RESUMEN
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.
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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.
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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.
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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.
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Antígeno B7-H1 , Inhibidores de Puntos de Control InmunológicoRESUMEN
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.
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Microbioma Gastrointestinal , Microbiota , Ratas , Animales , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/farmacología , ARN Ribosómico 16S , Motilidad Gastrointestinal , Bacterias/genética , Bacterias/metabolismo , Estreñimiento/microbiologíaRESUMEN
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.
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Oro , Nanopartículas del Metal , Aminas/química , Catálisis , Oro/química , HidrogenaciónRESUMEN
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.
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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.
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Anestésicos Locales , Descubrimiento de Drogas , Anestésicos Locales/farmacología , Animales , RatonesRESUMEN
The ubiquitous presence of the indole fragment in natural products and drugs asks for ever novel syntheses. We report an unprecedented mild, two-step synthesis of 2-tetrazolo substituted indoles based on the Ugi-tetrazole reaction combined with an acidic ring closure. A gram-scale synthesis, a bioactive compound and further transformations were performed.
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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.
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Tiazoles/síntesis química , Descubrimiento de Drogas , Estructura Molecular , Tiazoles/químicaRESUMEN
The area of covalent inhibitors is gaining momentum due to recently introduced clinical drugs, but libraries of these compounds are scarce. Multicomponent reaction (MCR) chemistry is well known for its easy access to a very large and diverse chemical space. Here, we show that MCRs are highly suitable to generate libraries of electrophiles based on different scaffolds and three-dimensional shapes and highly compatible with multiple functional groups. According to the building block principle of MCR, acrylamide, acrylic acid ester, sulfurylfluoride, chloroacetic acid amide, nitrile, and α,ß-unsaturated sulfonamide warheads can be easily incorporated into many different scaffolds. We show examples of each electrophile on 10 different scaffolds on a preparative scale as well as in a high-throughput synthesis mode on a nanoscale to produce libraries of potential covalent binders in a resource- and time-saving manner. Our operational procedure is simple, mild, and step economical to facilitate future covalent library synthesis.
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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.
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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.
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ADN/metabolismo , Indoles/metabolismo , Peptidomiméticos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Factores de Transcripción/metabolismo , Humanos , Unión ProteicaRESUMEN
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.
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Péptidos/química , Péptidos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteína p53 Supresora de Tumor/química , Aldehídos/química , Aminas/química , Secuencia de Aminoácidos , Dominio Catalítico , Cristalografía por Rayos X , Cianuros/química , Polarización de Fluorescencia , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Unión Proteica , Conformación ProteicaRESUMEN
The rapid growth of COVID-19 cases is causing an increasing death toll and also paralyzing the world economy. De novo drug discovery takes years to move from idea and/or pre-clinic to market, and it is not a short-term solution for the current SARS-CoV-2 pandemic. Drug repurposing is perhaps the only short-term solution, while vaccination is a middle-term solution. Here, we describe the discovery path of the HCV NS3-4A protease inhibitors boceprevir and telaprevir as SARS-CoV-2 main protease (3CLpro) inhibitors. Based on our hypothesis that α-ketoamide drugs can covalently bind to the active site cysteine of the SARS-CoV-2 3CLpro, we performed docking studies, enzyme inhibition and co-crystal structure analyses and finally established that boceprevir, but not telaprevir, inhibits replication of SARS-CoV-2 and mouse hepatitis virus (MHV), another coronavirus, in cell culture. Based on our studies, the HCV drug boceprevir deserves further attention as a repurposed drug for COVID-19 and potentially other coronaviral infections as well.
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Innovative and efficient hit-identification techniques are required to accelerate drug discovery. Protein-templated fragment ligations represent a promising strategy in early drug discovery, enabling the target to assemble and select its binders from a pool of building blocks. Development of new protein-templated reactions to access a larger structural diversity and expansion of the variety of targets to demonstrate the scope of the technique are of prime interest for medicinal chemists. Herein, we present our attempts to use a protein-templated reductive amination to target protein-protein interactions (PPIs), a challenging class of drug targets. We address a flexible pocket, which is difficult to achieve by structure-based drug design. After careful analysis we did not find one of the possible products in the kinetic target-guided synthesis (KTGS) approach, however subsequent synthesis and biochemical evaluation of each library member demonstrated that all the obtained molecules inhibit MDM2. The most potent library member (Ki =0.095â µm) identified is almost as active as Nutlin-3, a potent inhibitor of the p53-MDM2 PPI.
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Aldehídos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Aldehídos/síntesis química , Aldehídos/química , Aminación/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-ActividadRESUMEN
Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal ''lid'' segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.
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Antineoplásicos/farmacología , Proteínas Intrínsecamente Desordenadas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencilaminas/síntesis química , Bencilaminas/química , Bencilaminas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cianuros/síntesis química , Cianuros/química , Cianuros/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Formiatos/síntesis química , Formiatos/química , Formiatos/farmacología , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/metabolismo , Estructura Molecular , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The compatibility of free boronic acid building blocks in multicomponent reactions to readily create large libraries of diverse and complex small molecules was investigated. Traditionally, boronic acid synthesis is sequential, synthetically demanding, and time-consuming, which leads to high target synthesis times and low coverage of the boronic acid chemical space. We have performed the synthesis of large libraries of boronic acid derivatives based on multiple chemistries and building blocks using acoustic dispensing technology. The synthesis was performed on a nanomole scale with high synthesis success rates. The discovery of a protease inhibitor underscores the usefulness of the approach. Our acoustic dispensing-enabled chemistry paves the way to highly accelerated synthesis and miniaturized reaction scouting, allowing access to unprecedented boronic acid libraries.
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Ácidos Borónicos/química , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Ácidos Borónicos/síntesis química , Ácidos Borónicos/clasificación , Cianuros/síntesis química , Cianuros/química , Espectrometría de Masas/métodos , Microondas , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/clasificaciónRESUMEN
A concise and convergent synthesis of the atorvastatin, the best-selling cardiovascular drug of all time, is presented. Our approach is based on an Ugi reaction, which shortens the current synthetic route and is advantageous over the published syntheses.
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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.