RESUMO
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Assuntos
Amidas/síntese química , Amidoidrolases/antagonistas & inibidores , Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Prolina/análogos & derivados , Prolina/síntese química , Infecções Respiratórias/tratamento farmacológico , Administração Oral , Amidas/farmacologia , Amidoidrolases/metabolismo , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/crescimento & desenvolvimento , Humanos , Injeções Intravenosas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Prolina/farmacologia , Ratos , Infecções Respiratórias/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
Cyanide, a well-known toxic substance that could be used as a weapon of mass destruction, is likely responsible for a substantial percentage of smoke inhalation deaths. The vitamin B(12) precursor cobinamide binds cyanide with high affinity, changing color and, correspondingly, its spectrophotometric spectrum in the ultraviolet/visible light range. Based on these spectral changes, we developed a new facile method to measure cyanide in blood using cobinamide. The limit of detection was 0.25 nmol, while the limit of quantitation was approximately 0.5 nmol. The method was reliable, requires minimal equipment, and correlated well with a previously established method. Moreover, we adapted it for rapid qualitative assessment of cyanide concentration, which could be used in the field to identify cyanide-poisoned subjects for immediate treatment.
Assuntos
Cobamidas/química , Cianetos/sangue , Limite de Detecção , Espectrofotometria , Vitamina B 12/químicaRESUMO
We describe the structure-activity relationship of the C1-group of pyrano[3,4-b]indole based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compound 12.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Indóis/química , Piranos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Piranos/síntese química , Piranos/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
Gold islands, vapor deposited on silicon and quartz by microsphere lithography patterning, are used to nucleate arrays of ZnO nanorods. ZnO is grown on approximately 0.32 microm2 Au islands by carbothermal reduction in a tube furnace. Scanning electron microscopy (SEM) and energy dispersive atomic X-ray spectroscopy (EDS) confirm that the gold effectively controls the sites of nucleation of ZnO. Atomic force microscopy (AFM) shows that approximately 30 nm diameter nanorods grow horizontally, along the surface. Alloy droplets that are characteristic of the vapor-liquid-solid (VLS) mechanism are observed at the tips of the nanorods. The spatial growth direction of VLS catalyzed ZnO nanorods is along the substrate when they nucleate from gold islands on silicon and quartz. The energy of adhesion of the VLS droplet to the surface can account for the horizontal growth.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Microesferas , Quartzo/química , Silício/química , Óxido de Zinco/química , Catálise , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanoestruturas/química , Nanotecnologia/métodos , Nanotubos/química , Espectrometria por Raios X/métodos , Difração de Raios XRESUMO
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
Assuntos
Antineoplásicos/síntese química , Indazóis/síntese química , Morfolinas/síntese química , Piperidinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Indazóis/química , Indazóis/farmacologia , Camundongos , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Transplante de Neoplasias , Fosforilação , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil , Estereoisomerismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.
RESUMO
The synthesis of racemic nitrile (+/-)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5. Nitrile (+/-)-9 was resolved via preparative chiral HPLC to afford optically pure nitriles (+)-9 and (-)-9, from which 3,3-dimethylprolines (+)-1 and (-)-1 and 3,3-dimethylprolinamides (+)-2 and (-)-2 could be accessed in nearly quantitative yield, without loss of optical purity. The absolute configurations of the resolved prolines and prolinamides were determined by correlation with an intermediate of known absolute stereochemistry.