RESUMO
Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.
Assuntos
Compostos Bicíclicos com Pontes , Desenho de Fármacos , Heptanos , Ânions/química , Benzeno/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Descoberta de Drogas , Heptanos/síntese química , Heptanos/química , Pentanos/síntese química , Pentanos/química , SolubilidadeRESUMO
New biphenyl-based chimeric compounds containing pomalidomide were developed and evaluated for their activity to inhibit and degrade the programmed cell death-1/programmed cell death- ligand 1 (PD-1/PD-L1) complex. Most of the compounds displayed excellent inhibitory activity against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay. Among them, compound 3 is one of the best with an IC50 value of 60 nM. Using an ex vivo PD-1/PD-L1 blockade cell line bioassay that expresses human PD-1 and PD-L1, we show that compounds 4 and 5 significantly restore the repressed immunity in this co-culture model. Western blot data, however, demonstrated that these anti-PD-L1/pomalidomide chimeras could not reduce the protein levels of PD-L1.
Assuntos
Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Talidomida , Antígeno B7-H1/antagonistas & inibidores , Compostos de Bifenilo , Humanos , Ligantes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Talidomida/análogos & derivados , Talidomida/farmacologiaRESUMO
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.
Assuntos
Ouro , Nanopartículas Metálicas , Aminas/química , Catálise , Ouro/química , HidrogenaçãoRESUMO
Excessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro-inflammatory cytokine interleukin(IL)-1ß. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti-inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo. A specific inhibitor of the ß HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL-1ß and IL-6 in vivo when administered orally, and was brain-penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Citocinas/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/metabolismo , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologiaRESUMO
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.
RESUMO
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.
Assuntos
DNA/metabolismo , Indóis/metabolismo , Peptidomiméticos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Fatores de Transcrição/metabolismo , Humanos , Ligação ProteicaRESUMO
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.
RESUMO
There is an unmet need for late-stage 18F-fluorination strategies to label molecules with a wide range of relevant functionalities to medicinal chemistry, in particular (hetero)arenes, aiming to obtain unique in vivo information on the pharmacokinetics/pharmacodynamics (PK/PD) using positron emission tomography (PET). In the last few years, Cu-mediated oxidative radiofluorination of arylboronic esters/acids arose and has been successful in small molecules containing relatively simple (hetero)aromatic groups. However, this technique is sparsely used in the radiosynthesis of clinically significant molecules containing more complex backbones with several aromatic motifs. In this work, we add a new entry to this very limited database by presenting our recent results on the 18F-fluorination of an arylboronic ester derivative of atorvastatin. The moderate average conversion of [18F]F- (12%), in line with what has been reported for similarly complex molecules, stressed an overview through the literature to understand the radiolabeling variables and limitations preventing consistently higher yields. Nevertheless, the current disparity of procedures reported still hampers a consensual and conclusive output.
Assuntos
Atorvastatina/química , Ácidos Borônicos/química , Cobre/química , Radioisótopos de Flúor/química , Halogenação , Compostos Radiofarmacêuticos , Catálise , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/químicaRESUMO
Imaging techniques, such as positron emission tomography (PET), represent great progress in the clinical development of drugs and diagnostics. However, the efficient and timely synthesis of appropriately labeled compounds is a largely unsolved problem. Numerous small drug-like molecules with high structural diversity can be synthesized via convergent multicomponent reactions (MCRs). The combination of PET labeling with MCR synthesis of biologically active compounds can greatly simplify radioanalytical and imaging-based analysis. In a proof-of-concept study, we optimized robust on-site radiolabeling conditions that were subsequently applied to several structurally different drug-like MCR scaffolds (e.g., arenes, ß-lactam, tetrazole, and oxazole). These labeled scaffolds were synthesized via pinacol-derived aryl boronic esters (arylBPin) by copper-mediated oxidative 18F-fluorination with radiochemical conversions (RCCs) from 15% to 76%.
Assuntos
Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons , Coloração e Rotulagem , Cromatografia em Camada Fina , Radioquímica , Tetrazóis/químicaRESUMO
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.
RESUMO
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.
Assuntos
Benzopiranos/química , Oxirredutases Intramoleculares/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Benzopiranos/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Oxirredutases Intramoleculares/metabolismo , Cinética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The PD-1/PD-L1 interaction has emerged as a significant target in cancer immunotherapy. Current medications include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. The cocrystal structure of human PD-1 and PD-L1 is expected to be a valuable starting point for the design of novel inhibitors, along with the recent crystal structures with monoclonal antibodies, small molecules, and macrocycles.
Assuntos
Anticorpos Monoclonais/imunologia , Antígeno B7-H1/química , Antígeno B7-H1/imunologia , Desenho de Fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/química , Receptor de Morte Celular Programada 1/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Humanos , Imunoterapia , Ligantes , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Antígeno B7-H1/imunologia , Descoberta de Drogas , Humanos , Células Jurkat , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1/imunologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Multicomponent reactions (MCRs), which are located between one- and two-component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted.
Assuntos
Compostos Orgânicos/síntese química , Preparações Farmacêuticas/síntese química , Desenho de Fármacos , Humanos , Estrutura Molecular , Compostos Orgânicos/química , Preparações Farmacêuticas/química , PolimerizaçãoRESUMO
Glycolate oxidase (HAO1) catalyses the synthesis of glyoxylate, a common metabolic intermediate that causes renal failure if accumulated. HAO1 inhibition is an emerging treatment for primary hyperoxaluria, a rare disorder of glyoxylate metabolism. Here we report the first cell-based measurement of inhibitor uptake and engagement with HAO1, by adapting the cellular thermal shift assay (CETSA) based on Nano luciferase complementation and luminescence readout. By profiling the interaction between HAO1 and four well-characterised inhibitors in intact and lysed HEK293T cells, we showed that our CETSA method differentiates between low-permeability/high-engagement and high-permeability/low-engagement ligands and is able to rank HAO1 inhibitors in line with both recombinant protein methods and previously reported indirect cellular assays. Our methodology addresses the unmet need for a robust, sensitive, and scalable cellular assay to guide HAO1 inhibitor development and, in broader terms, can be rapidly adapted for other targets to simultaneously monitor compound affinity and cellular permeability.
RESUMO
The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure-activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.
RESUMO
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.
Assuntos
Antígeno B7-H1 , Inibidores de Checkpoint ImunológicoRESUMO
The reaction of the zwitterionic intermediate, generated in situ from either tert-butylisocyanide or cyclohexylisocyanide and acetylenedicarboxylates, with 3-cyanochromones is described, whereupon spirochromenofuran derivatives 5 or 6 were obtained in good yields. The subsequent acid-catalyzed rearrangement of the isolated 2-imino-spirochromenofurans 5 to 2-amino-spirochromenofurans 7 has also been studied. Rational mechanistic schemes for the formation of compounds 5, 6, and 7 are proposed. The structure elucidation of the products was accomplished by 1D and 2D NMR experiments and confirmed by X-ray crystallographic analysis. Full assignment of all (1)H and (13)C NMR chemical shifts has been unambiguously achieved with the aid of DFT/GIAO calculations.
Assuntos
Ácidos/química , Benzopiranos/síntese química , Compostos de Espiro/síntese química , Benzopiranos/química , Catálise , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Compostos de Espiro/químicaRESUMO
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.
Assuntos
Anestésicos Locais , Descoberta de Drogas , Anestésicos Locais/farmacologia , Animais , CamundongosRESUMO
Another aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel spirobenzofuranones has been described. The synthesis involves reaction of the zwitterionic intermediates formed by the 1:1 interaction between isocyanides and acetylenecarboxylates with 3-cyanochromones, whereupon through an unexpected and unprecedented reaction of the chromone moiety the isolated benzofuranones are formed. The regioselectivity of the reaction was investigated by DFT calculations. The geometries of the intermediates, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all (1)H and (13)C NMR chemical shifts has been achieved. A plausible mechanistic rationale is proposed.