RESUMO
The advent of template-directed synthesis has provided access to a range of new interlocked molecular architectures. Although many syntheses of molecular catenanes and rotaxanes have been reported, molecular knots are a class of molecules with topologically non-planar graphs that are rather rare. Here we report a synthetic strategy for the preparation of a molecular trefoil knot from a flexible bipyridine oligomer and a zinc(II) octahedral coordination template. The oligomer folds into a stable open-knot conformation in the presence of the template, and trapping of this arrangement through esterification or ring-closing metathesis produces the closed-knot complex. Subsequent removal of the template from the metathesis product results in a molecular trefoil knot.
RESUMO
A successful scaffold-hopping approach gave a novel series of inhibitors of bacterial glutamate racemase (MurI). Early SAR studies of the 8-benzyl pteridine-6,7-diones led to compounds with micromolar enzyme potency and antibacterial activity.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/enzimologia , Pteridinas/síntese química , Pteridinas/farmacologia , Antibacterianos/química , Técnicas de Química Combinatória , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pteridinas/química , Relação Estrutura-AtividadeRESUMO
Using a high-throughput screening campaign, we identified the 4,6-bis anilino pyrimidines as inhibitors of the cyclin-dependent kinase, CDK4. Herein we describe the further chemical modification and use of X-ray crystallography to develop potent and selective in vitro inhibitors of CDK4.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
Through chemical modification and X-ray crystallography we identified the 2,4-bis anilino pyrimidines as potent inhibitors of CDK4. Herein, we describe the optimisation of this series.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Pirimidinas/farmacologia , Trifosfato de Adenosina/química , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
High-throughput screening identified the imidazo[1,2-a]pyridine and bisanilinopyrimidine series as inhibitors of the cyclin-dependent kinase CDK4. Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2.