RESUMEN
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.
Asunto(s)
Antineoplásicos/síntesis química , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/química , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Semivida , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Ratones , Ratones SCID , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
A series of 4-aminopyrimidines (1) was identified as novel HIV inhibitors of unknown molecular target. Structural modifications were carried out to establish its SAR and identify the linking site for target identification. A number of analogs were found to possess single digit inhibitory activity for HIV replication. Several analogs with various potential linkers, including a biotinated analog, also exhibited excellent potency, and could serve as tools for the identification of novel anti-HIV targets.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Pirimidinas/química , Fármacos Anti-VIH/síntesis química , Relación Estructura-ActividadRESUMEN
A novel sulfanyltriazole was discovered as an HIV-1 non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Chemical modifications and molecular modeling studies were carried out to establish its SAR and understand its interactions with the enzyme. These modifications led to the identification of sulfanyltriazoles with low nanomolar potency for inhibiting HIV-1 replication and promising activities against selected NNRTI resistant mutants. These novel and potent sulfanyltriazoles could serve as advanced leads for further optimization.
Asunto(s)
Fármacos Anti-VIH/farmacología , Química Farmacéutica/métodos , VIH-1/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/química , Diseño de Fármacos , Farmacorresistencia Viral , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Mutación , Compuestos de Azufre/química , Temperatura , Replicación ViralRESUMEN
A novel series of quinolones was discovered as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a structure-based approach. The lead quinolones exhibited single digit nanomolar potency in the HIV-1 replication assays. The preliminary SAR of these quinolones was also established via systematic structural modifications. These novel and potent quinolones could serve as advanced leads for further optimization.
Asunto(s)
Inhibidores de la Transcriptasa Inversa/farmacología , Sitios de Unión , Farmacorresistencia Viral , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/metabolismo , Modelos Químicos , Modelos Moleculares , Mutación , Quinolonas/química , Relación Estructura-Actividad , Replicación ViralRESUMEN
The synthesis and preliminary structure-activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirrolidinonas/química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A series of novel benzimidazole derivatives were synthesized via parallel solution-phase chemistry. Many of these compounds were found to inhibit the growth of Staphylococcus aureus and Escherichia coli. Several analogues exhibited low micromolar minimal inhibitory concentrations (MIC) against both Gram-positive and Gram-negative bacteria of clinical relevance and could serve as leads for further optimizations for antibacterial research.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Evaluación Preclínica de Medicamentos/métodos , Pruebas de Sensibilidad Microbiana/estadística & datos numéricosRESUMEN
A series of novel benzimidazoles were efficiently synthesized using both solution- and solid-phase chemistry. These compounds were found to bind to the bacterial 16S ribosomal RNA A-site with micromolar affinities using unique mass spectrometry-based assays.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , ARN Bacteriano/metabolismo , ARN Ribosómico 16S/metabolismo , Emparejamiento Base , Bencimidazoles/metabolismo , Sitios de Unión , Escherichia coli , Espectrometría de Masas , Modelos Moleculares , Conformación de Ácido Nucleico , ARN Bacteriano/química , ARN Ribosómico 16S/química , Relación Estructura-ActividadRESUMEN
A library of linked molecules were synthesized from the common sugar moieties existing in the natural amino glycosides. These linked molecules were screened against bacterial 16S RNA for their binding affinity using a mass spectrometry-based technology. Some of these compounds exhibited low micromolar affinity and could serve as leads for further development as antibacterial agents.
Asunto(s)
Oligosacáridos/química , Oligosacáridos/síntesis química , ARN Ribosómico 16S/química , Secuencia de Bases , Sitios de Unión , Conformación de Carbohidratos , Secuencia de Carbohidratos , Escherichia coli/genética , Espectrometría de Masas , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , ARN Bacteriano/químicaRESUMEN
A series of 2-piperidin-4-yl-benzimidazoles were synthesized and evaluated for antibacterial activities. Certain compounds inhibit bacterial growth with low micromolar minimal inhibitory concentration (MIC). These benzimidazoles are effective against both Gram-positive and Gram-negative bacteria of clinical importance, particularly enterococci, and represent a new class of potential antibacterial agents.
Asunto(s)
Antibacterianos/química , Bencimidazoles/química , Piperidinas/química , Antibacterianos/farmacología , Bencimidazoles/farmacología , Enterococcus/efectos de los fármacos , Enterococcus/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana/métodos , Piperidinas/farmacologíaRESUMEN
Extracts of the root and trunk barks of the Chinese tree Pseudolarix kaempferi, which contain pseudolaric acids, are used in Chinese medicine for treatment of fungal infections. Pseudolaric acid B (PLAB) is the major constituent that exhibits anti-fungal activity. The nuclear peroxisome proliferator-activator receptors (PPAR) were proposed as a cellular target for the action of PLAB and its analogs. PLAB and two derivatives were tested for the activation of PPAR isoforms in two mammalian cell lines. CV-1 and H4IIEC3 cells were transfected with phorbol ester response element or PPAR response element reporter constructs, and CV-1 cells were co-transfected with the individual PPAR isoform expression plasmids. PLAB showed similar concentration-dependent effects for the activation of PPAR alpha, gamma and delta isoforms in CV-1 and H4IIEC3 cells. O-Deacetylation of PLAB (PLAC) or esterification of the free carboxy group of PLAB with beta-D-O-glucopyranoside (PLAG) markedly reduced or abolished the activation of these PPAR isoforms. In H4IIEC3 cells, PLAB increased the activation of endogenous PPARalpha and the phospholipase C signaling pathway; and stimulated peroxisomal fatty acyl-CoA oxidase activity. These effects of PLAB on the activation of endogenous PPARalpha and phospholipase C-dependent pathway were blocked by staurosporine. These results suggest that the action of PLAB on PPARalpha in H4IIEC3 cells is mediated by a protein kinase C dependent phosphorylation. Based upon these findings, the chemical class of biologically active diterpene acids related to PLAB may have promise for the treatment of metabolic and pathophysiological disorders that are regulated by these nuclear receptor isoforms.
Asunto(s)
Diterpenos/farmacología , Pinaceae/química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Línea Celular , Diterpenos/química , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos , Estructura Molecular , Corteza de la Planta/química , Raíces de Plantas/química , Plantas Medicinales/química , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
The degradation of neomycin B was reexamined, and a novel protocol was established to prepare the properly masked neomycin CD ring as a glycol donor in excellent yield. Glycosylation of the CD ring with glycol acceptors provided a facile access to versatile intermediates that could be utilized to synthesize a variety of novel neomycin B mimetics for RNA recognition. [reaction: see text]
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/metabolismo , Estabilidad de Medicamentos , Framicetina/síntesis química , Framicetina/metabolismo , Antibacterianos/química , Framicetina/química , Glicoles/química , Glicosilación , Estructura Molecular , ARN Bacteriano/química , ARN Bacteriano/metabolismo , Especificidad por SustratoRESUMEN
On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed a one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF(3)-etherate/Et(3)SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity. Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.