RESUMO
We have identified short N,C-capped peptides that selectively inhibit the proteasome of the malaria-causing pathogen Plasmodium falciparum. These compounds are highly potent in culture with no toxicity in host cells. One cyclic biphenyl ether compound inhibited intraerythrocytic growth of P. falciparum with an IC50 of 35 nM, and we show that even a pulse treatment with this cyclic peptide induced parasite death due to proteasome inhibition. These compounds represent promising new antimalarial agents that target the essential proteasomal machinery of the parasite without toxicity toward the host.
Assuntos
Antimaláricos/farmacologia , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Antimaláricos/química , Antimaláricos/toxicidade , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Peptídeos Cíclicos/química , Peptídeos Cíclicos/toxicidade , Plasmodium falciparum/crescimento & desenvolvimento , Inibidores de Proteassoma/química , Inibidores de Proteassoma/toxicidadeRESUMO
Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibitors. Constrained heterocyclic analogs based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine show further enhanced HDAC6 selectivity and inhibitory activity in cells. Homology models suggest that the heterocyclic spacer can more effectively access the wider catalytic channel of HDAC6 compared to other HDAC sub-types.
Assuntos
Inibidores de Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Pirazinas/metabolismo , Isoformas de ProteínasRESUMO
We identified N,C-capped dipeptides that are selective for the Mycobacterium tuberculosis proteasome over human constitutive and immunoproteasomes. Differences in the S3 and S1 binding pockets appeared to account for the species selectivity. The inhibitors can penetrate mycobacteria and kill nonreplicating M. tuberculosis under nitrosative stress.
Assuntos
Dipeptídeos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Sítios de Ligação/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/química , Relação Estrutura-AtividadeRESUMO
The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.
Assuntos
Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , Sequência de Aminoácidos , Sítios de Ligação , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Células HCT116 , Células HT29 , Humanos , Cinética , Luciferases/genética , Luciferases/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Pirazinas/farmacologia , Interferência de RNA , Homologia de Sequência de Aminoácidos , Ubiquitina/genética , Ubiquitina/metabolismoRESUMO
A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Substituição de Aminoácidos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the ß-5/6 active site of y20S. Derivative 25, (ß5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.
Assuntos
Quimotripsina/antagonistas & inibidores , Dipeptídeos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Treonina/química , Humanos , Modelos MolecularesRESUMO
The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Substituição de Aminoácidos , Sítios de Ligação , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/farmacocinética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8 antagonists is described. In vitro binding assay results of these investigations are reported, critical interactions of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for the naphthalene scaffold are presented.
Assuntos
Naftalenos/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Cálcio/metabolismo , Linhagem Celular , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Naftalenos/farmacocinética , Naftalenos/farmacologia , Ratos , Receptores CCR8 , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
Assuntos
Cumarínicos/síntese química , Piperidinas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Cumarínicos/efeitos adversos , Cumarínicos/farmacologia , Cães , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético , Humanos , Masculino , Camundongos , Camundongos Obesos , Contração Miocárdica/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Benzamidas/química , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/síntese química , Humanos , Especificidade por SubstratoRESUMO
Reductive aminations and further transformations of an azo dye and fluorous tagged aldehyde are described. The intensely colored 2,4-dialkoxybenzyl protected amines undergo Fmoc-based peptide coupling, Suzuki reactions, and sulfonamide formation with product isolation facilitated by visual monitoring of fluorous solid phase extraction. Target compounds are released from the supports in high yields and purities by treatment with trifluoroacetic acid (TFA).
Assuntos
Compostos Cromogênicos/química , Flúor/química , Compostos Azo/química , Estrutura Molecular , Extração em Fase Sólida , Ácidos Sulfínicos/químicaRESUMO
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Assuntos
Antineoplásicos/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Tetra-Hidronaftalenos/síntese química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Fármacos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The identification and optimization of a series of acylguanidine-based melanocortin-4 receptor antagonists is discussed.
Assuntos
Guanidina/química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Compostos de Sulfidrila/química , Animais , Sítios de Ligação , Encéfalo/metabolismo , Guanidina/análogos & derivados , Guanidina/farmacologia , Concentração Inibidora 50 , Camundongos , Plasma/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Fatores de TempoRESUMO
Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.
Assuntos
Quinazolinas/química , Quinazolinas/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Camundongos , Quinazolinas/farmacocinética , Quinolonas/farmacocinéticaRESUMO
Several potent, cell permeable 4-aryl-dihydropyrimidinones have been identified as inhibitors of FATP4. Lipophilic ester substituents at the 5-position and substitution at the para-position (optimal groups being -NO(2) and CF(3)) of the 4-aryl group led to active compounds. In two cases racemates were resolved and the S enantiomers shown to have higher potencies.
Assuntos
Proteínas de Transporte de Ácido Graxo/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Linhagem Celular , Humanos , Estrutura Molecular , Pirimidinonas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
[reaction: see text] Reaction of o-azidobenzenesulfonamides with polymer-supported triphenylphosphine affords the corresponding iminophosphoranes. Subsequent reaction with isocyanates gives 3-amino-1,2,4-benzothiadiazine 1,1-dioxides in high yields and purities. The reaction has been successfully applied to the synthesis of derivatives with various substituents at the 2- and 3-positions and in the benzenoid ring.
Assuntos
Azidas/química , Isocianatos/química , Compostos Organofosforados/química , Sulfonamidas/química , Triazinas/síntese química , Ciclização , Estrutura Molecular , Estereoisomerismo , Tirapazamina , Triazinas/químicaRESUMO
The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Benzamidas/síntese química , Ligação Competitiva , Modelos Animais de Doenças , Cães , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50.
Assuntos
Niacinamida/análogos & derivados , Receptores de Somatostatina/antagonistas & inibidores , ortoaminobenzoatos/síntese química , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos , Niacinamida/farmacocinética , Niacinamida/farmacologia , Farmacocinética , Receptores de Somatostatina/agonistas , Relação Estrutura-Atividade , Distribuição Tecidual , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologiaRESUMO
A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.