growing number of products, including many heterocycles, can be prepared by the one‐pot MultiComponent Reactions (MCRs) just by mixing three or more educts, and in many cases practically quantitative yields of pure products can be obtained. The 3CR by α‐aminoalkylations of nucleophiles began in the middle of the last century, and the syntheses of heterocycles by MCRs of three and four components were introduced by Hantzsch in the 1880s. The MCRs of the isocyanides with four and more educts began in 1959, and their compound libraries were mentioned since 1961. However, only since 1995 the often automated one‐pot chemistry of the MCR of the isocyanides is used extensively. If a chemical compound can be prepared by a sequence of two component reactions or a suitable MCR, the latter is always a superior procedure. The U‐4CR can be combined with other chemical reactions and MCRs as one‐pot reactions of n > 4 components, and such unions even have a much greater variety of structurally and stereochemically different products. The educts and products of Ugi‐type MCRs are more variable than those of all previous chemical reactions and other MCRs. Due to the progress in screening and automation processes in the last few years, many new compounds have been formed and investigated more rapidly than ever before. The search for new desirable products can be accomplished more than 10,000 times faster than by the older conventional methods. The now popular chemistry of the MCRs of the isocyanides fills the since long empty part of organic chemistry.

Combinatorial Chemistry. Synthesis, Analysis, Screening. Edited by Günther Jung (guenther.jung@uni-tuebingen.de). Wiley-VCH: Weinheim. 1999. XXXII+602 pp. 268 DM. ISBN 3-527-29869-X

first_page settings Order Article Reprints Font Type: Arial Georgia Verdana Font Size: Aa Aa Aa Line Spacing:    Column Width:    Background: Open AccessBook Review Combinatorial Chemistry. Synthesis, Analysis, Screening. Edited by Günther Jung ([email protected]). Wiley-VCH: Weinheim. 1999. XXXII+602 pp. 268 DM. ISBN 3-527-29869-X by Shu-Kun Lin Molecular Diversity Preservation International (MDPI), Saengergasse 25, CH-4054 Basel, Switzerland Molecules 2000, 5(2), 198-199; https://doi.org/10.3390/50200198 Received: 29 December 1999 / Published: 23 February 2000 Download Download PDF Download PDF with Cover Download XML Download Epub Versions Notes This is not only a book written by specialists for specialists, but also for everyone who wants to brush up on their knowledge on the rapidly and ever-growing field of combinatorial chemistry. It is an indispensable source of information for researchers working in organic synthesis, catalysis, biochemistry, and biotechnology, pharmaceutical and clinical chemistry, material sciences, and analytical chemistry.I was glad to see that Professor Ivar Ugi is the main author of a chapter (Chapter 4. Combinatorial Chemistry of Multicomponent Reactions). He has been long regarded by many as the father of combinatorial chemistry because of his initial studies on multicomponent organic reactions.It is a fact that the main topic of combinatorial chemistry is organic synthesis, and that for obvious reasons, quantitative (100%) yields are preferred for combinatorial synthesis. Solid-phase synthesis is also preferred. Chemistry is an experimental science. Chemists may find working on synthesis, analysis and all kinds of bioactivity tests to be tedious. If possible, chemists would like to use automatic processes for synthesis, analysis and screening. These may be possible if these complicated processes can be clearly defined as unit operations. Ideally, in future, all unit operations or chemical reactions, separations, characterization and bioactivity tests, etc., can be carried out by individual "modules" which are controlled by computer. Normally high-throughput screening has been regarded as the cause of sudden and extensive exploration in combinatorial chemistry. Expectations for automation might be another driving force. The processes handled by machine are expected to be much different than classical ones; for instance, the size of the container can be much smaller than the flask we hold in our hands when we perform synthetic experiments. We can rely on analytical instruments (probes) which can be much better than our eyes and noses.Actually, combinatorial chemistry may be a topic covering both combinatorial synthetic processes and combinatorial structures. Analysis as a step in the process can be inserted anywhere. For those compounds provided as part of compound libraries, the analysis of individual compounds might be necessary. Structural characterization of compounds can be carried out after activity assessments (another kind of analysis) and only for those active compounds.Screening is duly included as one of the three main topics in this book because many bioactivity tests are simplified to a single ligand-target combination, very much like a bimolecular reaction.The twenty chapters listed are the following: Combinatorial Chemistry.Survey of Solid Phase Organic Reactions.Solution Phase Combinatorial Chemistry.Combinatorial Chemistry of Multicomponent Reactions.Solid Phase Anchors in Organic Chemistry.The Use of Templates in Combinatorial Chemistry for Solid Phase Synthesis of Multiple Core Structure Libraries.Combinatorial Synthetic Oligomers.Glycopeptide and Oligosaccharide Libraries.RNA and DNA Aptamers.Combinatorial Approaches to Molecular Receptors for Chemosensors.Peptide Libraries in T-Cell Mediated Immune Response.Combinatorial Biosynthesis of Microbial Metabolites.Design and Diversity Analysis of Compound Libraries for Lead Discovery.How to Scale-up While Scaling Down: EVOscreen, a Miniaturized Ultra High Throughput Screening System.High Throughput Experimentation in Catalysis.FT-Infrared Spectroscopy and IR-Microscopy for On Bead Analysis of Solid Phase Synthesis.High-Resolution Magic Angle Spinning NMR Spectroscopy of On-Bead Analysis of Solid Phase Synthesis.Mass Spectrometric Analysis of Organic Compound Collections.Automation in Combinatorial Synthesis.Ion-Cyclotron-Resonance-FT-Mass Spectrometry for Elemental Composition Analysis of Library Components. AcknowledgmentsI am grateful to Günther Jung ([email protected]) and Wiley-VCH's Sonja Karlein ([email protected]) for their kind assistance. © 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes. Share and Cite MDPI and ACS Style Lin, S.-K. Combinatorial Chemistry. Synthesis, Analysis, Screening. Edited by Günther Jung ([email protected]). Wiley-VCH: Weinheim. 1999. XXXII+602 pp. 268 DM. ISBN 3-527-29869-X. Molecules 2000, 5, 198-199. https://doi.org/10.3390/50200198 AMA Style Lin S-K. Combinatorial Chemistry. Synthesis, Analysis, Screening. Edited by Günther Jung ([email protected]). Wiley-VCH: Weinheim. 1999. XXXII+602 pp. 268 DM. ISBN 3-527-29869-X. Molecules. 2000; 5(2):198-199. https://doi.org/10.3390/50200198 Chicago/Turabian Style Lin, Shu-Kun. 2000. "Combinatorial Chemistry. Synthesis, Analysis, Screening. Edited by Günther Jung ([email protected]). Wiley-VCH: Weinheim. 1999. XXXII+602 pp. 268 DM. 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