RESUMO
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.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/química , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Meia-Vida , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Camundongos , Camundongos SCID , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
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.
Assuntos
Antimaláricos/química , Artemisininas , Sesquiterpenos/química , Administração Oral , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Injeções Intravenosas , Malária/tratamento farmacológico , Camundongos , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/síntese química , Sesquiterpenos/farmacocinética , Sesquiterpenos/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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]
Assuntos
Antibacterianos/síntese química , Antibacterianos/metabolismo , Estabilidade de Medicamentos , Framicetina/síntese química , Framicetina/metabolismo , Antibacterianos/química , Framicetina/química , Glicóis/química , Glicosilação , Estrutura Molecular , RNA Bacteriano/química , RNA Bacteriano/metabolismo , Especificidade por SubstratoRESUMO
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.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinas/química , Fármacos Anti-HIV/síntese química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Química Farmacêutica/métodos , HIV-1/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/química , Desenho de Fármacos , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Mutação , Compostos de Enxofre/química , Temperatura , Replicação ViralRESUMO
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.
Assuntos
Inibidores da Transcriptase Reversa/farmacologia , Sítios de Ligação , Farmacorresistência Viral , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/metabolismo , Modelos Químicos , Modelos Moleculares , Mutação , Quinolonas/química , Relação Estrutura-Atividade , Replicação ViralRESUMO
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).
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirrolidinonas/química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Testes de Sensibilidade Microbiana/estatística & dados numéricosRESUMO
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.
Assuntos
Oligossacarídeos/química , Oligossacarídeos/síntese química , RNA Ribossômico 16S/química , Sequência de Bases , Sítios de Ligação , Configuração de Carboidratos , Sequência de Carboidratos , Escherichia coli/genética , Espectrometria de Massas , Dados de Sequência Molecular , Conformação de Ácido Nucleico , RNA Bacteriano/químicaRESUMO
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.
Assuntos
Diterpenos/farmacologia , Pinaceae/química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Linhagem Celular , Diterpenos/química , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos , Estrutura Molecular , Casca de Planta/química , Raízes de Plantas/química , Plantas Medicinais/química , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , RNA Bacteriano/metabolismo , RNA Ribossômico 16S/metabolismo , Pareamento de Bases , Benzimidazóis/metabolismo , Sítios de Ligação , Escherichia coli , Espectrometria de Massas , Modelos Moleculares , Conformação de Ácido Nucleico , RNA Bacteriano/química , RNA Ribossômico 16S/química , Relação Estrutura-AtividadeRESUMO
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.