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With the increasing need for effective compounds against cancer or pathogen-borne diseases, the development of new tools to investigate the enzymatic activity of biomarkers is necessary. Among these biomarkers are DNA topoisomerases, which are key enzymes that modify DNA and regulate DNA topology during cellular processes. Over the years, libraries of natural and synthetic small-molecule compounds have been extensively investigated as potential anti-cancer, anti-bacterial, or anti-parasitic drugs targeting topoisomerases. However, the current tools for measuring the potential inhibition of topoisomerase activity are time consuming and not easily adaptable outside specialized laboratories. Here, we present rolling circle amplification-based methods that provide fast and easy readouts for screening of compounds against type 1 topoisomerases. Specific assays for the investigation of the potential inhibition of eukaryotic, viral, or bacterial type 1 topoisomerase activity were developed, using human topoisomerase 1, Leishmania donovani topoisomerase 1, monkeypox virus topoisomerase 1, and Mycobacterium smegmatis topoisomerase 1 as model enzymes. The presented tools proved to be sensitive and directly quantitative, paving the way for new diagnostic and drug screening protocols in research and clinical settings.
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Nitrogen heterocycles are part of the structure of natural products and agents with important biological activity, such as antiviral, antibiotic, and antitumor drugs. For this reason, heterocyclic compounds are one of today's most desirable synthetic targets and the Povarov reaction is a powerful synthetic tool for the construction of highly functionalized heterocyclic systems. This process involves an aromatic amine, a carbonyl compound, and an olefin or acetylene to give rise to the formation of a nitrogen-containing heterocycle. This review illustrates advances in the synthetic aspects of the intramolecular Povarov reaction for the construction of intricate nitrogen-containing polyheterocyclic compounds. This original review presents research done in this field, with references to important works by internationally relevant research groups on this current topic, covering the literature from 1992 to 2022. The intramolecular Povarov reactions are described here according to the key processes involved, using different combinations of aromatic or heteroaromatic amines, and aliphatic, aromatic, or heteroaromatic aldehydes. Some catalytic reactions promoted by transition metals are detailed, as well as the oxidative Povarov reaction and some asymmetric intramolecular Povarov processes.
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Compostos Heterocíclicos , Elementos de Transição , Nitrogênio/química , Compostos Heterocíclicos/química , Aminas/química , AldeídosRESUMO
New antibiotic agents were prepared using Povarov and Ugi multicomponent reactions upon the known drugs sulfadoxine and dapsone. The prepared derivatives, with increased lipophilicity, showed improved efficiency against Mycolata bacteria. Microbiological guidance for medicinal chemistry is a powerful tool to design new and effective antimicrobials. In this case, the readily synthesized compounds open new possibilities in the search for antimicrobials active on mycolic acid-containing bacteria.
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INTRODUCTION: Topoisomerases are important targets for therapeutic improvement in the treatment of some diseases, including cancer. Inhibitors and poisons of topoisomerase I can limit the activity of this enzyme in its enzymatic cycle. This fact implies an anticancer effect of these drugs, since most cancer cells are characterized by both a higher activity of topoisomerase I and a higher replication rate compared to non-cancerous cells. Clinically approved inhibitors include camptothecin (CPT) and its derivatives. However, their limitations have encouraged different research groups to prepare new compounds, proof of which are the numerous research works and patents, some of them in the last five years. AREAS COVERED: This review covers patent literature on topoisomerase I inhibitors and their application published between 2016-present. EXPERT OPINION: The highest contribution toward patent development has been obtained from academics or small biotechnology companies. The most important fields of innovation include the preparation of prodrugs or inhibitors combined with other agents, as biocompatible polymers or antibodies. A promising development of topoisomerase I inhibitors is expected in the next years, directed to the treatment of diverse diseases, specifically toward different types of cancer and infectious diseases, among others.
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Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Animais , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Desenvolvimento de Medicamentos , Humanos , Neoplasias/patologia , Patentes como AssuntoRESUMO
Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.
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Naftiridinas/química , Alcaloides/biossíntese , Alcaloides/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Reação de Cicloadição , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Naftiridinas/síntese química , Naftiridinas/farmacologia , OxirreduçãoRESUMO
This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined.
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Química Farmacêutica , Complexos de Coordenação/síntese química , Naftiridinas/síntese química , Complexos de Coordenação/química , Indicadores e Reagentes/síntese química , Indicadores e Reagentes/química , Naftiridinas/químicaRESUMO
The Povarov multicomponent reaction consists on the condensation of an aniline, an aldehyde, and an activated olefin to generate a tetrahydroquinoline adduct with 3 diversity points. Hereby, we report the main features of this transformation and its uses in medicinal chemistry. Relevant examples of the impact of Povarov adducts in different therapeutic areas are provided.
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Aldeídos/química , Alcenos/química , Compostos de Anilina/química , Química Farmacêutica/métodos , Quinolinas/síntese química , Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Catálise , Descoberta de Drogas/métodos , Neurotransmissores/síntese química , EstereoisomerismoAssuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Células A549 , Animais , Células HCT116 , Células Hep G2 , Desacetilase 6 de Histona/genética , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Linfoma de Célula do Manto/enzimologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Células MCF-7 , Camundongos , Camundongos SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células PC-3 , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 â 252 and 444 â 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL(-1) . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80°C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat.
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Antineoplásicos/sangue , Inibidores de Histona Desacetilases/sangue , Ácidos Hidroxâmicos/sangue , Prolina/análogos & derivados , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Extração Líquido-Líquido/métodos , Masculino , Éteres Metílicos/química , Prolina/sangue , Ratos Wistar , Espectrometria de Massas em Tandem/métodosRESUMO
Michael addition of ethyl nitroacetate on α,ß-unsaturated ketones followed by Nef oxidation under hydrolytic conditions yields γ-oxoacids instead of the corresponding α,δ-dioxoesters. A concerted decarboxylation step is proposed on the basis of computational results. Finally, conversion of the γ-ketoacids thus prepared into 1H-pyrrol-2(5H)-ones by reaction with primary amines under Paal-Knorr conditions is also reported.
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Acetatos/química , Cetonas/química , Nitrocompostos/química , Oxigênio/química , Pirróis/química , Ácidos/química , Modelos Moleculares , Conformação MolecularRESUMO
Joined together, organocatalysts aldehydes and sulfones: A diaryl prolinol silyl ether was found to catalyse efficiently and enantioselectively the conjugate addition of aldehydes to vinyl sulfones (see scheme). The ample synthetic utility of the resulting adducts is illustrated.
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Prolyl oligopeptidase (POP) is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy terminus of proline residues. This peptidase has gained importance as a target for the treatment of cognitive disturbances of patients with neuropsychiatric diseases. Our research addresses the identification of POP inhibitors from a small focused library of polar heterocyclic compounds arising from multicomponent reactions. Two selective POP-specific inhibitors were identified on the basis of their inhibition of dipeptidyl peptidase IV. The most active compounds were evaluated for their in vitro transport through the blood-brain barrier (BBB) using a parallel artificial membrane permeability assay. Our results show for the first time that benzimidazolium salts are new POP-inhibitory scaffolds with properties of solubility, specificity, and lipophilicity that may allow them to cross the BBB by passive diffusion. These findings constitute an excellent starting point to synthesize new POP inhibitors with enhanced properties.
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Benzimidazóis/química , Benzimidazóis/metabolismo , Barreira Hematoencefálica/metabolismo , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/metabolismo , Benzimidazóis/farmacologia , Permeabilidade da Membrana Celular , Células Cultivadas , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV , Humanos , Concentração Inibidora 50 , Prolil Oligopeptidases , Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
The addition of isocyanides to pyridinium salts is studied. The process takes place efficiently when a carboxamido group is present in the 3 position of the pyridine ring. The outcome of the reaction involves the stabilization of the nitrilium intermediate by the amide, which suffers a mild dehydration, leading regioselectively to beta-cyano-gamma-carbamoyl-1,4-dihydropyridines. In this way, a variety of nicotinamide derivatives were carbamoylated. Extension to quinolinium, isoquinolinium, and N-acylpyridinium salts is also reported. [reaction: see text]