RESUMO
Trinucleotide repeat diseases such as myotonic dystrophy type 1 (DM1) and Huntington's disease (HD) are caused by expanded DNA repeats that can be used as templates to synthesize their own inhibitors. Because it would be particularly advantageous to reversibly assemble multivalent nucleic acid-targeting agents in situ, we sought to develop a target-guided screen that uses dynamic covalent chemistry to identify multitarget inhibitors. We report the synthesis of a library of amine- or aldehyde-containing fragments. The assembly of these fragments led to a diverse set of hit combinations that was confirmed by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) in the presence of DM1 and HD repeat sequences. Of interest for both diseases, the resulting hit combinations inhibited transcription selectively and in a cooperative manner in vitro, with inhibitory concentration (IC50) values in the micromolar range. This dynamic covalent library and screening approach could be applied to identify compounds that reversibly assemble on other nucleic acid targets.
Assuntos
Aldeídos , Aminas , Ácidos Nucleicos , Aldeídos/síntese química , Aldeídos/farmacologia , Aminas/síntese química , Aminas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Doença de Huntington/genética , Distrofia Miotônica/genética , Ácidos Nucleicos/antagonistas & inibidores , Ácidos Nucleicos/química , Sequências Repetitivas de Ácido Nucleico , Transcrição Gênica/efeitos dos fármacosRESUMO
Fatty amines represent an important class of commodity chemicals which have broad applicability in different industries. The synthesis of fatty amines starts from renewable sources such as vegetable oils or animal fats, but the process has multiple drawbacks that compromise the overall effectiveness and efficiency of the synthesis. Herein, we report a proof-of-concept biocatalytic alternative towards the synthesis of primary fatty amines from renewable triglycerides and oils. By coupling a lipase with a carboxylic acid reductase (CAR) and a transaminase (TA), we have accomplished the direct synthesis of multiple medium and long chain primary fatty amines in one pot with analytical yields as high as 97 %. We have also performed a 75â mL preparative scale reaction for the synthesis of laurylamine from trilaurin, obtaining 73 % isolated yield.
Assuntos
Aminas/síntese química , Gorduras/química , Óleos de Plantas/química , Triglicerídeos/química , Lipase/química , Oxirredutases/química , Transaminases/químicaRESUMO
Two novel amphiphilic polyethylene amine terephthalate have been prepared via the glycolsis of polyethylene terephthalate (PET). The product, bis (2-hydroxyethyl terephthalate) (BHET), was converted to the corresponding dialkyl halide, bis(2-chloroethyl) terephthalate (BCET), using thionyl chloride (TC). This dialkyl compound was used for alkylation of dodecyl amine (DOA) and tetraethylenepentamine (TEPA) or pentaethylenehexamine (PEHA) to form the corresponding polyethylene amine terephthalate, i.e., DOAT and DOAP, respectively. Their chemical structure, surface tension, interfacial tension (IFT), and dynamic light scattering (DLS) were determined using different techniques. The efficiency of the prepared polyethylene amine terephthalate to demulsify water in heavy crude (W/O) emulsions was also determined and found to increase as their concentrations increased. Moreover, DOAT showed faster and higher efficiency, and cleaner separation than DOAP.
Assuntos
Petróleo/análise , Polietilenotereftalatos/química , Aminas/síntese química , Aminas/química , Difusão Dinâmica da Luz , Emulsões/química , Espectroscopia de Ressonância Magnética , Micelas , Estrutura Molecular , Polietilenotereftalatos/síntese química , Eliminação de Resíduos/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , Tensão Superficial , Tensoativos/síntese química , Tensoativos/química , Águas Residuárias/químicaRESUMO
The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8â APIs/molecules of considerable medicinal interest.
Assuntos
Aminoácidos , Lactamas , Aminas/síntese química , Aminas/química , Anidridos/química , Isocianatos/químicaRESUMO
Our recent investigation uncovered that the acid ceramidase inhibitor LCL521 enhances the direct tumor cell killing effect of photodynamic therapy (PDT) treatment. The present study aimed at elucidating the mechanisms underlying this effect. Exposing mouse squamous cell carcinoma SCCVII cells treated with temoporfin-based PDT to LCL521 (rising ceramide concentration) produced a much greater decrease in cell survival than comparable exposure to the sphingosine kinase-1 inhibitor PF543 (that reduces sphingosine-1-phosphate concentration). This is consistent with recognizing the rising levels of pro-apoptotic sphingolipid ceramide as being more critical in promoting the death of PDT-treated cells than the reduction in the availability of pro-survival acting sphingosine-1 phosphate. This pro-apoptotic impact of LCL521, which was suppressed by the apoptosis inhibitor bongkrekic acid, involves the interaction with the cellular stress signaling network. Hence, inhibiting the key elements of these pathways markedly influenced the adjuvant effect of LCL521 on the PDT response. Particularly effective was the inositol-requiring element-1 (IRE1) kinase inhibitor STF-083010 that dramatically enhanced the killing of cells treated with PDT plus LCL521. An important role in the survival of these cells was exhibited by master transcription factors STAT3 and HIF-1α. The STAT3 inhibitor NSC 74859 was especially effective in further reducing the cell survival rates, suggesting its possible exploitation for therapeutic gain. An additional finding in this study is that LCL521-promoted PDT-mediated cell killing through ceramide-mediated lethal effects is extended to the interaction with other cancer treatment modalities with a rapid cellular stress impact such as photothermal therapy (PTT) and cryoablation therapy (CAT).
Assuntos
Acetatos/farmacologia , Aminas/farmacologia , Antineoplásicos/farmacologia , Ceramidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hipertermia Induzida , Fotoquimioterapia , Acetatos/síntese química , Acetatos/química , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ceramidases/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Células Tumorais CultivadasRESUMO
D-Glycero-D-mannno-heptose 1ß, 7-bisphosphate (HBPß) is an important intermediate for constructing the core structure of Gram-negative bacterial lipopolysaccharides and was reported as a pathogen-associated molecular pattern (PAMP) that regulates immune responses. HBPß with 3-O-amyl amine linker and its monophosphate derivative D-glycero-D-mannno-heptose 7-phosphate (HP) with 1α-amyl amine linker have been synthesized as candidates for immunity study of HBPß. The O3-amyl amine linker of heptose was installed by dibutyltin oxide-mediated regioselective alkylation under fine-tuned protecting condition. The stereoselective installation of 1ß-phosphate ester was achieved by NIS-mediated phosphorylation at low temperature. The strategy for installation of 3-O-amyl amine linker onto HBP derivative can be expanded to the syntheses of other conjugation-ready carbohydrates bearing anomeric phosphoester.
Assuntos
Aminas/síntese química , Bactérias Gram-Negativas/química , Heptoses/síntese química , Lipopolissacarídeos/química , Compostos Orgânicos de Estanho/síntese químicaRESUMO
In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC50 values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (ßA) aggregation and ß-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.
Assuntos
Inibidores da Colinesterase/farmacologia , Piridinas/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Butirilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Células Hep G2 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Piridinas/síntese química , Piridinas/química , Tacrina/síntese química , Tacrina/químicaRESUMO
Bacterial infections induced by drug-resistant strains have become a global crisis. A membrane-disrupted mechanism is considered as an effective way to kill bacteria with little chance to trigger drug resistance. It is necessary to explore and develop new materials based on the membrane-disrupted mechanism to combat bacterial resistance. Here we report the design of organic nanoparticles based on a polymer (PDCP) as highly effective inhibition and bactericidal reagents. The PDCP is devised to have a hydrophobic skeleton and hydrophilic side chain modified with protonated primary amines, which could self-assemble to form organic nanoparticles (PDCP-NPs). By taking advantage of the large surface to volume ratio of nanoparticles, the synthesized PDCP-NPs have enriched positive charges and multiple membrane-binding sites. Research results display that PDCP-NPs have highly potent antibacterial activity in vitro and vivo, especially for Gram-negative bacteria with low toxicity against mammalian cells. This work design will inspire researchers to develop more membrane-disrupted bactericide and advance the applications of organic nanoparticles in the antibacterial area.
Assuntos
Aminas/uso terapêutico , Antibacterianos/uso terapêutico , Nanopartículas/uso terapêutico , Polímeros/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Aminas/síntese química , Aminas/toxicidade , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Klebsiella pneumoniae/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nanopartículas/química , Nanopartículas/toxicidade , Polímeros/síntese química , Polímeros/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
2-Desoxy-4-epi-puchellin (PCL) is a sesquiterpene-lactone, which naturally occurs in many traditional Chinese medicinal plants, and has antitumor and anti-inflammatory activities. In this work, a series of 13-amino derivatives of PCL were synthesized through Michael addition reaction. Inhibition of IL-6-induced STAT3 signaling pathway and in vitro cytotoxicity of these compounds were evaluated, and their effect on the cell cycle was also studied. The methyl hydroxyethylamine derivatives showed higher potency than PCL, which could induce significant mitotic arrest via G2/M arrest in HCT116 cancer cells, indicating that these derivatives have the potential to be developed into anti-colon cancer drugs.
Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células HCT116 , Humanos , Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-AtividadeRESUMO
Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.
Assuntos
Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Supressores da Gota/farmacologia , Gota/tratamento farmacológico , Oximas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Animais , Benzoína/análogos & derivados , Benzoína/química , Benzoína/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Supressores da Gota/síntese química , Supressores da Gota/química , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Oximas/síntese química , Oximas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ácido Úrico/sangue , Xantina Oxidase/metabolismoRESUMO
Through this manuscript the green synthesis of palladium nanoparticles supported on reduced graphene oxide (Pd NPs/RGO) under the mild conditions through reduction of the graphene oxide and Pd(2+) ions using barberry fruit extract as reducing and stabilizing agent is reported. The as-prepared Pd NPs/RGO was characterized by UV-vis spectroscopy, X-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDS). The Pd NPs/RGO could be used as an efficient and heterogeneous catalyst for reduction of nitroarenes using sodium borohydride in an environmental friendly medium. Excellent yields of products were obtained with a wide range of substrates and the catalyst was recycled multiple times without any significant loss of its catalytic activity.
Assuntos
Aminas/síntese química , Grafite/química , Química Verde , Nanopartículas Metálicas/química , Nitrocompostos/química , Óxidos/química , Paládio/química , Extratos Vegetais/química , Aminas/química , Berberis/química , Catálise , Frutas/química , Estrutura Molecular , OxirreduçãoRESUMO
Copper oxide (CuO) nanoparticles (NPs) were synthesized by biological method using aqueous extract of Thymus vulgaris L. leaves as a reducing and capping agent. The progress of the reaction was monitored using UV-visible spectroscopy. The advantages of this procedure are simple operation, use of cheap, natural, nontoxic and benign precursors, absence of toxic reagents and mild and environmentally friendly conditions. The green synthesized CuO NPs was characterized by transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS), fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction analysis (XRD), thermogravimetric analysis (TGA) and differential thermal analysis (DTA). More importantly, the green synthesized CuO NPs was found to be an excellent heterogeneous catalyst for ligand-free N-arylation of indoles and amines. The N-arylated products were obtained in good to excellent yield and the catalyst can be recovered and reused for further catalytic reactions with almost no loss in activity.
Assuntos
Aminas/química , Cobre/química , Química Verde , Indóis/química , Nanopartículas/química , Extratos Vegetais/química , Thymus (Planta)/química , Aminas/síntese química , Catálise , Indóis/síntese química , Estrutura Molecular , Tamanho da Partícula , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Propriedades de Superfície , Água/químicaRESUMO
We describe a method for supporting palladium nanoparticles on magnetic nanoparticles using Euphorbia stracheyi Boiss root extract as the natural source of reducing and stabilizing agent. The progress of the reaction was monitored using UV-visible spectroscopy. The nanocatalyst was characterized by FE-SEM, TEM, XRD, EDS, FT-IR spectroscopy and ICP. The nanocatalyst was applied as an efficient, magnetically recoverable, highly reusable and heterogeneous catalyst for one-pot reductive amination of aldehydes at room temperature. The nanocatalyst was easily recovered by applying an external magnet and reused several times without considerable loss of activity.
Assuntos
Aldeídos/química , Aminas/química , Euphorbia/química , Nanopartículas/química , Paládio/química , Extratos Vegetais/química , Raízes de Plantas/química , Temperatura , Aminação , Aminas/síntese química , Catálise , Fenômenos Magnéticos , Estrutura Molecular , Oxirredução , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.
Assuntos
Aminas/química , Ansiolíticos/síntese química , Receptor de Glutamato Metabotrópico 5/química , Administração Oral , Regulação Alostérica , Aminas/síntese química , Aminas/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Cristalografia por Raios X , Modelos Animais de Doenças , Hipertermia Induzida , Camundongos , Conformação Molecular , Receptor de Glutamato Metabotrópico 5/metabolismo , Reto/efeitos dos fármacos , Reto/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , TemperaturaRESUMO
A rapid and general access to ortho-haloaminoarenes has been developed by aryne insertion into N-chloramine, N-bromoamine, and N-iodoamine bonds via two complementary protocols harnessing fluoride-promoted 1,2-elimination of ortho-trimethylsilyl aryltriflates. Typically, electron-deficient N-chloramines effectively react with aryne intermediates generated at elevated temperature with CsF, while less stable N-haloamines are found more efficient under milder, TBAF-mediated aryne formation at room temperature. Both protocols demonstrate a good level of regioselectivity and functional group tolerance. Efforts to elucidate the mechanism of N-X insertion are also discussed. The practical value of this transformation is highlighted by rapid synthesis of novel analogues of the antipsychotic cariprazine.
Assuntos
Aminas/síntese química , Fluoretos/química , Hidrocarbonetos Halogenados/síntese química , Nitrogênio/química , Fosfatos/química , Piperazinas/síntese química , Aminas/química , Catálise , Hidrocarbonetos Halogenados/química , Estrutura Molecular , Piperazinas/química , EstereoisomerismoRESUMO
The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.
Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Haemophilus influenzae/enzimologia , tRNA Metiltransferases/antagonistas & inibidores , Adenosina/metabolismo , Aminas/síntese química , Aminas/química , Aminas/metabolismo , Aminas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Haemophilus influenzae/efeitos dos fármacos , Humanos , Metionina/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Terciária de Proteína , RNA de Transferência/química , RNA de Transferência/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , tRNA Metiltransferases/química , tRNA Metiltransferases/metabolismoRESUMO
The natural product engelhardione is an underexplored chemotype for developing novel treatments for bacterial infections; we therefore explored this natural product scaffold for chemical diversification and structure-activity relationship studies. Macrocyclic engelhardione and structural regioisomers were synthesized using a series of aldol condensations and selective hydrogenations to generate the 1,7-diarylheptan-3-one derivatives, followed by microwave-assisted intramolecular Ullmann coupling to afford a series of macrocyclic diaryl ether analogs. An extended macrocyclic chemical library was then produced by oxime formation, reductive amination and O-alkylation. Antibacterial evaluation revealed that the reductive amination derivatives 7b and 7d showed moderate activities (minimum inhibitory concentrations: 12.5-25 µg ml(-1)) against Mycobacterium tuberculosis and Gram-positive pathogens, as well as anti-Gram-negative activity against an efflux impaired Escherichia coli strain. These results provide validated leads for further optimization and development.
Assuntos
Antibacterianos/farmacologia , Antituberculosos/farmacologia , Diarileptanoides/análogos & derivados , Compostos Macrocíclicos/síntese química , Aminação , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antituberculosos/síntese química , Antituberculosos/química , Cromatografia/métodos , Diarileptanoides/química , Diarileptanoides/farmacologia , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/efeitos dos fármacos , Hidrogenação , Isomerismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/síntese química , Oximas/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
Assuntos
Aminas/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
In the recent past sugar-derived cyclopropylamines were proposed as structurally new glycosidase inhibitors. In this Letter we report our efforts in the synthesis of a set of alpha-glucose configured oxabicyclo[4.1.0] heptanes, based on this hypothesis, bearing an amine substituent on the propyl ring and reveal that their inhibitory potential towards a range of mammalian glucosidases is modest.
Assuntos
Aminas/síntese química , Aminas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucosidases/antagonistas & inibidores , Aminas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A series of substituted 6-arylquinazolin-4-amines were prepared and analyzed as inhibitors of Clk4. Synthesis, structure-activity relationships and the selectivity of a potent analogue against a panel of 402 kinases are presented. Inhibition of Clk4 by these agents at varied concentrations of assay substrates (ATP and receptor peptide) highly suggests that this chemotype is an ATP competitive inhibitor. Molecular docking provides further evidence that inhibition is the result of binding at the kinase hinge region. Selected compounds represent novel tools capable of potent and selective inhibition of Clk1, Clk4, and Dyrk1A.