RESUMO
A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.
Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacosRESUMO
In the last years, we have investigated the click-chemical space covered by molecules containing the triazole ring and generated a database of 1,2,3-triazoles called ZINClick, starting from literature-reported alkynes and azides synthesizable in no more than three synthetic steps from commercially available products. This combinatorial database contains millions of 1,4-disubstituted 1,2,3-triazoles that are easily synthesizable. The library is regularly updated and can be freely downloaded from http://www.ZINClick.org . In this communication, the new implementation of ZINClick will be discussed as well as our new strategy for clustering the chemical space covered by 1,4-disubstituted 1,2,3-triazoles around their availability: from direct purchase to different degrees of synthetic feasibility of the compounds.
Assuntos
Quimioinformática , Triazóis/química , Triazóis/síntese química , Alcinos/química , Química Click , Internet , Modelos Moleculares , Conformação Molecular , Interface Usuário-ComputadorRESUMO
Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.
Assuntos
Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Inibidores de Fosfoinositídeo-3 Quinase , Pró-Fármacos/química , Animais , Sítios de Ligação , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Microssomos/metabolismo , Simulação de Dinâmica Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.
Assuntos
Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/farmacologia , Anti-Inflamatórios/química , Inibidores Enzimáticos/química , Análise Espectral/métodos , Triazóis/químicaRESUMO
The Ugi reaction has drawn considerable attention over the years leading to numerous libraries of heterocycles and various extensions changing the nature of the components of the coupling. We report here the use of nitric acid as carboxylic acids surrogates, displaying the first aminative Ugi-type reaction leading to nitramines.
RESUMO
The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed.
RESUMO
Synthetically useful aminodioximes are prepared via a novel three-component reaction among Z-chlorooximes, isocyanides, and hydroxylamines by exploiting the preferential attack of isocyanides to nitrile N-oxides via a [3 + 1] cycloaddition reaction. The results of quantum mechanical studies of the reaction mechanism are also discussed. Furthermore, the one-pot conversion of aminodioximes to 1,2,3-oxadiazole-5-amines via Mitsunobu-Beckmann rearrangement is reported for the first time.
RESUMO
An expeditious multicomponent reaction to synthesize tetrasubstituted furo[2,3-d]pyridazin-4(5H)-ones is reported. In brief, hydrazonoyl chlorides react with isocyanoacetamides, in the presence of TEA, to give 1,3-oxazol-2-hydrazones which, without being isolated, can react with dimethylacetylene dicarboxylate to afford furo[2,3-d]pyridazin-4(5H)-ones with an unprecedented level of complexity in a triple domino Diels-Alder/retro-Diels-Alder/lactamization reaction sequence.
Assuntos
Alcinos/química , Compostos Heterocíclicos com 2 Anéis/síntese química , Iminas/química , Nitrilas/química , Reação de Cicloadição , Compostos Heterocíclicos com 2 Anéis/química , Hidrazonas/síntese química , Hidrazonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
A library of 41 aryloxyimino amides was prepared via solution phase parallel synthesis by extending the multicomponent reaction of (Z)-chlorooximes and isocyanides to the use of electron-deficient phenols. The resulting aryloxyiminoamide derivatives can be used as intermediates for the synthesis of benzo[d]isoxazole-3-carboxamides, dramatically reducing the number of synthetic steps required by other methods reported in literature.
Assuntos
Amidas/síntese química , Técnicas de Química Combinatória/métodos , Cianetos/química , Oximas/química , Fenóis/química , Amidas/química , Cianetos/síntese química , Halogenação , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/química , Oximas/síntese química , Fenóis/síntese químicaRESUMO
A novel one-pot multicomponent synthesis of α-aminocarbonyl N-acylhydrazones starting from readily available hydrazonoyl chlorides, isocyanides, and carboxylic acids is reported. The strategy exploits the ability of the carboxylic acid as a third component to suppress all competing reactions between nitrile imines and isocyanides, channeling the course of the reaction toward the formation of this novel class of compounds.
RESUMO
Over the last decade, 1,2,3-triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3-dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3-triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X-ray crystal structures of complexes between 1,2,3-triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3-triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus.
Assuntos
Proteínas/química , Triazóis/química , Alcinos/química , Azidas/química , Sítios de Ligação , Catálise , Química Click , Cobre/química , Reação de Cicloadição , Bases de Dados de Proteínas , Estrutura Terciária de Proteína , Proteínas/metabolismo , Rutênio/química , Solubilidade , Eletricidade Estática , Triazóis/metabolismo , Água/químicaRESUMO
(Z)-Arylchlorooximes and α-isocyanoacetamides undergo a smooth reaction to produce 1,3-oxazol-2-oxime derivatives in good yields. Opening of the oxazole ring and deoximation reaction give a facile access to aryl-α-ketoamide amides, a class of privileged scaffolds in medicinal chemistry and important synthetic intermediates in organic chemistry.
Assuntos
Amidas/síntese química , Nitrilas/química , Oxazóis/química , Oximas/síntese química , Amidas/química , Catálise , Estrutura Molecular , Oxazóis/síntese química , Oximas/químicaRESUMO
By capitalizing on the different reactivity of nitrile N-oxides with isocyanides and amine, α-oximinoamidines, a so far elusive class of compounds, have been synthesized in a straightforward way by reacting isocyanides, syn-chlorooximes, and amines in a multicomponent fashion.