High Rotational Barrier Atropisomers.

Atropisomers have attracted a great deal of attention lately due to their numerous applications in organic synthesis and to their employment in drug discovery. However, the synthetic arsenal at our disposal with which to access them remains limited. The research described herein is two-pronged; we both demonstrate the use of MCR chemistry as a synthetic strategy for the de novo synthesis of a class of atropisomers having high barriers to rotation with the simultaneous insertion of multiple chiral elements and we study these unprecedented molecular systems by employing a combination of crystallography, NMR and DFT calculations. By fully exploiting the synthetic capabilities of our chemistry, we have been able to monitor a range of different types of interaction, i. e. π-π, CH-π, heteroatom-π and CD-π, in order to conduct structure-property studies. The results could be applied both to atroposelective synthesis and in drug discovery.

Instant Macrocyclizations via Multicomponent Reactions.

Macrocycles fascinate chemists due to both their structure and their applications. However, we still lack efficient and sustainable synthetic methods, giving us straightforward access to them. Herein, a rapid macrocyclization utilizing a two-step, one-pot approach based on orthogonal multicomponent reaction (MCR) tactics is introduced. This synthetic protocol, which is based on Ugi and Groebke-Blackburn-Bienaymé reactions with isocyanides tethered to alkyl tosylates, yields medium sized macrocycles that are otherwise difficult to achieve. Single crystal structures reveal conformational reorganization via intramolecular hydrogen bonding, and modeling studies profile the synthesized libraries.

New oxacycles on the block: benzodioxepinones via a Passerini reaction.

Oxacycles and benzoxepanes are privileged motifs present in a variety of natural products and functional molecules. However, their synthetic access is limited. Here, we demonstrate a rapid synthesis of unprecedented benzoxepanes from readily available starting materials in one step via a Passerini multicomponent reaction. The reaction proceeds smoothly under mild reaction conditions. We have obtained a single-crystal X-ray structure, revealing a butterfly conformation, combined with useful structural features. In addition, we have performed both a full interaction map on the X-ray structure and a profile analysis of a virtual library based on the proposed scaffold with a special focus on certain physicochemical parameters to demonstrate their potential usage in drug discovery.

Supported Gold Nanoparticle-Catalyzed Selective Reduction of Multifunctional, Aromatic Nitro Precursors into Amines and Synthesis of 3,4-Dihydroquinoxalin-2-Ones.

The synthesis of 3,4-dihydroquinoxalin-2-ones via the selective reduction of aromatic, multifunctional nitro precursors catalyzed by supported gold nanoparticles is reported. The reaction proceeds through the in situ formation of the corresponding amines under heterogeneous transfer hydrogenation of the initial nitro compounds catalyzed by the commercially available Au/TiO2-Et3SiH catalytic system, followed by an intramolecular C-N transamidation upon treatment with silica acting as a mild acid. Under the present conditions, the Au/TiO2-TMDS system was also found to catalyze efficiently the present selective reduction process. Both transfer hydrogenation processes showed very good functional-group tolerance and were successfully applied to access more structurally demanding products bearing other reducible moieties such as chloro, aldehyde or methyl ketone. An easily scalable (up to 1 mmol), low catalyst loading (0.6 mol%) synthetic protocol was realized, providing access to this important scaffold. Under these mild catalytic conditions, the desired products were isolated in good to high yields and with a TON of 130. A library analysis was also performed to demonstrate the usefulness of our synthetic strategy and the physicochemical profile of the derivatives.

Tetrazoles via Multicomponent Reactions.

Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1 H- or 2 H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

Multicomponent Reactions: "Kinderleicht".

A demonstration experiment of the synthesis of a novel tetrazole derivative via a multicomponent reaction (Ugi tetrazole four component reaction, UT-4CR) bearing a luminol moiety and a subsequent exploitation of its chemiluminescent properties is described. A complex product is generated in just one simple step, so simple that children can do it: "kinderleicht", German for dead easy. Students are stimulated, inspired, and involved in a multilevel active learning process using the Steps to Inquiry framework as a metacognitive tool that raises student awareness regarding scientific process and prompts them to ask their own questions discussing the merits of a mechanism and evaluating its effectiveness before they start their own cycles of inquiry.

Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.

Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.

TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics.

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or "hot spot", regions of protein-protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide "hexT", encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.

Glycoconjugates via phosphorus ylides.

A facile, high yielding access to rare chimeric compounds combining phosphorus ylides with complex glycosyl formamides is described. We determined x-ray structures gaining structural insight into this compounds class. In addition, data mining of similar compounds deposited within the Cambridge Structural Database was performed. These derivatives could be used either as synthetic intermediates via the ylide functionalization and glyco chemical biology synthons or improving the pharmacokinetic properties of a potential bioactive molecule, exploiting the glycosyl moiety.

Structure and Reactivity of Glycosyl Isocyanides.

3D structural information was obtained from mono-, di- and trisaccharide formamide and isocyanide derivatives by analysis of their X-ray crystal structure and NMR spectroscopy. The isocyanide anomeric effect was observed. Data mining of the Cambridge Structural Database (CSD) was performed and statistically confirmed our findings. Application of the glycoside isocyanides in the synthesis of novel glycoconjugates as drug-like scaffolds by MCR chemistry underscores the usefulness of the novel building blocks.

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists.

Macrocycles were designed to antagonize the protein-protein interaction p53-MDM2 based on the three-finger pharmacophore F19W23L25. The synthesis was accomplished by a rapid, one-pot synthesis of indole-based macrocycles based on Ugi macrocyclization. The reaction of 12 different α,ω-amino acids and different indole-3-carboxaldehyde derivatives afforded a unique library of macrocycles otherwise difficult to access. Screening of the library for p53-MDM2 inhibition by fluorescence polarization and 1H,15N HSQC NMR measurements confirm MDM2 binding.

Discovery of chromenes as inhibitors of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC50's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists.

The protein­protein interaction of p53 and MDM2/X is a promising non genotoxic anticancer target. A rapid and efficient methodology was developed to synthesize the 2,30-bis(10H-indole) heterocyclic scaffold 2 as ester, acid and amide derivatives. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and HSQC experiments, indicating good inhibition and a perfect starting point for further optimizations.

Towards a facile and convenient synthesis of highly functionalized indole derivatives based on multi-component reactions.

A library of potentially bioactive compounds through the novel 1H-indole-methyl-isocyanide and MCRs has been described. A flexible and efficient synthesis affording great complexity and diversity is achieved with moderate to good yields with no need for protection and deprotection steps.

C1 functionalization of imidazo heterocycles via carbon dioxide fixation.

Utilizing CO2 as a one-carbon building block in the preparation of high-value chemical entities is a cornerstone of modern organic synthesis. Herein, we exemplify this strategy through a mild, one-pot methodology that gives rapid access to N-heteroaryl substituted 6-, 8- and 9-membered carbamates via CO2 fixation.

Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats.

Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo, 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors.

In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties.

Local Anesthetics via Multicomponent Reactions.

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage-gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)-based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single-crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three-component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.

Synthesis of 2-keto-imidazoles utilizing N-arylamino-substituted N-heterocyclic carbenes.

A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl-substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino-substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts.

Still Relevant Today: The Asinger Multicomponent Reaction.

The Asinger multicomponent reaction is a versatile synthetic tool which gives access to multiple drug-like scaffolds such as 3-thiazolines. The diversity and easy access of its starting materials, its operational simplicity combined with mild conditions and relatively good yields, renders the Asinger reaction, today more than ever, a cornerstone not only in heterocyclic chemistry and modern synthesis but also in medicinal chemistry. In this review, we perform a thorough analysis of the scope and limitations on the different reaction variants with their starting materials, the three-dimensional solid-state conformations of the Asinger derivatives, and we underline and classify all the major post-modifications that have been described. In addition, we report all the major applications in drug discovery projects.